361 results on '"Daud, Adil I."'
Search Results
2. Phase 1 study of the pan-RAF inhibitor tovorafenib in patients with advanced solid tumors followed by dose expansion in patients with metastatic melanoma.
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Rasco, Drew W, Medina, Theresa, Corrie, Pippa, Pavlick, Anna C, Middleton, Mark R, Lorigan, Paul, Hebert, Chris, Plummer, Ruth, Larkin, James, Agarwala, Sanjiv S, Daud, Adil I, Qiu, Jiaheng, Bozon, Viviana, Kneissl, Michelle, Barry, Elly, and Olszanski, Anthony J
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Humans ,Neoplasms ,Melanoma ,Skin Neoplasms ,Neoplasms ,Second Primary ,Proto-Oncogene Proteins B-raf ,Mitogen-Activated Protein Kinase Kinases ,Protein Kinase Inhibitors ,Maximum Tolerated Dose ,Adult ,BRAF ,Pan-RAF inhibitor ,Phase 1 ,Tovorafenib ,Clinical Trials and Supportive Activities ,Clinical Research ,Cancer ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Pharmacology and Pharmaceutical Sciences ,Oncology & Carcinogenesis - Abstract
PurposeGenomic alterations of BRAF and NRAS are oncogenic drivers in malignant melanoma and other solid tumors. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan‑RAF inhibitor. This first-in-human phase 1 study explored the safety and antitumor activity of tovorafenib.MethodsThis two-part study in adult patients with relapsed or refractory advanced solid tumors included a dose escalation phase and a dose expansion phase including molecularly defined cohorts of patients with melanoma. Primary objectives were to evaluate the safety of tovorafenib administered once every other day (Q2D) or once weekly (QW), and to determine the maximum-tolerated and recommended phase 2 dose (RP2D) on these schedules. Secondary objectives included evaluation of antitumor activity and tovorafenib pharmacokinetics.ResultsTovorafenib was administered to 149 patients (Q2D n = 110, QW n = 39). The RP2D of tovorafenib was defined as 200 mg Q2D or 600 mg QW. In the dose expansion phase, 58 (73%) of 80 patients in Q2D cohorts and 9 (47%) of 19 in the QW cohort had grade ≥ 3 adverse events. The most common of these overall were anemia (14 patients, 14%) and maculo-papular rash (8 patients, 8%). Responses were seen in 10 (15%) of 68 evaluable patients in the Q2D expansion phase, including in 8 of 16 (50%) patients with BRAF mutation-positive melanoma naïve to RAF and MEK inhibitors. In the QW dose expansion phase, there were no responses in 17 evaluable patients with NRAS mutation-positive melanoma naïve to RAF and MEK inhibitors; 9 patients (53%) had a best response of stable disease. QW dose administration was associated with minimal accumulation of tovorafenib in systemic circulation in the dose range of 400-800 mg.ConclusionsThe safety profile of both schedules was acceptable, with QW dosing at the RP2D of 600 mg QW preferred for future clinical studies. Antitumor activity of tovorafenib in BRAF-mutated melanoma was promising and justifies continued clinical development across multiple settings.ClinicaltrialsGov identifierNCT01425008.
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- 2023
3. Phase II trial of pembrolizumab, ipilimumab, and aspirin in melanoma: clinical outcomes and translational predictors of response
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Quandt, Zoe, Jacob, Saya, Fadlullah, Muhammad Zaki Hidayatullah, Wu, Chaorong, Wu, Clinton, Huppert, Laura, Levine, Lauren S., Sison, Paula, Tsai, Katy K., Chow, Melissa, Kang, Jee Hye, Hwang, Jimmy, Lee, James C., Oglesby, Ariel, Venegas, Jessica, Brintz, Ben J., Tan, Aik Choon, Anderson, Mark S., Rosenblum, Michael D., Young, Arabella, and Daud, Adil I.
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- 2024
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4. Metastatic melanoma to small bowel: metastasectomy is supported in the era of immunotherapy and checkpoint inhibitors
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Wong, Paul, Wisneski, Andrew D., Tsai, Katy K., Chang, Tammy T., Hirose, Kenzo, Nakakura, Eric K., Daud, Adil I., Maker, Ajay V., and Corvera, Carlos U.
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- 2024
- Full Text
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5. Intratumoral therapies and in-situ vaccination for melanoma
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Huppert, Laura A and Daud, Adil I
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Cancer ,Immunization ,Biotechnology ,Vaccine Related ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Cancer Vaccines ,Humans ,Immunotherapy ,Injections ,Intralesional ,Melanoma ,Tumor Microenvironment ,Vaccination ,Intratumoral ,intralesional ,melanoma ,in situ vaccination ,Immunology ,Medical Microbiology ,Pharmacology and Pharmaceutical Sciences ,Virology - Abstract
Skin cancers are among the most physically accessible malignancies, so local delivery of a medication into the tumor, so-called intratumoral therapy, is an appealing route of drug administration. Intratumoral therapies have the potential to increase local drug concentration and/or attract immune cells to the local tumor microenvironment, possibly with fewer systemic side effects. A wide array of intratumoral agents have been studied to date in patients with advanced melanoma, including chemotherapeutic drugs, immune modulating agents, and cancer-directed vaccines. In this review, we will summarize the key pre-clinical and clinical data supporting the use of intratumoral therapy for advanced unresectable and metastatic melanoma. First, we will discuss the history of intratumoral immunotherapy for the treatment of melanoma and the various agents studied to date. Second, we will explore how intratumoral therapies can constitute an in situ vaccine, potentially leading to disease control both locally and systemically. Finally, we will highlight opportunities in the field and key future directions.
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- 2022
6. TCR-sequencing in cancer and autoimmunity: barcodes and beyond
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Pauken, Kristen E, Lagattuta, Kaitlyn A, Lu, Benjamin Y, Lucca, Liliana E, Daud, Adil I, Hafler, David A, Kluger, Harriet M, Raychaudhuri, Soumya, and Sharpe, Arlene H
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Cancer ,Genetics ,Generic health relevance ,Inflammatory and immune system ,Autoimmunity ,Humans ,Neoplasms ,Receptors ,Antigen ,T-Cell ,T-Lymphocytes ,PD-1 immunotherapy ,T cell ,TCR sequencing ,cancer ,molecular barcode ,single cell sequencing ,Immunology - Abstract
The T cell receptor (TCR) endows T cells with antigen specificity and is central to nearly all aspects of T cell function. Each naïve T cell has a unique TCR sequence that is stably maintained during cell division. In this way, the TCR serves as a molecular barcode that tracks processes such as migration, differentiation, and proliferation of T cells. Recent technological advances have enabled sequencing of the TCR from single cells alongside deep molecular phenotypes on an unprecedented scale. In this review, we discuss strengths and limitations of TCR sequences as molecular barcodes and their application to study immune responses following Programmed Death-1 (PD-1) blockade in cancer. Additionally, we consider applications of TCR data beyond use as a barcode.
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- 2022
7. The Liver–Immunity Nexus and Cancer Immunotherapy
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Lee, James C, Green, Michael D, Huppert, Laura A, Chow, Christine, Pierce, Robert H, and Daud, Adil I
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Lung Cancer ,Immunization ,Liver Disease ,Rare Diseases ,Vaccine Related ,Digestive Diseases ,Cancer ,Lung ,Animals ,B7-H1 Antigen ,CD8-Positive T-Lymphocytes ,Carcinoma ,Non-Small-Cell Lung ,Humans ,Immunotherapy ,Liver ,Lung Neoplