65 results on '"Trupti Trivedi"'
Search Results
2. Bone-derived excess TGF-ß release is associated with cognitive dysfunction due to oxidation of RyR, Ca2+ leak and mitochondrial dysfunction
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Lei Shi, Sukanya Suresh, Truc Kuo, Anand Singh, Jade Martinez, Trupti Trivedi, Gabriel M. Pagnotti, Leah D. Guerra, Xu Cao, and Theresa A. Guise
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Diseases of the musculoskeletal system ,RC925-935 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2024
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3. #5. Activating RET mutations in medullary thyroid cancer cells promotes osteoblastic bone metastasis by inhibiting osteoclastogenesis and stimulating osteoblast activity
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Rozita Bagheri-Yarmand, Gabriel M Pagnotti, Trupti Trivedi, Leah Guerra, Joseph L. Kidd, Jade A. Martinez, Jian H. Song, Sua-Hwa Lin, and Theresa A. Guise
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Diseases of the musculoskeletal system ,RC925-935 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2024
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4. #49. Complete estrogen-deprived athymic nude mice are susceptible to changes in metabolism and musculoskeletal function mediated by a high-fat diet
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Trupti Trivedi, Gabriel M. Pagnotti, Sukanya Suresh, Yun She, Sreemala Murthy, Jade Martinez, Carmella-Evans Molina, Khalid S. Mohammad, and Theresa A. Guise
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Diseases of the musculoskeletal system ,RC925-935 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2024
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5. Editorial: Bone and muscle interactions in bone pathologies
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Trupti Trivedi and Mark Hamrick
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pathologic bone destruction ,musculoskeletal ,bone resorption ,bone-targeted therapies ,bone marrow adiposity ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Published
- 2023
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6. Prognostic significance of STAT3 gene expression in patients with glioblastoma tumors: a study from Western India
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Trupti Trivedi, Kinjal Panchal, Neha Bhalala, and Priti Trivedi
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STAT3 ,IDH ,Glioblastoma ,Multivariate ,Prognostic significance ,Tumor Location ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Objective Glioblastoma Multiforme (GBM), a devastating the most common primary malignant intracranial brain tumors. In India, the incidence of this malignancy is escalating, however, there are very few studies on this tumor entity from Indian population. The present study sought to investigate the prevalence and prognostic significance of Signal Transducer and Activator of Transcription 3 (STAT3) gene expression in GBM patients from Western India. Method STAT3 gene expression using real-time PCR was detected in total 55 GBM patients. The impact of STAT3 aberrant expression on progression-free survival (PFS) and overall (OS) was analysed using univariate and multivariate survival analysis. The data were analysed using SPSS statistical software and p value ≤0.05 was considered as significant. Results The aberrant STAT3 expression was found in 85% (47/55) of patients with -1.12 fold change down-regulation in 49% (23/47) and 3.36 fold change up-regulation was noted in 51% (24/47) of patients. In wild type IDH tumors (n=30), down regulation and up regulation of STAT3 was noted in 63% and 27% of patients, respectively, whereas, for IDH mutant GBM tumors (n=25), the incidence of low expression and high expression of STAT3 was noted in 16% and 68% of patients, respectively. Thus, we found that incidence of STAT3 down regulation was significantly high in patients with IDH wild type tumors, whereas, in IDH mutant GBM tumors, the incidence of up-regulated STAT3 was significantly high (P=0.021, χ2=12.81, r=+0.310). In Kaplan-Meier univariate survival analysis, a part from age (P=0.006), tumor location (P=0.025), and KPS score (P=0.002), co-detection of STAT3 up regulation and presence of IDH mutation (P=0.030) remained significant prognostic factors for PFS and OS. In multivariate survival analysis also, co-detection of STAT3 high expression and presence of IDH mutation remained independent prognosticators for PFS (HR=6.45, 95% CI=1.32-31.40, P=0.021) and OS (HR=8.69, 95% CI=1.66-45.51, P=0.010). Conclusion For GBM tumors, STAT3 up-regulation and presence of IDH mutations together predicts better survival. This reflects unique molecular etiology for GBM patients. Therefore, they would be useful in the future for targeted therapy and for clinicians they would be useful for better patient management. However, study on a larger sample size is required for validation.
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- 2022
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7. Tocilizumab improves survival in severe COVID-19 pneumonia with persistent hypoxia: a retrospective cohort study with follow-up from Mumbai, India
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Yojana Gokhale, Rakshita Mehta, Uday Kulkarni, Nitin Karnik, Sushant Gokhale, Uma Sundar, Swati Chavan, Akshay Kor, Sonal Thakur, Trupti Trivedi, Naveen Kumar, Sujata Baveja, Aniket Wadal, Shaonak Kolte, Aukshan Deolankar, Sangeeta Pednekar, Lalana Kalekar, Rupal Padiyar, Charulata Londhe, Pramod Darole, Sujata Pol, Seema Bansode Gokhe, Namita Padwal, Dharmendra Pandey, Dhirendra Yadav, Anagha Joshi, Harshal Badgujar, Mayuri Trivedi, Priyanshu Shah, and Prerna Bhavsar
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IL-6 ,Interlukin-6 ,Cytokine storm ,Hyperinflammatory syndrome ,CO-RADS ,CT-severity score ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background Cytokine storm triggered by Severe Coronavirus Disease 2019 (COVID-19) is associated with high mortality. With high Interleukin -6 (IL-6) levels reported in COVID-19 related deaths in China, IL-6 is considered to be the key player in COVID-19 cytokine storm. Tocilizumab, a monoclonal antibody against IL-6 receptor, is used on compassionate grounds for treatment of COVID-19 cytokine storm. The aim of this study was to assess effect of tocilizumab on mortality due to COVID-19 cytokine storm. Method This retrospective, observational study included patients of severe COVID-19 pneumonia with persistent hypoxia (defined as saturation 94% or less on supplemental Oxygen of 15 L per minute through non-rebreathing mask or PaO2/FiO2 ratio of less than 200) who were admitted to a tertiary care center in Mumbai, India, between 31st March to 5th July 2020. In addition to standard care, single Inj. Tocilizumab 400 mg was given intravenously to 151 consecutive COVID-19 patients with persistent hypoxia, from 13th May to 5th July 2020. These 151 patients were retrospectively analysed and compared with historic controls, ie consecutive COVID-19 patients with persistent hypoxia, defined as stated above (N = 118, from our first COVID-19 admission on 31st March to 12th May 2020 i.e., till tocilizumab was available in hospital). Univariate and multivariate Cox regression analysis was performed for identifying predictors of survival. Statistical analysis was performed using IBM SPSS version 26. Results Out of 269 (151 in tocilizumab group and 118 historic controls) patients studied from 31st March to 5th July 2020, median survival in the tocilizumab group was significantly longer than in the control group; 18 days (95% CI, 11.3 to 24.7) versus 9 days (95% CI, 5.7 to 12.3); log rank p 0.007. On multivariate Cox regression analysis, independent predictors of survival were use of tocilizumab (HR 0.621, 95% CI 0.427–0.903, P 0.013) and higher oxygen saturation. Conclusion Tocilizumab may improve survival in severe COVID-19 pneumonia with persistent hypoxia. Randomised controlled trials on use of tocilizumab as rescue therapy in patients of severe COVID-19 pneumonia with hypoxia (PaO2/FiO2 less than 200) due to hyperinflammatory state, are warranted.
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- 2021
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8. Aging‐associated skeletal muscle defects in HER2/Neu transgenic mammary tumour model
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Ruizhong Wang, Brijesh Kumar, Poornima Bhat‐Nakshatri, Mayuri S. Prasad, Max H. Jacobsen, Gabriela Ovalle, Calli Maguire, George Sandusky, Trupti Trivedi, Khalid S. Mohammad, Theresa Guise, Narsimha R. Penthala, Peter A. Crooks, Jianguo Liu, Teresa Zimmers, and Harikrishna Nakshatri
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Breast cancer ,Functional limitations ,Skeletal muscle ,Cytokines/chemokines ,NF‐κB ,Internal medicine ,RC31-1245 - Abstract
Abstract Background Loss of skeletal muscle volume and functional limitations are poor prognostic markers in breast cancer patients. Several molecular defects in skeletal muscle including reduced myoblast determination protein 1 (MyoD) levels and increased protein turn over due to enhanced proteosomal activity have been suggested as causes of skeletal muscle loss in cancer patients. However, it is unknown whether molecular defects in skeletal muscle are dependent on tumour aetiology. Methods We characterized functional and molecular defects of skeletal muscle in mouse mammary tumour virus (MMTV)‐Neu (Neu+) mice (n = 6–12), an animal model that represents HER2 + human breast cancer, and compared the results with well‐characterized luminal B breast cancer model MMTV‐PyMT (PyMT+). Functional studies such as grip strength, rotarod performance, and ex vivo muscle contraction were performed to measure the effects of cancer on skeletal muscle. Expression of muscle‐enriched genes and microRNAs as well as circulating cytokines/chemokines were measured. Because nuclear factor‐kappaB (NF‐κB) pathway plays a significant role in skeletal muscle defects, the ability of NF‐κB inhibitor dimethylaminoparthenolide (DMAPT) to reverse skeletal muscle defects was examined. Results Neu+ mice showed skeletal muscle defects similar to accelerated aging. Compared with age and sex‐matched wild type mice, Neu+ tumour‐bearing mice had lower grip strength (202 ± 6.9 vs. 179 ± 6.8 g grip force, P = 0.0069) and impaired rotarod performance (108 ± 12.1 vs. 30 ± 3.9 s, P
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- 2021
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9. Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma
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Indu Ramachandran, Daniel E. Lowther, Rebecca Dryer-Minnerly, Ruoxi Wang, Svetlana Fayngerts, Daniel Nunez, Gareth Betts, Natalie Bath, Alex J. Tipping, Luca Melchiori, Jean-Marc Navenot, John Glod, Crystal L. Mackall, Sandra P. D’Angelo, Dejka M. Araujo, Warren A. Chow, George D. Demetri, Mihaela Druta, Brian A. Van Tine, Stephan A. Grupp, Albiruni R. Abdul Razak, Breelyn Wilky, Malini Iyengar, Trupti Trivedi, Erin Van Winkle, Karen Chagin, Rafael Amado, Gwendolyn K. Binder, and Samik Basu
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Adoptive immunotherapy ,Synovial sarcoma ,NY-ESO-1 ,Fludarabine ,Cyclophosphamide ,T cell ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Gene-modified autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) reactive against the NY-ESO-1-specific HLA-A*02-restricted peptide SLLMWITQC (NY-ESO-1 SPEAR T-cells; GSK 794), have demonstrated clinical activity in patients with advanced synovial sarcoma (SS). The factors contributing to gene-modified T-cell expansion and the changes within the tumor microenvironment (TME) following T-cell infusion remain unclear. These studies address the immunological mechanisms of response and resistance in patients with SS treated with NY-ESO-1 SPEAR T-cells. Methods Four cohorts were included to evaluate antigen expression and preconditioning on efficacy. Clinical responses were assessed by RECIST v1.1. Engineered T-cell persistence was determined by qPCR. Serum cytokines were evaluated by immunoassay. Transcriptomic analyses and immunohistochemistry were performed on tumor biopsies from patients before and after T-cell infusion. Gene-modified T-cells were detected within the TME via an RNAish assay. Results Responses across cohorts were affected by preconditioning and intra-tumoral NY-ESO-1 expression. Of the 42 patients reported (data cut-off 4June2018), 1 patient had a complete response, 14 patients had partial responses, 24 patients had stable disease, and 3 patients had progressive disease. The magnitude of gene-modified T-cell expansion shortly after infusion was associated with response in patients with high intra-tumoral NY-ESO-1 expression. Patients receiving a fludarabine-containing conditioning regimen experienced increases in serum IL-7 and IL-15. Prior to infusion, the TME exhibited minimal leukocyte infiltration; CD163+ tumor-associated macrophages (TAMs) were the dominant population. Modest increases in intra-tumoral leukocytes (≤5%) were observed in a subset of subjects at approximately 8 weeks. Beyond 8 weeks post infusion, the TME was minimally infiltrated with a TAM-dominant leukocyte infiltrate. Tumor-associated antigens and antigen presentation did not significantly change within the tumor post-T-cell infusion. Finally, NY-ESO-1 SPEAR T cells trafficked to the TME and maintained cytotoxicity in a subset of patients. Conclusions Our studies elucidate some factors that underpin response and resistance to NY-ESO-1 SPEAR T-cell therapy. From these data, we conclude that a lymphodepletion regimen containing high doses of fludarabine and cyclophosphamide is necessary for SPEAR T-cell persistence and efficacy. Furthermore, these data demonstrate that non-T-cell inflamed tumors, which are resistant to PD-1/PD-L1 inhibitors, can be treated with adoptive T-cell based immunotherapy. Trial registration ClinicalTrials.gov, NCT01343043, Registered 27 April 2011.
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- 2019
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10. Long‐term safety and activity of NY-ESO‐1 SPEAR T cells after autologous stem cell transplant for myeloma
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Edward A. Stadtmauer, Thomas H. Faitg, Daniel E. Lowther, Ashraf Z. Badros, Karen Chagin, Karen Dengel, Malini Iyengar, Luca Melchiori, Jean-Marc Navenot, Elliot Norry, Trupti Trivedi, Ruoxi Wang, Gwendolyn K. Binder, Rafael Amado, and Aaron P. Rapoport
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Specialties of internal medicine ,RC581-951 - Abstract
Abstract: This study in patients with relapsed, refractory, or high-risk multiple myeloma (MM) evaluated the safety and activity of autologous T cells engineered to express an affinity-enhanced T-cell receptor (TCR) that recognizes a peptide shared by cancer antigens New York esophageal squamous cell carcinoma-1 (NY-ESO-1) and L-antigen family member 1 (LAGE-1) and presented by HLA-A*02:01. T cells collected from 25 HLA-A*02:01-positive patients with MM expressing NY-ESO-1 and/or LAGE-1 were activated, transduced with self-inactivating lentiviral vector encoding the NY-ESO-1c259TCR, and expanded in culture. After myeloablation and autologous stem cell transplant (ASCT), all 25 patients received an infusion of up to 1 × 1010 NY-ESO-1 specific peptide enhanced affinity receptor (SPEAR) T cells. Objective response rate (International Myeloma Working Group consensus criteria) was 80% at day 42 (95% confidence interval [CI], 0.59-0.93), 76% at day 100 (95% CI, 0.55-0.91), and 44% at 1 year (95% CI, 0.24-0.65). At year 1, 13/25 patients were disease progression-free (52%); 11 were responders (1 stringent complete response, 1 complete response, 8 very good partial response, 1 partial response). Three patients remained disease progression-free at 38.6, 59.2, and 60.6 months post-NY-ESO-1 SPEAR T-cell infusion. Median progression-free survival was 13.5 months (range, 3.2-60.6 months); median overall survival was 35.1 months (range, 6.4-66.7 months). Infusions were well tolerated; cytokine release syndrome was not reported. No fatal serious adverse events occurred during study conduct. NY-ESO-1 SPEAR T cells expanded in vivo, trafficked to bone marrow, demonstrated persistence, and exhibited tumor antigen-directed functionality. In this MM patient population, NY-ESO-1 SPEAR T-cell therapy in the context of ASCT was associated with antitumor activity. This trial was registered at www.clinicaltrials.gov as #NCT01352286.
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- 2019
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11. 379 Initial safety, efficacy, and product attributes from the SURPASS trial with ADP-A2M4CD8, a SPEAR T-cell therapy incorporating an affinity optimized TCR targeting MAGE-A4 and a CD8α co-receptor
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Gareth Betts, Natalie Bath, Mark Dudley, Tanner Johanns, Ahmed Galal, Samuel Saibil, Adrian Sacher, Spinner William, Alex Tipping, Jessica Tucci, Raymond Luke, Trupti Trivedi, Quan Lin, and Karen Miller
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2020
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12. Translational Strategies to Target Metastatic Bone Disease
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Gabriel M. Pagnotti, Trupti Trivedi, and Khalid S. Mohammad
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metastatic bone disease ,osteolytic lesions ,osteoblastic lesions ,bone marrow microenvironment ,radiotherapy ,palliative therapy ,Cytology ,QH573-671 - Abstract
Metastatic bone disease is a common and devastating complication to cancer, confounding treatments and recovery efforts and presenting a significant barrier to de-escalating the adverse outcomes associated with disease progression. Despite significant advances in the field, bone metastases remain presently incurable and contribute heavily to cancer-associated morbidity and mortality. Mechanisms associated with metastatic bone disease perpetuation and paralleled disruption of bone remodeling are highlighted to convey how they provide the foundation for therapeutic targets to stem disease escalation. The focus of this review aims to describe the preclinical modeling and diagnostic evaluation of metastatic bone disease as well as discuss the range of therapeutic modalities used clinically and how they may impact skeletal tissue.
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- 2022
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13. The Role of TGF-β in Bone Metastases
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Trupti Trivedi, Gabriel M. Pagnotti, Theresa A. Guise, and Khalid S. Mohammad
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bone metastases ,transforming growth factor-β (TGF-β) ,programmed cell death ligand (PD-L1) ,immune cells ,TGF-β therapeutic targets ,check-point inhibitors ,Microbiology ,QR1-502 - Abstract
Complications associated with advanced cancer are a major clinical challenge and, if associated with bone metastases, worsen the prognosis and compromise the survival of the patients. Breast and prostate cancer cells exhibit a high propensity to metastasize to bone. The bone microenvironment is unique, providing fertile soil for cancer cell propagation, while mineralized bone matrices store potent growth factors and cytokines. Biologically active transforming growth factor β (TGF-β), one of the most abundant growth factors, is released following tumor-induced osteoclastic bone resorption. TGF-β promotes tumor cell secretion of factors that accelerate bone loss and fuel tumor cells to colonize. Thus, TGF-β is critical for driving the feed-forward vicious cycle of tumor growth in bone. Further, TGF-β promotes epithelial-mesenchymal transition (EMT), increasing cell invasiveness, angiogenesis, and metastatic progression. Emerging evidence shows TGF-β suppresses immune responses, enabling opportunistic cancer cells to escape immune checkpoints and promote bone metastases. Blocking TGF-β signaling pathways could disrupt the vicious cycle, revert EMT, and enhance immune response. However, TGF-β’s dual role as both tumor suppressor and enhancer presents a significant challenge in developing therapeutics that target TGF-β signaling. This review presents TGF-β’s role in cancer progression and bone metastases, while highlighting current perspectives on the therapeutic potential of targeting TGF-β pathways.
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- 2021
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14. Autologous T cell therapy for MAGE-A4+ solid cancers in HLA-A*02+ patients: a phase 1 trial
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David S. Hong, Brian A. Van Tine, Swethajit Biswas, Cheryl McAlpine, Melissa L. Johnson, Anthony J. Olszanski, Jeffrey M. Clarke, Dejka Araujo, George R. Blumenschein, Partow Kebriaei, Quan Lin, Alex J. Tipping, Joseph P. Sanderson, Ruoxi Wang, Trupti Trivedi, Thejo Annareddy, Jane Bai, Stavros Rafail, Amy Sun, Lilliam Fernandes, Jean-Marc Navenot, Frederic D. Bushman, John K. Everett, Derin Karadeniz, Robyn Broad, Martin Isabelle, Revashnee Naidoo, Natalie Bath, Gareth Betts, Zohar Wolchinsky, Dzmitry G. Batrakou, Erin Van Winkle, Erica Elefant, Armin Ghobadi, Amanda Cashen, Anne Grand’Maison, Philip McCarthy, Paula M. Fracasso, Elliot Norry, Dennis Williams, Mihaela Druta, David A. Liebner, Kunle Odunsi, and Marcus O. Butler
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General Medicine ,General Biochemistry, Genetics and Molecular Biology - Abstract
Affinity-optimized T cell receptors can enhance the potency of adoptive T cell therapy. Afamitresgene autoleucel (afami-cel) is a human leukocyte antigen-restricted autologous T cell therapy targeting melanoma-associated antigen A4 (MAGE-A4), a cancer/testis antigen expressed at varying levels in multiple solid tumors. We conducted a multicenter, dose-escalation, phase 1 trial in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4, including synovial sarcoma (SS), ovarian cancer and head and neck cancer (NCT03132922). The primary endpoint was safety, and the secondary efficacy endpoints included overall response rate (ORR) and duration of response. All patients (N = 38, nine tumor types) experienced Grade ≥3 hematologic toxicities; 55% of patients (90% Grade ≤2) experienced cytokine release syndrome. ORR (all partial response) was 24% (9/38), 7/16 (44%) for SS and 2/22 (9%) for all other cancers. Median duration of response was 25.6 weeks (95% confidence interval (CI): 12.286, not reached) and 28.1 weeks (95% CI: 12.286, not reached) overall and for SS, respectively. Exploratory analyses showed that afami-cel infiltrates tumors, has an interferon-γ-driven mechanism of action and triggers adaptive immune responses. In addition, afami-cel has an acceptable benefit–risk profile, with early and durable responses, especially in patients with metastatic SS. Although the small trial size limits conclusions that can be drawn, the results warrant further testing in larger studies.
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- 2023
15. Long-Term Durable FVIII Expression with Improvements in Bleeding Rates Following AAV-Mediated FVIII Gene Transfer for Hemophilia A: Multiyear Follow-up on the Phase I/II Trial of SPK-8011
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Stacy E. Croteau, M. Elaine Eyster, Huyen Tran, Margaret V. Ragni, Benjamin J. Samelson-Jones, Lindsey George, Spencer Sullivan, John E.J. Rasko, Jill Moormeier, Pantep Angchaisuksiri, Jerome Teitel, Gili Kenet, Tung Wynn, Kristen Jaworski, Amy Macdougall, Savina Jaeger, Trupti Trivedi, Federico Mingozzi, Tiffany Chang, and Gallia Levy
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
16. Data from Antitumor Activity Associated with Prolonged Persistence of Adoptively Transferred NY-ESO-1 c259T Cells in Synovial Sarcoma
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Crystal L. Mackall, Rafael Amado, Lini Pandite, Tom Holdich, Trupti Trivedi, Gabor Kari, Erin Van Winkle, Daniel K. Wells, Hua Zhang, Jean-Marc Navenot, Indu Ramachandran, Gareth Betts, Alex Tipping, Natalie Bath, Ruoxi Wang, Daniel E. Lowther, Samik Basu, Gwendolyn K. Binder, Karen Chagin, William D. Tap, Stephan Grupp, Rosandra Kaplan, John Glod, Donna Bernstein, Melinda S. Merchant, Luca Melchiori, and Sandra P. D'Angelo
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We evaluated the safety and activity of autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) recognizing an HLA-A2–restricted NY-ESO-1/LAGE1a–derived peptide, in patients with metastatic synovial sarcoma (NY-ESO-1c259T cells). Confirmed antitumor responses occurred in 50% of patients (6/12) and were characterized by tumor shrinkage over several months. Circulating NY-ESO-1c259T cells were present postinfusion in all patients and persisted for at least 6 months in all responders. Most of the infused NY-ESO-1c259T cells exhibited an effector memory phenotype following ex vivo expansion, but the persisting pools comprised largely central memory and stem-cell memory subsets, which remained polyfunctional and showed no evidence of T-cell exhaustion despite persistent tumor burdens. Next-generation sequencing of endogenous TCRs in CD8+ NY-ESO-1c259T cells revealed clonal diversity without contraction over time. These data suggest that regenerative pools of NY-ESO-1c259T cells produced a continuing supply of effector cells to mediate sustained, clinically meaningful antitumor effects.Significance: Metastatic synovial sarcoma is incurable with standard therapy. We employed engineered T cells targeting NY-ESO-1, and the data suggest that robust, self-regenerating pools of CD8+ NY-ESO-1c259T cells produce a continuing supply of effector cells over several months that mediate clinically meaningful antitumor effects despite prolonged exposure to antigen. Cancer Discov; 8(8); 944–57. ©2018 AACR.See related commentary by Keung and Tawbi, p. 914.This article is highlighted in the In This Issue feature, p. 899
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- 2023
17. Figures S1-S7 from Antitumor Activity Associated with Prolonged Persistence of Adoptively Transferred NY-ESO-1 c259T Cells in Synovial Sarcoma
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Crystal L. Mackall, Rafael Amado, Lini Pandite, Tom Holdich, Trupti Trivedi, Gabor Kari, Erin Van Winkle, Daniel K. Wells, Hua Zhang, Jean-Marc Navenot, Indu Ramachandran, Gareth Betts, Alex Tipping, Natalie Bath, Ruoxi Wang, Daniel E. Lowther, Samik Basu, Gwendolyn K. Binder, Karen Chagin, William D. Tap, Stephan Grupp, Rosandra Kaplan, John Glod, Donna Bernstein, Melinda S. Merchant, Luca Melchiori, and Sandra P. D'Angelo
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Figure S1. Consort diagram. Figure S2. Longitudinal analyses of persistence, memory cells and exhaustion marker expression. Figure S3. NY-ESO-1c259T cells exhibit and maintain polyfunctionality prior to and postinfusion. Figure S4. NY-ESO-1c259TCR+CD3+ T cells from the manufactured product and post-infusion PBMCs from a representative patient. Figure S5. Tumor analyses following NY-ESO-1c259T cell therapy in patient 202. Figure S6. NY-ESO-1 Expression at Screening and Relapse. Figure S7. Analysis of TCRBV sequences within sorted cell subsets.
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- 2023
18. Low-Magnitude Mechanical Signals Combined with Zoledronic Acid Reduce Musculoskeletal Weakness and Adiposity in Estrogen-Deprived Mice
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Gabriel M. Pagnotti, Trupti Trivedi, Laura E. Wright, Sutha K. John, Sreemala Murthy, Ryan R. Pattyn, Monte S. Willis, Yun She, Sukanya Suresh, William R. Thompson, Clinton T. Rubin, Khalid S. Mohammad, and Theresa A. Guise
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Article - Abstract
Combination treatment of Low-Intensity Vibration (LIV) with zoledronic acid (ZA) was hypothesized to preserve bone mass and muscle strength while reducing adipose tissue accrual associated with complete estrogen (E2)-deprivation in young and skeletally mature mice. Complete E2-deprivation (surgical-ovariectomy (OVX) and daily injection of aromatase inhibitor (AI) letrozole) were performed on 8-week-old C57BL/6 female mice for 4 weeks following commencement of LIV administration or control (no LIV), for 28 weeks. Additionally, 16-week-old C57BL/6 female E2-deprived mice were administered ±LIV twice daily and supplemented with ±ZA (2.5 ng/kg/week). By week 28, lean tissue mass quantified by dual-energy X-ray absorptiometry was increased in younger OVX/AI+LIV(y) mice, with increased myofiber cross-sectional area of quadratus femorii. Grip strength was greater in OVX/AI+LIV(y) mice than OVX/AI(y) mice. Fat mass remained lower in OVX/AI+LIV(y) mice throughout the experiment compared with OVX/AI(y) mice. OVX/AI+LIV(y) mice exhibited increased glucose tolerance and reduced leptin and free fatty acids than OVX/AI(y) mice. Trabecular bone volume fraction and connectivity density increased in the vertebrae of OVX/AI+LIV(y) mice compared to OVX/AI(y) mice; however, this effect was attenuated in the older cohort of E2-deprived mice, specifically in OVX/AI+ZA mice, requiring combined LIV with ZA to increase trabecular bone volume and strength. Similar improvements in cortical bone thickness and cross-sectional area of the femoral mid-diaphysis were observed in OVX/AI+LIV+ZA mice, resulting in greater fracture resistance. Our findings demonstrate that the combination of mechanical signals in the form of LIV and anti-resorptive therapy via ZA improve vertebral trabecular bone and femoral cortical bone, increase lean mass, and reduce adiposity in mice undergoing complete E2-deprivation.One Sentence Summary:Low-magnitude mechanical signals with zoledronic acid suppressed bone and muscle loss and adiposity in mice undergoing complete estrogen deprivation.Translational RelevancePostmenopausal patients with estrogen receptor-positive breast cancer treated with aromatase inhibitors to reduce tumor progression experience deleterious effects to bone and muscle subsequently develop muscle weakness, bone fragility, and adipose tissue accrual. Bisphosphonates (i.e., zoledronic acid) prescribed to inhibit osteoclast-mediated bone resorption are effective in preventing bone loss but may not address the non-skeletal effects of muscle weakness and fat accumulation that contribute to patient morbidity. Mechanical signals, typically delivered to the musculoskeletal system during exercise/physical activity, are integral for maintaining bone and muscle health; however, patients undergoing treatments for breast cancer often experience decreased physical activity which further accelerates musculoskeletal degeneration. Low-magnitude mechanical signals, in the form of low-intensity vibrations, generate dynamic loading forces similar to those derived from skeletal muscle contractility. As an adjuvant to existing treatment strategies, low-intensity vibrations may preserve or rescue diminished bone and muscle degraded by breast cancer treatment.
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- 2023
19. Combined Detection of Copy Number Variations of MYCN and ALK using Droplet Digital Polymerase Chain Reaction to Identify High-Risk Patients with Neuroblastoma
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Trupti Trivedi, Harsha Panchal, Kinjal Panchal, Neha Bhalala, and Priti Trivedi
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N-Myc Proto-Oncogene Protein ,DNA Copy Number Variations ,business.industry ,Multivariate survival ,Polymerase Chain Reaction ,Neuroblastoma ,Cancer research ,Circulating DNA ,Medicine ,Humans ,Surgery ,Digital polymerase chain reaction ,High risk neuroblastoma ,Anaplastic Lymphoma Kinase ,Neurology (clinical) ,Copy-number variation ,business ,Cell-Free Nucleic Acids - Abstract
The current study sought to explore the significance of copy number variations (CNVs) of MYCN (v-myc myelocytomatosis viral related oncogene, neuroblastoma derived [avian]) and ALK (anaplastic lymphoma kinase) genes individually as well as their combined impact on clinical outcome and overall survival of patients with neuroblastoma (NB).A total 71 individuals including healthy controls (n = 11), circulating DNA (n = 11), and primary tumors (n = 49) were evaluated to detect CNVs of MYCN and ALK genes using droplet digital polymerase chain reaction. Data were correlated with univariate and multivariate survival analysis.CNVs of MYCN and ALK were detected in 27% and 18.2% from circulating DNA samples. A statistically significant difference in CNVs was noted between healthy controls and circulating DNA samples for MYCN (P = 0.001) and ALK (P = 0.004) genes. Further, we noted70% concordance in CNVs of MYCN (P = 0.030) and ALK (P = 0.040) from primary tumors and concordant plasma samples of patients with NB. Multivariate survival analysis for disease-free survival (P = 0.031) and overall survival (P = 0.011) showed that CNVs of both genes emerged at step 1 and thus remained as significant markers for predicting early recurrence and shorter survival, respectively, for patients with NB.Our study showed that the analysis of circulating DNA by droplet digital polymerase chain reaction is a helpful technique to identify high-risk patients for aggressive therapy at an early stage of disease. We also concluded that codetection of MYCN and ALK is a more powerful tool for identifying high-risk patients with NB. Thus, this study showed a novel coordinately significant prognostic role of MYCN and ALK CNVs.
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- 2021
20. Ischemic Stroke in COVID 19- Management Dilemmas
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Uma, Sundar, Niteen, Karnik, Yojana, Gokhale, Sangeeta, Pednekar, Swati, Chavan, and Trupti, Trivedi
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Stroke ,SARS-CoV-2 ,COVID-19 ,Humans ,Brain Ischemia ,Ischemic Stroke - Published
- 2021
21. COVID-19 Associated Stroke-A Single Centre Experience
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Uma, Sundar, Niteen D, Karnik, Amita, Mukhopadhyay, Pramod, Darole, Shaonak, Kolte, Ashank, Bansal, Yojana A, Gokhale, Dnaneshwar, Asole, Anagha, Joshi, Sangeeta, Pednekar, Swati, Chavan, Trupti, Trivedi, Namita, Padwal, Lalana, Kalekar, and Charulata, Londhe
- Subjects
Adult ,Aged, 80 and over ,Hospitalization ,Stroke ,Young Adult ,Adolescent ,SARS-CoV-2 ,COVID-19 ,Humans ,Hospital Mortality ,Middle Aged ,Aged - Abstract
Various neurological complications have been reported in association with COVID-19. We report our experience of COVID-19 with stroke at a single center over a period of eight months spanning 1 March to 31 October 2020.We recruited all patients admitted to Internal Medicine with an acute stroke, who also tested positive for COVID-19 on RTPCR. We included all stroke cases in our analysis for prediction of in-hospital mortality, and separately analyzed arterial infarcts for vascular territory of ischemic strokes.There were 62 stroke cases among 3923 COVID-19 admissions (incidence 1.6%). Data was available for 58 patients {mean age 52.6 years; age range 17-91; F/M=20/38; 24% (14/58) aged ≤40; 51% (30/58) hypertensive; 36% (21/58) diabetic; 41% (24/58) with O2 saturationlt;95% at admission; 32/58 (55.17 %) in-hospital mortality}. Among 58 strokes, there were 44 arterial infarcts, seven bleeds, three arterial infarcts with associated cerebral venous sinus thrombosis, two combined infarct and bleed, and two of indeterminate type. Among the total 49 infarcts, Carotid territory was the commonest affected (36/49; 73.5%), followed by vertebrobasilar (7/49; 14.3%) and both (6/49; 12.2%). Concordant arterial block was seen in 61% (19 of 31 infarcts with angiography done). 'Early stroke' (within 48 hours of respiratory symptoms) was seen in 82.7% (48/58) patients. Patients with poor saturation at admission were older (58 vs 49 years) and had more comorbidities and higher mortality (79% vs 38%). Mortality was similar in young strokes and older patients, although the latter required more intense respiratory support. Logistic regression analysis showed that low Glasgow coma score (GCS) and requirement for increasing intensity of respiratory support predicted in-hospital mortality.We had a 1.6% incidence of COVID-19 related stroke of which the majority were carotid territory infarcts. In-hospital mortality was 55.17%, predicted by low GCS at admission.
- Published
- 2021
22. Factors Affecting Maternal Outcome in Urban Setting (FAMOUS)-ICU Experience
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Sneha, Sabesan, Trupti, Trivedi, Priyanshu, Shah, Sonal, Honrao, Pratima, Acharya, Gaurav, Zope, Digambar, Panchal, and Niteen, Karnik
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Pregnancy Complications ,Intensive Care Units ,Adolescent ,Pregnancy ,Critical Illness ,Humans ,Female ,APACHE ,Retrospective Studies - Abstract
Pregnant women in India are at higher risk of dying as compared to middle to high income countries. Deaths can be prevented if risk factors are identified, critical illness is diagnosed early and timely care is provided. The present research was undertaken to study the clinical profile and factors affecting the outcome of pregnant and postpartum patients in the Medical Intensive Care Unit (MICU).A total of 75 consecutive patients of agegt;18 years with confirmed pregnancy or postpartum females within 42 days from date of delivery requiring admission in ICU for at least one organ dysfunction as per APACHE II criteria1 were enrolled in the study. Clinical profiles of patients and outcomes were measured till hospital discharge.Among 75 patients, 18(24%) patients were postpartum while 57(76%) were antepartum.The commonest symptom was fever (64%), followed by breathlessness (62.7%). Respiratory distress (58.7%) was the commonest indication for transfer to MICU. While 60(80%) patients were admitted for medical illnesses in pregnancy, 15(20%) patients were admitted for obstetric complications. Acute infections including malaria, dengue and leptospirosis were the commonest illness diagnosed in 19(25.3%) patients. Severity of illness measured using APACHE II score varied from 4 to 35 points with a mean score of 10.61.Longer duration of symptoms before seeking medical attention, lower pH, lower paO2/FiO2 ratio and serum bicarbonate, a diagnosis of tuberculosis and a higher APACHE II score were associated with a higher mortality.With institution of intensive therapy in critically ill maternal patients, 80% of patients could be saved and 61% of fetuses had uneventful outcomes.The prognosis was better for obstetric illnesses than for medical illnesses with only 3 patients dying of obstetric causes whereas 12 patients died of medical illnesses common to the general population. Even though APACHE II score was higher in the group with obstetric conditions (mean=11 vs. 8.1), the mortality was lower.
- Published
- 2021
23. Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma
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Gwendolyn K. Binder, Dejka M. Araujo, Daniel Nunez, Samik Basu, Luca Melchiori, Rafael G. Amado, Gareth Betts, Natalie Bath, Rebecca Dryer-Minnerly, Ruoxi Wang, Sandra P. D'Angelo, Mihaela Druta, Malini Iyengar, Albiruni Ryan Abdul Razak, Stephan A. Grupp, Breelyn A. Wilky, Jean Marc Navenot, George D. Demetri, Alex Tipping, Brian A. Van Tine, Erin Van Winkle, Warren Chow, Trupti Trivedi, Indu R. Ramachandran, Svetlana Fayngerts, Karen Chagin, Crystal L. Mackall, Daniel E. Lowther, and John Glod
- Subjects
Cytotoxicity, Immunologic ,Engineered cell therapy ,0301 basic medicine ,Cancer Research ,Adoptive cell transfer ,T-Lymphocytes ,Cytotoxicity ,medicine.medical_treatment ,Adoptive ,T-Cell Antigen Receptor Specificity ,Checkpoint therapy ,Immunotherapy, Adoptive ,Fludarabine ,0302 clinical medicine ,Immunologic ,Receptors ,Tumor Microenvironment ,2.1 Biological and endogenous factors ,Immunology and Allergy ,NY-ESO-1 ,Lymphocytes ,Antigen loss ,Aetiology ,Cancer ,education.field_of_study ,Receptors, Chimeric Antigen ,Clinical Trials, Phase I as Topic ,Sarcoma ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Immunohistochemistry ,Treatment Outcome ,Cytokine ,medicine.anatomical_structure ,IL-15 ,Oncology ,Antigen ,030220 oncology & carcinogenesis ,Cytokines ,Molecular Medicine ,Immunotherapy ,TCR ,Research Article ,Biotechnology ,T cell ,Immunology ,Population ,Receptors, Antigen, T-Cell ,Phase I as Topic ,lcsh:RC254-282 ,Vaccine Related ,Synovial sarcoma ,Sarcoma, Synovial ,03 medical and health sciences ,Clinical Trials, Phase II as Topic ,Lymphocytes, Tumor-Infiltrating ,Antigens, Neoplasm ,Clinical Research ,Adoptive immunotherapy ,medicine ,Humans ,Clinical Trials ,Tumor-Infiltrating ,Antigens ,education ,Cyclophosphamide ,Pharmacology ,Tumor microenvironment ,Synovial ,HLA-A Antigens ,business.industry ,Phase II as Topic ,Membrane Proteins ,Chimeric Antigen ,T-Cell ,medicine.disease ,030104 developmental biology ,Neoplasm ,Immunization ,business ,Biomarkers ,Progressive disease - Abstract
Background Gene-modified autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) reactive against the NY-ESO-1-specific HLA-A*02-restricted peptide SLLMWITQC (NY-ESO-1 SPEAR T-cells; GSK 794), have demonstrated clinical activity in patients with advanced synovial sarcoma (SS). The factors contributing to gene-modified T-cell expansion and the changes within the tumor microenvironment (TME) following T-cell infusion remain unclear. These studies address the immunological mechanisms of response and resistance in patients with SS treated with NY-ESO-1 SPEAR T-cells. Methods Four cohorts were included to evaluate antigen expression and preconditioning on efficacy. Clinical responses were assessed by RECIST v1.1. Engineered T-cell persistence was determined by qPCR. Serum cytokines were evaluated by immunoassay. Transcriptomic analyses and immunohistochemistry were performed on tumor biopsies from patients before and after T-cell infusion. Gene-modified T-cells were detected within the TME via an RNAish assay. Results Responses across cohorts were affected by preconditioning and intra-tumoral NY-ESO-1 expression. Of the 42 patients reported (data cut-off 4June2018), 1 patient had a complete response, 14 patients had partial responses, 24 patients had stable disease, and 3 patients had progressive disease. The magnitude of gene-modified T-cell expansion shortly after infusion was associated with response in patients with high intra-tumoral NY-ESO-1 expression. Patients receiving a fludarabine-containing conditioning regimen experienced increases in serum IL-7 and IL-15. Prior to infusion, the TME exhibited minimal leukocyte infiltration; CD163+ tumor-associated macrophages (TAMs) were the dominant population. Modest increases in intra-tumoral leukocytes (≤5%) were observed in a subset of subjects at approximately 8 weeks. Beyond 8 weeks post infusion, the TME was minimally infiltrated with a TAM-dominant leukocyte infiltrate. Tumor-associated antigens and antigen presentation did not significantly change within the tumor post-T-cell infusion. Finally, NY-ESO-1 SPEAR T cells trafficked to the TME and maintained cytotoxicity in a subset of patients. Conclusions Our studies elucidate some factors that underpin response and resistance to NY-ESO-1 SPEAR T-cell therapy. From these data, we conclude that a lymphodepletion regimen containing high doses of fludarabine and cyclophosphamide is necessary for SPEAR T-cell persistence and efficacy. Furthermore, these data demonstrate that non-T-cell inflamed tumors, which are resistant to PD-1/PD-L1 inhibitors, can be treated with adoptive T-cell based immunotherapy. Trial registration ClinicalTrials.gov, NCT01343043, Registered 27 April 2011.
- Published
- 2019
24. Long-term safety and activity of NY-ESO-1 SPEAR T cells after autologous stem cell transplant for myeloma
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Gwendolyn K. Binder, Thomas H. Faitg, Karen Chagin, Elliot Norry, Jean-Marc Navenot, Edward A. Stadtmauer, Trupti Trivedi, Karen Dengel, Aaron P. Rapoport, Daniel E. Lowther, Rafael G. Amado, Malini Iyengar, Luca Melchiori, Ashraf Badros, and Ruoxi Wang
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Adolescent ,T-Lymphocytes ,medicine.medical_treatment ,Receptors, Antigen, T-Cell ,Context (language use) ,Immunotherapy, Adoptive ,Transplantation, Autologous ,Young Adult ,Antigen ,Antigens, Neoplasm ,Internal medicine ,medicine ,Humans ,Multiple myeloma ,Aged ,Aged, 80 and over ,Receptors, Chimeric Antigen ,business.industry ,Hematopoietic Stem Cell Transplantation ,Membrane Proteins ,Gene Therapy ,Hematology ,Immunotherapy ,Middle Aged ,medicine.disease ,Combined Modality Therapy ,Transplantation ,Cytokine release syndrome ,Treatment Outcome ,medicine.anatomical_structure ,Cytokines ,Female ,Bone marrow ,Stem cell ,Multiple Myeloma ,business - Abstract
This study in patients with relapsed, refractory, or high-risk multiple myeloma (MM) evaluated the safety and activity of autologous T cells engineered to express an affinity-enhanced T-cell receptor (TCR) that recognizes a peptide shared by cancer antigens New York esophageal squamous cell carcinoma-1 (NY-ESO-1) and L-antigen family member 1 (LAGE-1) and presented by HLA-A*02:01. T cells collected from 25 HLA-A*02:01-positive patients with MM expressing NY-ESO-1 and/or LAGE-1 were activated, transduced with self-inactivating lentiviral vector encoding the NY-ESO-1c259TCR, and expanded in culture. After myeloablation and autologous stem cell transplant (ASCT), all 25 patients received an infusion of up to 1 × 1010 NY-ESO-1 specific peptide enhanced affinity receptor (SPEAR) T cells. Objective response rate (International Myeloma Working Group consensus criteria) was 80% at day 42 (95% confidence interval [CI], 0.59-0.93), 76% at day 100 (95% CI, 0.55-0.91), and 44% at 1 year (95% CI, 0.24-0.65). At year 1, 13/25 patients were disease progression-free (52%); 11 were responders (1 stringent complete response, 1 complete response, 8 very good partial response, 1 partial response). Three patients remained disease progression-free at 38.6, 59.2, and 60.6 months post-NY-ESO-1 SPEAR T-cell infusion. Median progression-free survival was 13.5 months (range, 3.2-60.6 months); median overall survival was 35.1 months (range, 6.4-66.7 months). Infusions were well tolerated; cytokine release syndrome was not reported. No fatal serious adverse events occurred during study conduct. NY-ESO-1 SPEAR T cells expanded in vivo, trafficked to bone marrow, demonstrated persistence, and exhibited tumor antigen-directed functionality. In this MM patient population, NY-ESO-1 SPEAR T-cell therapy in the context of ASCT was associated with antitumor activity. This trial was registered at www.clinicaltrials.gov as #NCT01352286.
- Published
- 2019
25. COVID-19 Associated Stroke—A Single Centre Experience
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Uma Sundar, Niteen D Karnik, Amita Mukhopadhyay, Pramod Darole, Shaonak Kolte, Ashank Bansal, Yojana A Gokhale, Dnaneshwar Asole, Anagha Joshi, Sangeeta Pednekar, Swati Chavan, Trupti Trivedi, Namita Padwal, Lalana Kalekar, Charulata Londhe, Rupal Padhiyar, Dharmendra Pandey, Dhirendra Yadav, Sonal U Honrao, Prerana Bhavsar, Priyanshu Shah, Satish Gosavi, Aniket Wadal, Awesh P Shingare, Mayuri Trivedi, and Gauri Pathak Oak
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medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Incidence (epidemiology) ,Glasgow Coma Scale ,Bleed ,medicine.disease ,Single Center ,Internal medicine ,Angiography ,medicine ,Cardiology ,Respiratory system ,Cerebral venous sinus thrombosis ,business ,Stroke - Abstract
Background and PurposeVarious neurological complications have been reported in association with COVID-19. We report our experience of COVID-19 with stroke at a single center over a period of eight months spanning 1 March to 31 October 2020.MethodsWe recruited all patients admitted to Internal Medicine with an acute stroke, who also tested positive for COVID-19 on RTPCR. We included all stroke cases in our analysis for prediction of in-hospital mortality, and separately analyzed arterial infarcts for vascular territory of ischemic strokes.ResultsThere were 62 stroke cases among 3923 COVID-19 admissions (incidence 1.6%). Data was available for 58 patients {mean age 52.6 years; age range 17–91; F/M=20/38; 24% (14/58) aged ≤40; 51% (30/58) hypertensive; 36% (21/58) diabetic; 41% (24/58) with O2 saturation ConclusionsWe had a 1.6% incidence of COVID-19 related stroke of which the majority were carotid territory infarcts. In-hospital mortality was 55.17%, predicted by low GCS at admission.
- Published
- 2021
26. 379 Initial safety, efficacy, and product attributes from the SURPASS trial with ADP-A2M4CD8, a SPEAR T-cell therapy incorporating an affinity optimized TCR targeting MAGE-A4 and a CD8α co-receptor
- Author
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Mark E. Dudley, Jeffrey M. Clarke, Adrian G. Sacher, Gareth Betts, Natalie Bath, Alex Tipping, Karen Miller, Tanner M. Johanns, John V. Heymach, Elliot Norry, Francine Brophy, Trupti Trivedi, David S. Hong, Paula M. Fracasso, Raymond Luke, Jean-Marc Navenot, Jessica Tucci, Marcus O. Butler, Ahmed Galal, Partow Kebriaei, Quan Lin, Samuel Saibil, and Spinner William
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Oncology ,medicine.medical_specialty ,Cyclophosphamide ,business.industry ,T cell ,Head and neck cancer ,T-cell receptor ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,lcsh:RC254-282 ,Fludarabine ,medicine.anatomical_structure ,Antigen ,Internal medicine ,medicine ,Ovarian cancer ,business ,CD8 ,medicine.drug - Abstract
Background The ongoing SURPASS trial (NCT04044859) evaluates safety and efficacy of next-generation ADP-A2M4CD8 SPEAR T-cells co-expressing the CD8α co-receptor with the engineered MAGE-A4c1032T cell receptor (TCR). Methods First-in-human trial in HLA-A*02 positive patients (pts) with advanced cancers expressing MAGE-A4 antigen by immunohistochemistry. Eligible pts undergo apheresis, T-cells are isolated, transduced with a Lentiviral vector containing the MAGE-A4c1032 TCR and CD8α co receptor, and expanded. Expansion, transduction level, cellular composition and function of the manufactured product (MP) are assessed in vitro. Prior to infusion, pts receive lymphodepletion with fludarabine 30 mg/m2/day for 4 days and cyclophosphamide 600 mg/m2/day for 3 days. Results As of 16 July 2020, 5 pts (1 with MRCLS, 2 with esophagogastric junction [EGJ] cancers, 1 with ovarian cancer, and 1 with head and neck cancer) were treated with ADP-A2M4 CD8 (range ~1 to 5.7 billion transduced cells). No DLTs or SAEs have been reported. To date, 1 pt with EGJ cancer had a partial response (PR per RECIST) and has had progression-free survival >6 months. One pt with head and neck cancer also had a PR. All other pts have had best overall response of stable disease.MP expanded by an average of 15.3 fold during manufacturing (range 5.9 to 25.6-fold). On average, 43% of T-cells in the MP expressed the TCR (range 23 to 63%). The fraction of CD4+ cells in the final MP varied (range 45 to 84%). Co-expression of the MAGE-A4 TCR and CD8α in CD4+ T-cells in the patient MP enabled CD4+ T-cells to kill tumor target cells directly in vitro. MAGE-A4 expression in tumor biopsies varied (H-score range 55 to 300). Transduced T-cells were detected in peripheral blood of all pts. IFN-gamma increased transiently in the serum of 1 pt who responded. Conclusions ADP-A2M4CD8 SPEAR T-cells have shown an acceptable safety profile and pts with EGJ cancer and head and neck cancer have demonstrated evidence of antitumor activity. Translational data and early clinical results indicate that co-expression of the CD8α co-receptor on CD4+ SPEAR T-cells may increase the potency of the product by conferring additional killing activity to the helper T-cell subset. This dose escalation trial is ongoing and updated clinical and translational data will be presented. Trial Registration NCT04044859 Ethics Approval The trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines and was approved by local authorities. An independent ethics committee or institutional review board approved the clinical protocol at each participating center. All the patients provided written informed consent before study entry.
- Published
- 2020
27. Aging-associated skeletal muscle defects in HER2/Neu transgenic mammary tumor model
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Trupti Trivedi, Peter A. Crooks, Teresa Zimmers, Narsimha Reddy Penthala, Jianguo Liu, Khalid S. Mohammad, Mayuri S. Prasad, Ruizhong Wang, Brijesh Kumar, Max Jacobsen, Theresa A. Guise, Harikrishna Nakshatri, George E. Sandusky, Calli Maguire, Poornima Bhat-Nakshatri, and Gabriela Ovalle
- Subjects
medicine.medical_specialty ,lcsh:Internal medicine ,Skeletal muscle ,MyoD ,HER2/neu ,Article ,Cachexia ,Breast cancer ,Internal medicine ,medicine ,Cytokines/chemokines ,Progenitor cell ,lcsh:RC31-1245 ,Mammary tumor ,biology ,Chemistry ,NF‐κB ,Cancer ,medicine.disease ,Functional limitations ,medicine.anatomical_structure ,Endocrinology ,biology.protein ,medicine.symptom ,Muscle contraction - Abstract
Background Loss of skeletal muscle volume and functional limitations are poor prognostic markers in breast cancer patients. Several molecular defects in skeletal muscle including reduced myoblast determination protein 1 (MyoD) levels and increased protein turn over due to enhanced proteosomal activity have been suggested as causes of skeletal muscle loss in cancer patients. However, it is unknown whether molecular defects in skeletal muscle are dependent on tumour aetiology. Methods We characterized functional and molecular defects of skeletal muscle in mouse mammary tumour virus (MMTV)‐Neu (Neu+) mice (n = 6–12), an animal model that represents HER2 + human breast cancer, and compared the results with well‐characterized luminal B breast cancer model MMTV‐PyMT (PyMT+). Functional studies such as grip strength, rotarod performance, and ex vivo muscle contraction were performed to measure the effects of cancer on skeletal muscle. Expression of muscle‐enriched genes and microRNAs as well as circulating cytokines/chemokines were measured. Because nuclear factor‐kappaB (NF‐κB) pathway plays a significant role in skeletal muscle defects, the ability of NF‐κB inhibitor dimethylaminoparthenolide (DMAPT) to reverse skeletal muscle defects was examined. Results Neu+ mice showed skeletal muscle defects similar to accelerated aging. Compared with age and sex‐matched wild type mice, Neu+ tumour‐bearing mice had lower grip strength (202 ± 6.9 vs. 179 ± 6.8 g grip force, P = 0.0069) and impaired rotarod performance (108 ± 12.1 vs. 30 ± 3.9 s, P
- Published
- 2020
28. Systemic effects of abnormal bone resorption on muscle, metabolism, and cognition
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Theresa A. Guise and Trupti Trivedi
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Histology ,Physiology ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Osteoporosis ,Bone Neoplasms ,Bioinformatics ,Bone resorption ,Bone remodeling ,Cognition ,Tumor Microenvironment ,medicine ,Humans ,Bone Resorption ,Diphosphonates ,business.industry ,Muscles ,Muscle weakness ,Skeletal muscle ,Bone metastasis ,Bisphosphonate ,medicine.disease ,Denosumab ,medicine.anatomical_structure ,medicine.symptom ,business ,medicine.drug - Abstract
Skeletal tissue is dynamic, undergoing constant remodeling to maintain musculoskeletal integrity and balance in the human body. Recent evidence shows that apart from maintaining homeostasis in the local microenvironment, the skeleton systemically affects other tissues. Several cancer-associated and noncancer-associated bone disorders can disrupt the physiological homeostasis locally in the bone microenvironment and indirectly contribute to dysregulation of systemic body function. The systemic effects of bone on the regulation of distant organ function have not been widely explored. Recent evidence suggests that bone can interact with skeletal muscle, pancreas, and brain by releasing factors from mineralized bone matrix. Currently available bone-targeting therapies such as bisphosphonates and denosumab inhibit bone resorption, decrease morbidity associated with bone destruction, and improve survival. Bisphosphonates have been a standard treatment for bone metastases, osteoporosis, and cancer treatment-induced bone diseases. The extraskeletal effects of bisphosphonates on inhibition of tumor growth are known. However, our knowledge of the effects of bisphosphonates on muscle weakness, hyperglycemia, and cognitive defects is currently evolving. To be able to identify the molecular link between bone and distant organs during abnormal bone resorption and then treat these abnormalities and prevent their systemic effects could improve survival benefits. The current review highlights the link between bone resorption and its systemic effects on muscle, pancreas, and brain.
- Published
- 2022
29. Antitumor Activity Associated with Prolonged Persistence of Adoptively Transferred NY-ESO-1 c259T Cells in Synovial Sarcoma
- Author
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Tom Holdich, Rafael G. Amado, Rosandra N. Kaplan, Gabor Kari, Erin Van Winkle, Hua Zhang, Daniel K. Wells, Karen Chagin, Crystal L. Mackall, Samik Basu, Gwendolyn K. Binder, Daniel E. Lowther, Luca Melchiori, John Glod, Melinda S. Merchant, Sandra P. D'Angelo, Lini Pandite, Jean-Marc Navenot, Natalie Bath, Stephan A. Grupp, Ruoxi Wang, Donna Bernstein, Alex Tipping, William D. Tap, Gareth Betts, Trupti Trivedi, and Indu R. Ramachandran
- Subjects
0301 basic medicine ,Metastatic Synovial Sarcoma ,Adoptive cell transfer ,business.industry ,Effector ,T-cell receptor ,medicine.disease ,Synovial sarcoma ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Antigen ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,Sarcoma ,business ,CD8 - Abstract
We evaluated the safety and activity of autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) recognizing an HLA-A2–restricted NY-ESO-1/LAGE1a–derived peptide, in patients with metastatic synovial sarcoma (NY-ESO-1c259T cells). Confirmed antitumor responses occurred in 50% of patients (6/12) and were characterized by tumor shrinkage over several months. Circulating NY-ESO-1c259T cells were present postinfusion in all patients and persisted for at least 6 months in all responders. Most of the infused NY-ESO-1c259T cells exhibited an effector memory phenotype following ex vivo expansion, but the persisting pools comprised largely central memory and stem-cell memory subsets, which remained polyfunctional and showed no evidence of T-cell exhaustion despite persistent tumor burdens. Next-generation sequencing of endogenous TCRs in CD8+ NY-ESO-1c259T cells revealed clonal diversity without contraction over time. These data suggest that regenerative pools of NY-ESO-1c259T cells produced a continuing supply of effector cells to mediate sustained, clinically meaningful antitumor effects. Significance: Metastatic synovial sarcoma is incurable with standard therapy. We employed engineered T cells targeting NY-ESO-1, and the data suggest that robust, self-regenerating pools of CD8+ NY-ESO-1c259T cells produce a continuing supply of effector cells over several months that mediate clinically meaningful antitumor effects despite prolonged exposure to antigen. Cancer Discov; 8(8); 944–57. ©2018 AACR. See related commentary by Keung and Tawbi, p. 914. This article is highlighted in the In This Issue feature, p. 899
- Published
- 2018
30. The Role of TGF-β in Bone Metastases
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Theresa A. Guise, Trupti Trivedi, Khalid S. Mohammad, and Gabriel M. Pagnotti
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TGF-β therapeutic targets ,Epithelial-Mesenchymal Transition ,Angiogenesis ,transforming growth factor-β (TGF-β) ,Cell ,Bone Neoplasms ,Review ,Microbiology ,Biochemistry ,Bone and Bones ,Bone resorption ,Prostate cancer ,immune cells ,Immune system ,bone metastases ,Transforming Growth Factor beta ,medicine ,Humans ,programmed cell death ligand (PD-L1) ,check-point inhibitors ,Molecular Biology ,business.industry ,Cancer ,medicine.disease ,QR1-502 ,medicine.anatomical_structure ,Cancer cell ,Cancer research ,business ,bone resorption ,Transforming growth factor - Abstract
Complications associated with advanced cancer are a major clinical challenge and, if associated with bone metastases, worsen the prognosis and compromise the survival of the patients. Breast and prostate cancer cells exhibit a high propensity to metastasize to bone. The bone microenvironment is unique, providing fertile soil for cancer cell propagation, while mineralized bone matrices store potent growth factors and cytokines. Biologically active transforming growth factor β (TGF-β), one of the most abundant growth factors, is released following tumor-induced osteoclastic bone resorption. TGF-β promotes tumor cell secretion of factors that accelerate bone loss and fuel tumor cells to colonize. Thus, TGF-β is critical for driving the feed-forward vicious cycle of tumor growth in bone. Further, TGF-β promotes epithelial-mesenchymal transition (EMT), increasing cell invasiveness, angiogenesis, and metastatic progression. Emerging evidence shows TGF-β suppresses immune responses, enabling opportunistic cancer cells to escape immune checkpoints and promote bone metastases. Blocking TGF-β signaling pathways could disrupt the vicious cycle, revert EMT, and enhance immune response. However, TGF-β’s dual role as both tumor suppressor and enhancer presents a significant challenge in developing therapeutics that target TGF-β signaling. This review presents TGF-β’s role in cancer progression and bone metastases, while highlighting current perspectives on the therapeutic potential of targeting TGF-β pathways.
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- 2021
31. SPEARHEAD-1: A phase 2 trial of afamitresgene autoleucel (Formerly ADP-A2M4) in patients with advanced synovial sarcoma or myxoid/round cell liposarcoma
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Swethajit Biswas, Erin Van Winkle, Albiruni Ryan Abdul Razak, Brian A. Van Tine, Dejka M. Araujo, Jean-Yves Blay, Sandra J. Strauss, Elliot Norry, Claudia Maria Valverde Morales, Dennis Williams, Steven Attia, Trupti Trivedi, and Sandra P. D'Angelo
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Cancer Research ,Pathology ,medicine.medical_specialty ,Oncology ,Tolerability ,business.industry ,Myxoid/Round Cell Liposarcoma ,medicine ,In patient ,medicine.disease ,business ,Synovial sarcoma - Abstract
11504 Background: This phase 2, open-label trial (SPEARHEAD-1; NCT04044768) is designed to evaluate the efficacy, safety, and tolerability of afamitresgene autoleucel in 45 patients (pts) with advanced/metastatic synovial sarcoma or Myxoid/Round Cell Liposarcoma (MRCLS). Methods: Eligible pts are HLA-A*02 positive with MAGE-A4-expressing tumors. Pts undergo leukapheresis for collection of autologous T-cells for processing and manufacture into afamitresgene autoleucel cells. Pts were treated with afamitresgene autoleucel doses between 1–10 × 109 transduced T-cells after receiving lymphodepleting chemotherapy. The primary endpoint is overall response rate per RECIST v1.1 by independent review. An independent Data Safety Monitoring Board reviews ongoing safety and benefit: risk during the interventional phase. Results: As of Feb 4, 2021, 32 pts received afamitresgene autoleucel. Of these pts, 59% were male, 87.5% had synovial sarcoma, the median age was 43 yrs (range: 24–73), and they had a median of 3 prior systemic lines of therapy. The MAGE-A4 antigen expression level (histoscore) ranged from 112–300, and the transduced cell dose ranged from 2.7–9.9 x 109. At the data cutoff, 25 pts were evaluable for preliminary efficacy (23 with synovial sarcoma and 2 with MRCLS) and 7 pts (5 with synovial sarcoma and 2 with MRCLS) had insufficient follow-up (30% pts) were neutropenia, lymphopenia, nausea, cytokine release syndrome, leukopenia, fatigue, pyrexia, and anemia. Cytokine release syndrome of any grade occurred in 19/32 pts; 95% of those events were ≤Grade 2. No immune effector cell-associated neurotoxicity syndrome (ICANS) has been reported to date. Cytopenia (≥G3) at 4 wks post-infusion was observed in 6 pts (anemia 3 pts, neutropenia 2 pts, and thrombocytopenia 1 pt). Conclusion: These preliminary data demonstrate afamitresgene autoleucel is efficacious and well tolerated in heavily pre-treated pts. Objective responses are reported across a wide range of MAGE-A4 antigen levels and deep responses have been observed. Initial durability data is encouraging. Preliminary response data in SPEARHEAD-1 is comparable to the findings of the prior Phase 1 trial [1]. To date, the safety profile of afamitresgene autoleucel has been favorable, with mainly low-grade cytokine release syndrome and tolerable/reversible hematologic toxicities. [1]. Van Tine BA, et al. CTOS; November 18-21, 2020; Virtual. Clinical trial information: NCT04044768.
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- 2021
32. The vitamin D receptor is involved in the regulation of human breast cancer cell growth via a ligand-independent function in cytoplasm
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Sutha John, Suzanne Schillo, Colin R. Dunstan, Hong Zhou, Yu Zheng, Theresa A. Guise, Pierrick G.J. Fournier, Khalid S. Mohammad, Sreemala Murthy, Trupti Trivedi, and Markus J. Seibel
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0301 basic medicine ,Cytoplasm ,Gene Expression ,Apoptosis ,vitamin D ,Ligands ,Calcitriol receptor ,Mice ,0302 clinical medicine ,polycyclic compounds ,bone metastasis ,Gene knockdown ,digestive, oral, and skin physiology ,Bone metastasis ,3. Good health ,Protein Transport ,Oncology ,Gene Knockdown Techniques ,030220 oncology & carcinogenesis ,Heterografts ,lipids (amino acids, peptides, and proteins) ,Female ,Signal transduction ,Osteosclerosis ,Research Paper ,musculoskeletal diseases ,medicine.medical_specialty ,ligand independent ,Bone Neoplasms ,Breast Neoplasms ,03 medical and health sciences ,breast cancer ,Cell Line, Tumor ,Internal medicine ,medicine ,Vitamin D and neurology ,Animals ,Humans ,vitamin D receptor ,Cell Proliferation ,business.industry ,Cell growth ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Mutation ,Cancer cell ,Cancer research ,Receptors, Calcitriol ,business - Abstract
// Trupti Trivedi 1, 2 , Yu Zheng 1 , Pierrick G.J. Fournier 2, 5 , Sreemala Murthy 2 , Sutha John 2 , Suzanne Schillo 1 , Colin R. Dunstan 3 , Khalid S. Mohammad 2 , Hong Zhou 1 , Markus J. Seibel 1, 4 , Theresa A. Guise 2 1 Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia 2 Division of Endocrinology, Department of Medicine, Indiana University-Purdue University at Indianapolis, Indianapolis, Indiana, USA 3 Department of Biomedical Engineering, University of Sydney, Sydney, Australia 4 Department of Endocrinology and Metabolism, Concord Hospital, Concord, Sydney, Australia 5 Biomedical Innovation Department, Scientific Research and High Education Center from Ensenada (CICESE), Ensenada, Baja California, Mexico Correspondence to: Theresa A. Guise, email: tguise@iu.edu Markus J. Seibel, email: markus.seibel@sydney.edu.au Keywords: breast cancer, vitamin D, vitamin D receptor, ligand independent, bone metastasis Received: November 04, 2016 Accepted: February 15, 2017 Published: March 01, 2017 ABSTRACT Vitamin D has pleiotropic effects on multiple tissues, including malignant tumors. Vitamin D inhibits breast cancer growth through activation of the vitamin D receptor (VDR) and via classical nuclear signaling pathways. Here, we demonstrate that the VDR can also function in the absence of its ligand to control behaviour of human breast cancer cells both outside and within the bone microenvironment. Stable shRNA expression was used to knock down VDR expression in MCF-7 cells, generating two VDR knockdown clonal lines. In ligand-free culture, knockdown of VDR in MCF-7 cells significantly reduced proliferation and increased apoptosis, suggesting that the VDR plays a ligand-independent role in cancer cell growth. Implantation of these VDR knockdown cells into the mammary fat pad of nude mice resulted in reduced tumor growth in vivo compared with controls. In the intra-tibial xenograft model, VDR knockdown greatly reduced the ability of the cells to form tumors in the bone microenvironment. The in vitro growth of VDR knockdown cells was rescued by the expression of a mutant form of VDR which is unable to translocate to the nucleus and hence accumulates in the cytoplasm. Thus, our data indicate that in the absence of ligand, the VDR promotes breast cancer growth both in vitro and in vivo and that cytoplasmic accumulation of VDR is sufficient to produce this effect in vitro . This new mechanism of VDR action in breast cancer cells contrasts the known anti-proliferative nuclear actions of the VDR-vitamin D ligand complex.
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- 2017
33. The Role of TGFβ in Bone-Muscle Crosstalk
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Jenna N. Regan, Trupti Trivedi, David L. Waning, and Theresa A. Guise
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0301 basic medicine ,medicine.medical_specialty ,Anabolism ,Endocrinology, Diabetes and Metabolism ,Skeletal muscle weakness ,Osteoporosis ,Bone Neoplasms ,030209 endocrinology & metabolism ,medicine.disease_cause ,Bone and Bones ,Article ,Cachexia ,03 medical and health sciences ,0302 clinical medicine ,Transforming Growth Factor beta ,Internal medicine ,medicine ,Humans ,Muscle, Skeletal ,Pathological ,Muscle Weakness ,business.industry ,Skeletal muscle ,medicine.disease ,Oxidative Stress ,Crosstalk (biology) ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Cancer research ,business ,Oxidative stress ,Signal Transduction - Abstract
PURPOSE OF REVIEW: The role of bone-derived factors in regulation of skeletal muscle function is an important emerging aspect of research into bone-muscle crosstalk. Implications for this area of research are far reaching and include understanding skeletal muscle weakness in cancer, osteoporosis, cachexia, rare diseases of bone, and aging. RECENT FINDINGS: Recent research shows that bone-derived factors can lead to changes in the skeletal muscle. These changes can either be anabolic or catabolic, and we focus this review on the role of TGFβ in driving oxidative stress and skeletal muscle weakness in the setting of osteolytic cancer in the bone. SUMMARY: The bone is a preferred site for breast cancer metastasis and leads to pathological bone loss. Osteolytic cancer in the bone leads to release of TGFβ from the bone via osteoclast-mediated bone destruction. Our appreciation of crosstalk between the muscle and bone has recently expanded beyond mechanical force-driven events to encompass a variety of signaling factors originating in one tissue and communicating to the other. This review summarizes some previously known mediators of bone-to-muscle signaling and also recent work identifying a new role for bone-derived TGFβ as a cause of skeletal muscle weakness in the setting of osteolytic cancer in the bone. Multiple points of potential therapeutic intervention are discussed.
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- 2017
34. Impact of a Long-Term High Fat Diet on Bone Microarchitecture and Muscle Structure in Adult Male and Female Normal Mice
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Sutha John, Gabriel M. Pagnotti, Yun She, Weston He, Trupti Trivedi, Jack Truitt, Khalid S. Mohammad, Sreemala Murthy, and Theresa A. Guise
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Bone mineral ,medicine.medical_specialty ,Medullary cavity ,business.industry ,Muscle weakness ,Ocean Engineering ,Histology ,medicine.disease ,Endocrinology ,medicine.anatomical_structure ,Insulin resistance ,Osteoclast ,Internal medicine ,Cohort ,medicine ,Myocyte ,medicine.symptom ,business - Abstract
Background and Hypothesis: Hyperglycemia is a major source of disease and morbidity among the adult population. Prior studies correlate long-term high fat diet (HFD) mediated hyperglycemia with bone fragility and muscle weakness. Furthermore, the mechanism driving hyperglycemia between sexes are unknown. Our group previously showed that HFDs induced insulin resistance in male mice and glucose intolerance in female mice. This establishes the need to study the impact of long-term HFDs on the bones and muscles using an older cohort of both male and female mice. For that, we hypothesized a long-term HFD mediated hyperglycemia will change bone and muscle structures and impair their functions in adult male and female mice. Experimental Design or Project Methods: 22-week C57Bl6 mice were fed either a HFD or low fat diet (LFD) for 25 weeks. After euthanasia, bones and muscles were harvested and evaluated using MicroCT, histology, and mechanical testing. Statistical analysis was performed using GraphPad Prism with p
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- 2019
35. Pulmonary Renal Syndrome: Experience from Tertiary Centre in Mumbai
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Yojana, Gokhale, Raosaheb, Rathod, Trupti, Trivedi, N T, Awadh, Utkarsh, Deshmukh, Lalana, Jadhav, and Amol, Pawar
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Lung Diseases ,Glomerulonephritis ,Anti-Glomerular Basement Membrane Disease ,Humans ,India ,Hemorrhage ,Prospective Studies ,Churg-Strauss Syndrome ,Retrospective Studies - Abstract
Pulmonary Renal Syndrome (PRS), is characterized by diffuse alveolar haemorrhage (DAH) and glomerulonephritis (GN), occurring simultaneously. It has high mortality and dialysis dependence at one year, if not timely diagnosed and aggressively treated.To study etiology and short term outcome of PRS in India.This study included patients of PRS seen in a tertiary care center in Mumbai, by one consultant from 1997- 2013, analyzed retrospectively and from January 2014 to December 2015 collected prospectively from six medical units, intensive care unit, nephrology and respiratory units. Patients with DAH (haemoptysis, breathlessness and x-ray chest with bilateral alveolar shadows with sparing of apices) and glomerulonephritis (Proteinuria, heamaturia, hypertension with or without raised serum Creatinine) were included in the study after carefully excluding other causes of haemoptysis and breathless like tuberculosis, pulmonary oedema, pneumonia, ARDS. During prospective enrollment of patients, in all admitted patients with haemoptysis, urine examination was carried out to specifically look for proteinuria and red blood cells in urine, same was also followed in those admitted for breathlessness with chest x-ray suggestive of alveolar haemorrhage. Patients were extensively investigated for etiology and were treated with steroids and pulse cyclophosphamide (after ruling out infectious etiology). Supportive care with ventilator or dialysis was given as per usual indications. Palsmapheresis was initiated in those with serum Creatinine ≥ 5.7mg/dl. Rituximab was used in refractory cases, as per treating physicians' choice. Final outcome was death or discharge.There were 25 patients of PRS (13 retrospective, 12 prospective), with following etiology : Granulomatosis with polyangiitis (GPA) 7, Microscopic polyangiitis (MPO) 4, Churg Strauss Syndrome (EGPA) 1, Goodpasture's syndrome 1, lupus 5, leptospirosis 5, dengue 2. All were given steroids, 18 (72%) were given pulse Cyclophosphamide (barring those with leptospirosis and dengue), ventilator support in 14 (56%) patients (8 invasive, 6 non-invasive), haemodialysis 3, plasmapheresis 1, Rituximab 2. Seventeen (68%) patients survived, mortality was high in those requiring invasive ventilator.Most common etiology of PRS is ANCA positive vasculitis in India. With high degree of suspicion for DAH in patients presenting with haemoptysis, breathlessness and alveolar opacities in chest x-ray and carefully investigating by simple urine examination for evidence of GN, timely diagnosis of PRS can be made. With timely appropriate treatment survival is 68%. Patients with PRS due to leptospirosis or dengue have features suggestive of underlying disease (like icterus with raised bilirubin but200U SGOT/SGPT, subconjunctival haemorrhage, typical rash of dengue with thrombocytopenia).
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- 2019
36. MOESM3 of Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma
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Ramachandran, Indu, Lowther, Daniel, Dryer-Minnerly, Rebecca, Ruoxi Wang, Fayngerts, Svetlana, Nunez, Daniel, Betts, Gareth, Bath, Natalie, Tipping, Alex, Melchiori, Luca, Jean-Marc Navenot, Glod, John, Mackall, Crystal, DâAngelo, Sandra, Dejka Araujo, Chow, Warren, Demetri, George, Druta, Mihaela, Tine, Brian, Grupp, Stephan, Albiruni Abdul Razak, Breelyn Wilky, Iyengar, Malini, Trupti Trivedi, Winkle, Erin, Chagin, Karen, Amado, Rafael, Binder, Gwendolyn, and Samik Basu
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sense organs - Abstract
Additional file 3: Figure S2. Change in antigen expression at progression. NY-ESO-1 protein expression H-scores as determined by IHC in pre-infusion and post-progression biopsies from all patients whose progression biopsies were evaluable (NÂ =â 15). Paired Mann-Whitney U statistical test was used to evaluate changes between pre-infusion and progression time points.
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- 2019
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37. Impact of excess TGFβ on bone and muscle in condition of diet-induced obesity in mice with Camurati-Engelmann Disease
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Theresa A. Guise, Khalid M. Mohammad, Trupti Trivedi, Asma S. Bahrami, and Gabriel M. Pagnotti
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medicine.medical_specialty ,Endocrinology ,business.industry ,Internal medicine ,Medicine ,Ocean Engineering ,Camurati–Engelmann disease ,business ,medicine.disease ,Obesity - Abstract
Background and Hypothesis: Camurati-Engelmann Disease (CED) is characterized by extreme bone turnover and excess TGF-β release. We previously showed that bone-derived TGF-β causes glucose intolerance, increases skeletal muscle weakness, and exacerbates diet-induced obesity in CED mice. However, it is unknown whether glucose intolerance and obesity alter bone and muscle phenotypes. Thus, we hypothesized that impaired glucose metabolism and diet-induced obesity exacerbate bone and muscle loss in a mouse model of CED. Experimental Design: 45-week WT and CED mice were fed either high-fat diet (HFD) or low-fat diet (LFD) for 15 weeks. Ex vivo bone micro-CT and histomorphometry were used to evaluate bone and muscle. Statistical analysis was performed using GraphPad Prism with p
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- 2018
38. 976TiP SPEARHEAD-2 trial design: A phase II pilot trial of ADP-A2M4 in combination with pembrolizumab in patients with recurrent or metastatic head and neck cancer
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Trupti Trivedi, D Williams, Prakash Neupane, Rom Leidner, N. Hyland, S Biswas, P Savvides, Ezra E.W. Cohen, Lara Dunn, M Dudley, M. K. Gibson, and Elliot Norry
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Head and neck cancer ,Pilot trial ,medicine ,In patient ,Hematology ,Pembrolizumab ,medicine.disease ,business - Published
- 2020
39. Data from the third dose cohort of an ongoing study with ADP-A2AFP SPEAR T cells
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Bruno Sangro, Mitesh J. Borad, Petr F. Hausner, Tim Meyer, Amit Mahipal, Lipika Goyal, Matthew J. Frigault, Debashis Sarker, Lynn G. Feun, Kit Wong, Anthony El-Khoureiry, Richard Finn, Ahmed Kaseb, Benjamin R. Tan, Fiona Thistlethwaite, Bassel El-Rayes, Jordi Bruix, Joana Senra, Trupti Trivedi, Paula Fracasso, Svetlana Fayngerts, Erica Elefant, Jennifer Sampson, Swethajit Biswas, and Elliot Norry
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Hepatology - Published
- 2020
40. Phase I dose escalation and expansion trial to assess the safety and efficacy of ADP-A2M4 SPEAR T cells in advanced solid tumors
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Melissa Lynne Johnson, Rebecca Dryer-Minnerly, Trupti Trivedi, Elliot Norry, Indu R. Ramachandran, Marcus O. Butler, Dennis Williams, Brian A. Van Tine, David A. Liebner, Anthony J. Olszanski, Paula M. Fracasso, David S. Hong, Jean-Marc Navenot, Erica Elefant, and Quan Lin
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Cancer Research ,Cell cycle checkpoint ,Cell growth ,business.industry ,Cancer ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,Antigen ,Apoptosis ,030220 oncology & carcinogenesis ,Dose escalation ,Cancer research ,Medicine ,business ,030215 immunology - Abstract
102 Background: MAGE-A4 is a cancer/testis antigen with expression in many solid tumors promoting cell growth by preventing cell cycle arrest and apoptosis. This study (NCT03132922) evaluated safety and efficacy of SPEAR T-cells directed against the MAGE-A4 peptide expressed in 9 tumor types. Methods: This Phase I dose-escalation, expansion trial evaluated patients (pt) who were HLA-A*02 positive with advanced cancers that expressed the MAGE-A4 protein. Autologous T-cells from eligible patients were isolated, transduced with a lentiviral vector containing the MAGE-A4c1032 TCR, and expanded. Prior to ADP-A2M4 infusion, pts received a lymphodepletion regimen of cyclophosphamide and fludarabine. Cohorts 1, 2, 3, and expansion were to receive transduced cell doses of up to: 0.12 × 109, 1.2 × 109, 6 × 109, and 10 x 109, respectively. Results: As of 23 October 2019, 9 pts were treated in dose escalation with no DLTs; 25 pts were treated in expansion. Median age was 56.5 yr (range: 31-78). All pts received prior chemotherapy. Most common ( > 30%) AEs ≥Grade 3 were lymphopenia, leukopenia, neutropenia, anemia, thrombocytopenia, and febrile neutropenia. Two pts had trial-related deaths (aplastic anemia and CVA) leading to modification of the lymphodepletion regimen and eligibility criteria. In Cohort 3/expansion (28 pts), Best Overall Response was PR (7), SD (11), PD (5), non-evaluable (5). All PRs, at the time of data cut-off, were in patients with synovial sarcoma. Transduced T-cells were detectable in all patients. Tumor infiltration of SPEAR T-cells was detectable in several cohort 3/expansion pts. Conclusions: The Phase I single agent ADP-A2M4 trial will complete enrollment shortly and updated data will be presented. ADP-A2M4 shows promising efficacy and a manageable safety profile at a dose range of 1.2 – 10 × 109. Clinical activity in various tumors has led to a separate on-going low dose radiation sub-study of this trial, a Phase II trial in sarcoma (SPEARHEAD-1, NCT04044768), and a Phase I trial (SURPASS, NCT04044859) with ADP-A2M4CD8, a next-generation SPEAR T-cell targeting MAGE-A4. Clinical trial information: NCT03132922.
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- 2020
41. Mortality in Malaria: Intensive Care (MIMIC)
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Trupti, Trivedi, Poonam, Bajaj, Nivedita, Moulick, and Namita, Padwal
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Critical Care ,Plasmodium falciparum ,Malaria, Vivax ,Humans ,Malaria, Falciparum ,Plasmodium vivax ,Malaria - Abstract
While global incidence of malaria has fallen in last decade, it continues to be an important cause of mortality and morbidity in acutely ill febrile patients. Many patients with complicated malaria require ICU care. In past it was believed that vivax is a benign form of malaria, but now all complications of malaria are reported in vivax. .1. To find out proportion of patients with plasmodium vivax and plasmodium falciparum malaria requiring treatment in Medical ICU. 2. To compare clinical profile and severity of illness in these patients. 3. To study treatment received including organ support requirement in these patients and compare outcome in patients with vivax and falciparum malaria.During study period total 932 patients were diagnosed as confirmed malaria (601 vivax, 240 falciparum and 91 mixed) and 107 (vivax 74, falciparum 20, mixed 13) required ICU admission. Common symptoms observed apart from fever were, oliguria (48), dyspnea(41), bleeding (29), hemoptysis (15) and petechial rash (13). Mean BUN and creatinine and PT INR of falciparum/mixed malaria patients was significantly higher and HCO3 and pH significantly lower than vivax patients. But PaO2/FiO2 of vivax patient was significantly lower as compared falciparum/mixed patients. There was no significant difference between two groups with regards to requirement of supportive treatment like inotropes (11/70 vs 5/30, p=0.858), mechanical ventilation (28/70 vs 7/30, p=0.17), platelet transfusion (24/70 vs 9/30, p=0.853) and renal replacement therapy (5/70 vs 3/30 p=0.936). Out of 100 patients, 21 patients expired. Mortality in mixed malaria group (4/12, 33.3%) and vivax group ( 16/70, 22.9%) was more as compared to falciparum group (1/18, 5.6%,0.05).Incidence of Plasmodium vivax malaria is higher compared to falciparum malaria in hospitalized patients and higher percentage of these need ICU care. Most common complications of malaria are thrombocytopenia followed by renal failure, hepatic dysfunction, ARDS, shock and cerebral dysfunction respectively. Mortality was higher in vivax and mixed malaria compared to falciparum. Higher SOFA score (Sequential organ failure assessment score), lower GCS score (Glasgow coma scale), hypotension, ARDS and metabolic acidosis are predictors of mortality.
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- 2018
42. Snake Bite Envenomation in a Tertiary Care Centre
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Rupal, Padhiyar, Swati, Chavan, Swapnil, Dhampalwar, Trupti, Trivedi, and Nivedita, Moulick
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Adult ,Male ,Antivenins ,India ,Snake Bites ,Prognosis ,Tertiary Care Centers ,Young Adult ,Cross-Sectional Studies ,Animals ,Humans ,Female ,Prospective Studies ,Snake Venoms - Abstract
In India, it is estimated that up to 20,000 people die annually from snake bites. The present study was carried to out to estimate the snake bite related epidemiology, predictors of severity, relationship between type of snake, clinical severity, complications, outcome and usage pattern of polyvalent anti snake venom (ASV) in a tertiary care center.All indoor patients admitted in our institute with definitive history of bite by a snake, with or without presence of fang marks, Evidence of cellulitis, acute onset of neurotoxicity or bleeding diathesis were serially recruited in the study.The majority of cases were in the range of 21- 40 years (54.7%). There were 82.8% males (53/64), 17.2% females (11/64) and 60.9% (39/64) bites were during day time. Upper limb bites were seen in 34% (22/64) of the patients and lower limb bites in 54% (35/64), and axial body bites in 6%. There were 43.8% (28/64) vasculotoxic bites, 34.4% (22/64) neurotoxic bites and 20.3% (14/64) non-poisonous bites. Viper was the most common (9%) identified snake, followed by krait (5%). References from Rural Health Centers were 57.8% (57/64), 11% were from Primary health centers and rest from private sector. Anti snake venom (ASV) was received by 68.75% (44/64) patients before reaching tertiary care. Local swelling was present in 90.6% (58/64) patients, Systemic bleeding was seen in 35.9% (23/64), and Neuromuscular weakness in 35.9% (23/64) patients. Complications like Respiratory paralysis developed in 18.75% (12/64), Acute kidney injury in 12% (8/64), DIC in 9% (6/64), and hepatic involvement in 7% (5/64) of snake bite patients. Blood transfusion was required in 20.3% (13/64) p0.001), 18.75% (12/64) required Mechanical ventilation (p=0.001), 4 received hemodailysis and 4 required ionotropic support (p0.001). Improvement was seen in 57.8% (37/64), morbidity during hospital stay was seen in 39% (25/64) and 2 patients expired (3%). ASV was received within 4 hours in 67% (42/64) patients, 22.5% (14/64) received ASV between 4 to 24 hours and remaining after 24 hours (p=0.016). Total ASV requierment was 24.05 vials in patients who improved and 34.4vials in patients in Morbid group and 29.0 vials in mortality group (p0.05). The SSS score amongst improved was 4.76 ± 2.46 whereas among morbid, it was 8.48 ± 1.75 and amongst expired, it was 8.5 ± 0.707 (p0.05).Patients requiring various supportive treatments like blood transfusion, Inotropes, Haemodialysis and Mechanical ventilation, had a statistically significant correlation with poor outcome. Early administration of ASV that is within 4 hours was, associated with better outcome. The total amount of ASV (in vials) had no a significant correlation with outcome. Snakebite Severity Score correlates significantly with early recovery in vasculotoxic snake bites (p=0.03).
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- 2018
43. ADP-A2M4 (MAGE-A4) in patients with synovial sarcoma
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David S. Hong, F. Brophy, Kunle Odunsi, Melissa Lynne Johnson, Jeffrey M. Clarke, Trupti Trivedi, Anthony J. Olszanski, David A. Liebner, B.A. Van Tine, Marcus O. Butler, Tom Holdich, Rafael G. Amado, Dejka M. Araujo, and Samik Basu
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0301 basic medicine ,Antitumor activity ,Genetically engineered ,business.industry ,Stock options ,Context (language use) ,Hematology ,Expansion phase ,Peripheral blood ,Management ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Dose escalation ,Medicine ,In patient ,business - Abstract
Background This study (NCT03132922) evaluates safety, tolerability, and antitumor activity of ADP-A2M4, genetically engineered autologous specific peptide enhanced affinity receptor (SPEAR) T-cells directed towards a MAGE-A4 peptide expressed in the context of HLA-A*02. Here, we report on a subset of patients (pts) with synovial sarcoma (SS). Methods In this first-in-human T-cell dose-escalation study, pts who are HLA-A*02+ (excluding *02:05, *02:07), have inoperable or metastatic MAGE-A4+ disease, and meet entry criteria are eligible for treatment. Following apheresis, T-cells are isolated, transduced with MAGE-A4c1032TCR, and expanded. The lymphodepletion chemotherapy increased in intensity as the study progressed, with max dose of 30mg/m2/d fludarabine x 4 d and 1800mg/m2/d cyclophosphamide x 2 d. During dose escalation, 3 pts with various tumor types received 0.1x109 (±20%), 1x109 (range: 0.5 – 1.2 × 109), or 5x109 (range: 1.2 – 6 × 109) transduced cells and were monitored for dose-limiting toxicities (DLTs). During expansion, 30 pts (not only SS) will be treated with 1.2 – 10x109 transduced cells. Disease is assessed per RECIST by CT/MRI at wk 6, 12, 18, and 24, and every 3mo for 2yr, then every 6mo or until progression. Correlative studies will investigate transduced cell persistence, phenotype, and function, and serum and tumor microenvironment factors. Results No DLTs were reported. ADP-A2M4 was well tolerated, with adverse events consistent with chemotherapy or other immunotherapies. 10 pts with SS have been treated in cohort 3 and the expansion phase (30Apr19). Median T-cell dose was 9.7x109 (4.49 - 9.98x109). 8 pts have post-baseline tumor assessments. There are 3 confirmed partial responses (PR) (-86%, -44%, -54), and 1 unconfirmed PR (-31%) at wk 6. Best response was stable disease in 3 pts (-27% and -15%, ongoing, and +12%, progressed) and progressive disease in 1. 2 pts have yet to be assessed. Ex vivo analysis of transduced cells from peripheral blood and tumor showed cells were cytolytic and activated in an antigen-specific manner. Conclusions ADP-A2M4 induced clinical responses in pts with SS. Transduced T-cells expand upon exposure to antigen and are functional. Updated data from this ongoing study will be presented. Clinical trial identification NCT03132922, First posted on April 28, 2017. Editorial acknowledgement Debra Brocksmith, MB ChB, PhD, of Envision Pharma Group; contracted by Adaptimmune. Legal entity responsible for the study Adaptimmune. Funding Adaptimmune. Disclosure B.A. Van Tine: Research grant / Funding (self): Pfizer; Research grant / Funding (self): Tracon; Research grant / Funding (self): Merck; Advisory / Consultancy: Epizyme; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy: CytRX; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy: Immune Design; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Plexxicon; Advisory / Consultancy: Adaptimmune; Speaker Bureau / Expert testimony: Caris. M.O. Butler: Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Merck; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self): Roche; Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: GSK; Advisory / Consultancy: Immunocore; Advisory / Consultancy: Immunovaccine; Research grant / Funding (institution): Takara Bio. M.L. Johnson: Research grant / Funding (institution): BerGenBio; Research grant / Funding (institution): Lilly; Research grant / Funding (institution), Travel / Accommodation / Expenses: EMD Serono; Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): Genmab; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Additional travel from: Astellas, AstraZeneca, Boehringer Ingelheim, Clovis, Daiichi Sankyo, Bristol-Myers Squibb, Exelixis, Incyte, Merck, Sysmex Inostics, Vapotherm: Genentech; Research grant / Funding (institution): Stemcentrix; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Checkpoint Therapeutics; Research grant / Funding (institution): Array Biopharma; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Apexigen; Research grant / Funding (institution), Travel / Accommodation / Expenses: AbbVie; Research grant / Funding (institution): Tarveda; Research grant / Funding (institution): Adaptimmune; Research grant / Funding (institution), Additional advisory for: Gelgene, Boehringer Ingelheim, Sanofi, LOXO, Calithera, Merck, Araxes Pharma, Mersana Therapeutics, BeiGene, Incyte, Guardant Health, Bristol-Myers Squibb, Ribon Therapeutics: Syndax; Research grant / Funding (institution), Additional grant funding from: Boehringer Ingelheim, Sanofi, Hengrui Therapuetics INC, Merck, Daiichi-Sankyo, Lycera, G1 Therapeutics, Dynavax, LOXO, Cytomx, BeiGene, Birdie, Corvus, Incyte, Genocea, Gritstone, Amgen, Bristol-Myers Squibb, Kadmon, Clovis, Acerta, OncoMed, Guardant Health, Takeda, Shattuck Labs, GSK: Neovia. J. Clarke: Research grant / Funding (self): MedPacto; Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Eli Lilly; Research grant / Funding (self): Genentech; Research grant / Funding (self): Spectrum; Research grant / Funding (self): Adaptimmune; Research grant / Funding (self): Bayer; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Moderna; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: Guardant; Advisory / Consultancy: AstraZeneca. D. Liebner: Advisory / Consultancy: Foundation Medicine; Advisory / Consultancy: Blueprint Medicines. K. Odunsi: Research grant / Funding (self): ITeos Therapeutics. A.J. Olszanski: Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy: Merck; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Array; Advisory / Consultancy, Research grant / Funding (self): EMD Serono; Advisory / Consultancy: Iovance; Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (self): Alkermes; Research grant / Funding (self): Adaptimmune; Research grant / Funding (self): Astellas; Research grant / Funding (self): Boston Biomedical; Research grant / Funding (self): Checkmate Pharmaceutics; Research grant / Funding (self): GSK; Research grant / Funding (self): Immunocore; Research grant / Funding (self): Intensity Therapeutics; Research grant / Funding (self): Kartos; Research grant / Funding (self): Kura; Research grant / Funding (self): Oncoceutics; Research grant / Funding (self): Targovax. S. Basu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Adaptimmune. F. Brophy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Adaptimmune. T. Holdich: Shareholder / Stockholder / Stock options, Full / Part-time employment: Adaptimmune. T. Trivedi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Adaptimmune. R.G. Amado: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Adaptimmune. D.S. Hong: Research grant / Funding (self): AbbVie; Advisory / Consultancy, Research grant / Funding (self): Adaptimmune; Research grant / Funding (self): Amgen; Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Bayer; Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): Daiichi-Sankyo; Research grant / Funding (self): Eisai; Research grant / Funding (self): Fate Therapeutics; Advisory / Consultancy, Research grant / Funding (self): Genentech; Research grant / Funding (self), Travel / Accommodation / Expenses: Genmab; Research grant / Funding (self): Ignyta; Advisory / Consultancy, Research grant / Funding (self): Infinity; Research grant / Funding (self): Kite; Research grant / Funding (self): Kyowa; Research grant / Funding (self): Lilly; Research grant / Funding (self), Travel / Accommodation / Expenses: LOXO; Research grant / Funding (self): MedImmune; Research grant / Funding (self): Merck; Research grant / Funding (self), Additional grant funding from: miRNA, Molecular Templates, Mologen, NCI-CTEP, Novartics, Pfizer, Seattle Genetics, Takeda. Additional advisory consulting for: Alpha Insights, Axiom, Baxter, GLG, Group H, Guidepoint Global, Merrimack, Medscape, Numab, Pfizer, Seattle Genetics, Takeda, Trieza Therapeutics, WebMD; Travel support from MiRNA, AACR, ASCO, SITC; ownership interests in Molecular Match, OncoResponse, Presagia Inc: Mirati. All other authors have declared no conflicts of interest.
- Published
- 2019
44. Antitumor Activity Associated with Prolonged Persistence of Adoptively Transferred NY-ESO-1
- Author
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Sandra P, D'Angelo, Luca, Melchiori, Melinda S, Merchant, Donna, Bernstein, John, Glod, Rosandra, Kaplan, Stephan, Grupp, William D, Tap, Karen, Chagin, Gwendolyn K, Binder, Samik, Basu, Daniel E, Lowther, Ruoxi, Wang, Natalie, Bath, Alex, Tipping, Gareth, Betts, Indu, Ramachandran, Jean-Marc, Navenot, Hua, Zhang, Daniel K, Wells, Erin, Van Winkle, Gabor, Kari, Trupti, Trivedi, Tom, Holdich, Lini, Pandite, Rafael, Amado, and Crystal L, Mackall
- Subjects
Adult ,Male ,T-Lymphocytes ,Receptors, Antigen, T-Cell ,Membrane Proteins ,Pilot Projects ,CD8-Positive T-Lymphocytes ,Middle Aged ,Adoptive Transfer ,Sarcoma, Synovial ,Young Adult ,Treatment Outcome ,Antigens, Neoplasm ,Humans ,Female ,Neoplasm Metastasis - Abstract
We evaluated the safety and activity of autologous T cells expressing NY-ESO-1
- Published
- 2017
45. Clinical Evaluation of Pazopanib Eye Drops versus Ranibizumab Intravitreal Injections in Subjects with Neovascular Age-Related Macular Degeneration
- Author
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Michael Fries, Deborah S. Kelly, Ronald P. Danis, John I. Wurzelmann, Trupti Trivedi, Chun-Fang Xu, Pravin U. Dugel, Amy J. Pierce, Karl G. Csaky, and Mohammad Hossain
- Subjects
Male ,medicine.medical_specialty ,Indazoles ,Visual acuity ,genetic structures ,medicine.medical_treatment ,Visual Acuity ,Angiogenesis Inhibitors ,Antibodies, Monoclonal, Humanized ,Placebo ,Pazopanib ,Double-Blind Method ,Ranibizumab ,Ophthalmology ,medicine ,Humans ,Fluorescein Angiography ,Aged ,Sulfonamides ,medicine.diagnostic_test ,business.industry ,Eye drop ,Macular degeneration ,Fluorescein angiography ,medicine.disease ,eye diseases ,Neoplasm Proteins ,Surgery ,Pyrimidines ,Receptors, Vascular Endothelial Growth Factor ,Choroidal neovascularization ,Pharmacogenetics ,Intravitreal Injections ,Wet Macular Degeneration ,Female ,sense organs ,Ophthalmic Solutions ,medicine.symptom ,business ,Biomarkers ,Tomography, Optical Coherence ,medicine.drug - Abstract
Purpose To evaluate pazopanib eye drops in subjects with active subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). Design Multicountry, randomized, parallel-group, double-masked, active and placebo-controlled, dose-ranging study of eye drops. Participants A total of 510 subjects (93% white; 58% female; mean age, 75.3 years) whose AMD was previously managed by anti–vascular endothelial growth factor intravitreal injections. Methods Treatments administered for 52 weeks included placebo eye drops instilled 4 times daily (n = 73); pazopanib 5 mg/ml instilled 3 (n = 72) or 4 times daily (n = 74); pazopanib 10 mg/ml instilled 2 (n = 73), 3 (n = 73), or 4 times daily (n = 72); or ranibizumab injection administered once every 4 weeks (n = 73). In addition, for all eye drop treatment groups, open-label ranibizumab was administered as needed. Main Outcome Measures The main outcome measures were best-corrected visual acuity (BCVA) and injection frequency assessed at week 52. Safety was assessed every 4 weeks and pazopanib plasma concentrations were determined at weeks 4 and 24. Results At week 52, pazopanib, with allowance for as-needed ranibizumab injections, was noninferior to monthly ranibizumab as well as to as-needed ranibizumab administered with placebo eye drops in maintaining BCVA (estimated BCVA gains of 0.3–1.8 vs. 1.4 vs. 0.2 letters, respectively). Pazopanib treatment did not reduce as-needed ranibizumab injections by ≥50% (prespecified efficacy criterion). At week 52, there were no clinically meaningful changes from baseline in retinal thickness or morphology, CNV size, or lesion characteristics on optical coherence tomography or fluorescein angiography. Complement factor H genotype had no effect on the responses to pazopanib and/or ranibizumab (BCVA, injection rate, or optical coherence tomography/fluorescein angiography changes). Steady-state concentrations of pazopanib in plasma seemed to be reached by week 4. The most common ocular adverse events related to pazopanib and ranibizumab were application site pain (3%) and injection site hemorrhage (1%), respectively. No treatment-related serious adverse events were reported. Conclusions Pazopanib was well tolerated. Daily pazopanib eye drops in neovascular AMD subjects did not result in therapeutic benefit beyond that obtained with ranibizumab alone.
- Published
- 2015
46. Loss of the vitamin D receptor in human breast and prostate cancers strongly induces cell apoptosis through downregulation of Wnt/β-catenin signaling
- Author
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Hong Zhou, Yu Zheng, Konstantin Horas, Musharraf Hossain, Ruby C.Y. Lin, Colette Fong-Yee, Colin R. Dunstan, Jeline Manibo, Rick Nolte, Yunzhao Chen, Markus J. Seibel, and Trupti Trivedi
- Subjects
0301 basic medicine ,Gene knockdown ,Histology ,Physiology ,Chemistry ,Cell growth ,Endocrinology, Diabetes and Metabolism ,Wnt signaling pathway ,medicine.disease ,Calcitriol receptor ,Article ,03 medical and health sciences ,Prostate cancer ,030104 developmental biology ,0302 clinical medicine ,Cyclin D1 ,Downregulation and upregulation ,030220 oncology & carcinogenesis ,Cancer research ,medicine ,Signal transduction - Abstract
Vitamin D co-regulates cell proliferation, differentiation and apoptosis in numerous tissues, including cancers. The known anti-proliferative and pro-apoptotic actions of the active metabolite of vitamin D, 1,25-dihydroxy-vitamin D [1,25(OH)2D] are mediated through binding to the vitamin D receptor (VDR). Here, we report on the unexpected finding that stable knockdown of VDR expression in the human breast and prostate cancer cell lines, MDA-MB-231 and PC3, strongly induces cell apoptosis and inhibits cell proliferation in vitro. Implantation of these VDR knockdown cells into the mammary fat pad (MDA-MB-231), subcutaneously (PC3) or intra-tibially (both cell lines) in immune-incompetent nude mice resulted in reduced tumor growth associated with increased apoptosis and reduced cell proliferation compared with controls. These growth-retarding effects of VDR knockdown occur in the presence and absence of vitamin D and are independent of whether cells were grown in bone or soft tissues. Transcriptome analysis of VDR knockdown and non-target control cell lines demonstrated that loss of the VDR was associated with significant attenuation in the Wnt/β-catenin signaling pathway. In particular, cytoplasmic and nuclear β-catenin protein levels were reduced with a corresponding downregulation of downstream genes such as Axin2, Cyclin D1, interleukin-6 (IL-6), and IL-8. Stabilization of β-catenin using the GSK-3β inhibitor BIO partly reversed the growth-retarding effects of VDR knockdown. Our results indicate that the unliganded VDR possesses hitherto unknown functions to promote breast and prostate cancer growth, which appear to be operational not only within but also outside the bone environment. These novel functions contrast with the known anti-proliferative nuclear actions of the liganded VDR and may represent targets for new diagnostic and therapeutic approaches in breast and prostate cancer.
- Published
- 2017
47. CLINICAL EVALUATION OF PAZOPANIB EYE DROPS IN HEALTHY SUBJECTS AND IN SUBJECTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION
- Author
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Trupti Trivedi, Rishi Singh, Linda S. Henderson, Li Ye, John I. Wurzelmann, Mohammad Hossain, and Deborah S. Kelly
- Subjects
Adult ,Male ,medicine.medical_specialty ,Indazoles ,genetic structures ,Administration, Topical ,Visual Acuity ,Biological Availability ,Angiogenesis Inhibitors ,Single Center ,Retina ,law.invention ,Pazopanib ,Young Adult ,Double-Blind Method ,Randomized controlled trial ,law ,Ophthalmology ,medicine ,Humans ,Tissue Distribution ,Young adult ,Aged ,Aged, 80 and over ,Sulfonamides ,business.industry ,Healthy subjects ,General Medicine ,Middle Aged ,Protein-Tyrosine Kinases ,Macular degeneration ,medicine.disease ,Healthy Volunteers ,eye diseases ,Clinical trial ,Pyrimidines ,Receptors, Vascular Endothelial Growth Factor ,Choroidal neovascularization ,Wet Macular Degeneration ,Female ,sense organs ,Ophthalmic Solutions ,medicine.symptom ,business ,medicine.drug - Abstract
To evaluate pazopanib 10 mg/mL eye drops (pazopanib) in healthy subjects and in subjects with previously untreated subfoveal choroidal neovascularization secondary to age-related macular degeneration.Study 1 (single center, randomized, placebo-controlled, double-masked) included 3 cohorts of 12 to 13 healthy subjects each who instilled pazopanib or placebo 4 times daily for 2 weeks. Study 2 (multicenter open-label) included 19 subjects with neovascular age-related macular degeneration who instilled pazopanib 4 times daily for 12 weeks. Both studies evaluated pharmacokinetics and safety. Study 2 also evaluated efficacy.Steady-state concentrations of pazopanib in plasma seemed to be reached by Week 2. At Week 4 (Study 2), there were no meaningful changes from baseline in the mean central retinal thickness (37.9 μm) or best-corrected visual acuity (0.1 letters) (primary endpoint), retinal morphology, choroidal neovascularization size, or total lesion size. Complement Factor H genotype had no effect on changes from baseline in the best-corrected visual acuity or central retinal thickness. The most common pazopanib-related ocular adverse events included eye irritation (Study 1, n = 7) and instillation site pain (Study 2, n = 3). No serious adverse events were reported.Pazopanib was well tolerated. In subjects with previously untreated neovascular age-related macular degeneration, pazopanib instilled 4 times daily as monothereapy did not seem to improve the best-corrected visual acuity or decrease the central retinal thickness.
- Published
- 2014
48. Direct Crosstalk Between Cancer and Osteoblast Lineage Cells Fuels Metastatic Growth in Bone via Auto-Amplification of IL-6 and RANKL Signaling Pathways
- Author
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Hong Zhou, Katja Boernert, Colin R. Dunstan, Yu Zheng, Colette Fong-Yee, Trupti Trivedi, Frank Buttgereit, Sarah Kim, Markus J. Seibel, Shu Oi Chow, Robert L. Sutherland, Dennis Basel, and Anastasia Mikuscheva
- Subjects
medicine.medical_specialty ,biology ,Chemistry ,Endocrinology, Diabetes and Metabolism ,Bone metastasis ,Osteoblast ,medicine.disease ,Breast cancer ,Endocrinology ,medicine.anatomical_structure ,Cancer stem cell ,RANKL ,Internal medicine ,Cancer cell ,Bone cell ,medicine ,biology.protein ,Cancer research ,Orthopedics and Sports Medicine ,Signal transduction - Abstract
The bone microenvironment and its modification by cancer and host cell interactions is a key driver of skeletal metastatic growth. Interleukin-6 (IL-6) stimulates receptor activator of NF-κB ligand (RANKL) expression in bone cells, and serum IL-6 levels are associated with poor clinical outcomes in cancer patients. We investigated the effects of RANKL on cancer cells and the role of tumor-derived IL-6 within the bone microenvironment. Using human breast cancer cell lines to induce tumors in the bone of immune-deficient mice, we first determined whether RANKL released by cells of the osteoblast lineage directly promotes IL-6 expression by cancer cells in vitro and in vivo. We then disrupted of IL-6 signaling in vivo either via knockdown of IL-6 in tumor cells or through treatment with specific anti-human or anti-mouse IL-6 receptor antibodies to investigate the tumor effect. Finally, we tested the effect of RANK knockdown in cancer cells on cancer growth. We demonstrate that osteoblast lineage-derived RANKL upregulates secretion of IL-6 by breast cancers in vivo and in vitro. IL-6, in turn, induces expression of RANK by cancer cells, which sensitizes the tumor to RANKL and significantly enhances cancer IL-6 release. Disruption in vivo of this auto-amplifying crosstalk by knockdown of IL-6 or RANK in cancer cells, or via treatment with anti-IL-6 receptor antibodies, significantly reduces tumor growth in bone but not in soft tissues. RANKL and IL-6 mediate direct paracrine-autocrine signaling between cells of the osteoblast lineage and cancer cells, significantly enhancing the growth of metastatic breast cancers within bone.
- Published
- 2014
49. Abstract A007: Comparison of pretreatment conditioning on efficacy in two cohorts of a pilot study of genetically engineered NY-ESO-1c259T-cells in patients with synovial sarcoma
- Author
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Alibiruni Abdul Razak, Brian A. Van Tine, George D. Demetri, Dejka M. Araujo, Rafael G. Amado, Samik Basu, Erin Van Winkle, John Glod, S. Grupp, Trupti Trivedi, Malini Iyengar, Karen Chagin, Crystal L. Mackall, Warren Chow, Sandra P. D'Angelo, William D. Tap, Breelyn A. Wilky, Mihaela Dutra, and Elliott Norry
- Subjects
Oncology ,Cancer Research ,Chemotherapy ,medicine.medical_specialty ,Cyclophosphamide ,business.industry ,medicine.medical_treatment ,Immunology ,Fludarabine ,Clinical trial ,Regimen ,Tolerability ,Internal medicine ,Cohort ,medicine ,Adverse effect ,business ,medicine.drug - Abstract
Background: NY-ESO-1c259T-cells recognizing an NY-ESO-1 derived peptide complexed with HLA-A*02 (SPEAR T-cells) are being studied in an ongoing multi-cohort clinical trial in synovial sarcoma (NCT01343043). We compared safety, efficacy and cell persistence between two cohorts using different doses of lymphodepleting chemotherapy. Methods: There are four cohorts separated by differing antigen expression levels and lymphodepletion regimens, and this assessment compares cohorts 1 (closed) and 4 (ongoing). In both, ≥50% patient tumor cells expressed NY-ESO-1 at 2+/3+ levels by immunohistochemistry. Following apheresis, T-cells are isolated, activated, transduced to express NY-ESO-1c259T and expanded. Lymphodepletion in cohort 1 consists of fludarabine 30 mg/m2/d × 4 d and cyclophosphamide 1800 mg/m2/d × 2d, and in cohort 4 consists of fludarabine 30 mg/m2/d × 3d and cyclophosphamide 600 mg/m2/d × 3d. Target dose is 1–6 × 109 transduced cells. Disease is assessed at weeks 4, 8 and 12 and every 3 months until disease progression. Results: 12 patients were treated in cohort 1 and 14 patients in cohort 4 (as of 23Nov17). Median transduced cell dose was 3.6 × 109 cells in cohort 1 and 2.6 × 109 cells in cohort 4. Treatment-related adverse events (AEs) were observed in 100% of patients in cohort 1 and 86% in cohort 4; related serious adverse events (SAEs) were reported in 50% of cohort 1 and 14% of cohort 4. There were no fatal AEs. Overall response rate (ORR) in cohort 4 is 29% vs 50% in cohort 1, and duration of response is in cohort 4 is 16 weeks vs 31 weeks in cohort 1. The best overall response of stable is 50% in cohort 1 and 64% in cohort 4. Median peak expansion of transduced T-cells in peripheral blood in responders is lower in cohort 4 (40,137 copies/μg DNA) vs cohort 1 (106,174 copies/μg DNA). Median absolute lymphocyte counts following lymphodepletion were 1×107/L (range 0-3) in cohort 1 and 9×107/L (0-40) in cohort 4. Conclusions: The greater ORR and higher peak expansion in cohort 1 may be attributable to the dose intensity of the lymphodepleting regimen. Although related SAEs were reported in a higher proportion in cohort 1 than 4, the safety and tolerability are acceptable in both, and cell doses were similar. The data and overall benefit:risk considerations support utilizing higher doses of preconditioning chemotherapy in future trials. Citation Format: Sandra P. D'Angelo, Dejka Araujo, Brian Van Tine, George Demetri, Mihaela Dutra, John Glod, Warren Chow, Stephen Grupp, Alibiruni Abdul Razak, William Tap, Breelyn Wilky, Erin Van Winkle, Elliott Norry, Samik Basu, Karen Chagin, Malini Iyengar, Trupti Trivedi, Rafael Amado, Crystal Mackall. Comparison of pretreatment conditioning on efficacy in two cohorts of a pilot study of genetically engineered NY-ESO-1c259T-cells in patients with synovial sarcoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A007.
- Published
- 2019
50. Abstract A002: Autologous Tcells transduced with the affinity enhanced NY-ESO-1c259TCR in patients with synovial sarcoma expressing low levels of the NY-ESO-1 antigen
- Author
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Sandra P. D'Angelo, Rachel Abbott, Rafael G. Amado, Erin Van Winkle, Dejka M. Araujo, Warren Chow, Andrew B. Gerry, Malini Iyengar, Miguel Maroto, Mihaela Druta, William D. Tap, John Glod, Elliot Norry, Karen Chagin, Joana Senra, Crystal L. Mackall, George D. Demetri, and Trupti Trivedi
- Subjects
Cancer Research ,business.industry ,Microgram ,Immunology ,T-cell receptor ,Human leukocyte antigen ,medicine.disease ,Molecular biology ,Synovial sarcoma ,Antigen ,In vivo ,Medicine ,Immunohistochemistry ,NY-ESO-1 ,business - Abstract
Background: NY-ESO-1c259 is an affinity optimized TCR recognizing an NY-ESO-1-derived peptide complexed with HLA-A*02 (SPEAR T-cells). NY-ESO-1c259TCR therapy induced responses in ~50% of patients whose tumors express high level NY-ESO-1 (NCT01343043). Here we report on preclinical studies of TCR activity and results from a cohort of patients whose tumors express low NY-ESO-1 levels. Methods: T-cell response against tumor-derived cell lines with differential NY-ESO-1 expression levels was assessed by ELISA. Patients had selected HLA subtypes (HLA-A*02:01, 02:05, 02:06) and advanced NY-ESO-1+ SS. In this cohort, tumors express NY-ESO-1 at ≥ 1+ in > 1% but < 2+ or 3+ in ≥ 50% cells by immunohistochemistry (IHC). Following apheresis, T-cells are isolated, activated, transduced to express NY-ESO-1c259T and expanded. Lymphodepletion is with fludarabine 30 mg/m2/d × 4d and cyclophosphamide 1800 mg/m2/d × 2d. Target dose is 1–6 × 10e9 transduced cells. Disease is assessed at weeks 4, 8 and 12 and then every 3 months until disease progression. Results: NY-ESO-1c259T-cells produce IFNγ responses across a spectrum of NY-ESO-1 expressing tumor cell lines. A threshold for activation was observed at ~1×10e4 mRNA copies/10e6 reference gene transcripts. The IHC clinical trial assay was tested in FFPE tumor-derived cell lines, and staining was observed in cell lines expressing >1×10e4 mRNA copies/10e6 reference gene transcripts. Ten patients in this cohort have been treated (as of 23Nov17). One died due to disease progression 2 days post infusion. Four have had a partial response (ORR 40%), and median duration of response was 8.5 weeks (range, 8-13). Antigen expression level by IHC (% 1+, 2+, and/or 3+), best overall response (BOR) by RECIST v1.1, and transduced cell expansion (copies/microgram DNA) are listed below for the 9 evaluable patients: Pt 264, 30% 1+/2+, PR, 86320; Pt 313, 90% 1+, PR, 45430; Pt 325, 10% 2+, PR, 13365; Pt 331, 40% 1+, 10% 2+, 10% 3+, PR, 197546; Pt 324, 50% 1+, 10% 2+, SD, 133334; Pt 305, 5% 1+, 5% 2+, 5% 3+, SD, 74855; Pt 322, 50% 1+, 10% 2+, SD, 54569; Pt 323, 20% 1+, 10% 2+, SD, 50912; Pt 211, 10% 1+, 20% 2+, 20% 3+, PD, 22627. Conclusions: In vitro assays can assess mRNA levels and protein expression of target antigen required for T-cell activation and cytotoxicity, predicting expression levels required for anti-tumor activity in vivo. The patient data suggest that affinity optimized TCRs can be used to treat tumors with low target antigen expression. Citation Format: Dejka Araujo, Sandra D'Angelo, George Demetri, Mihaela Druta, John Glod, Warren Chow, William Tap, Joana Senra, Rachel Abbott, Erin Van Winkle, Karen Chagin, Miguel Maroto, Elliot Norry, Malini Iyengar, Trupti Trivedi, Andrew Gerry, Rafael Amado, Crystal Mackall. Autologous Tcells transduced with the affinity enhanced NY-ESO-1c259TCR in patients with synovial sarcoma expressing low levels of the NY-ESO-1 antigen [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A002.
- Published
- 2019
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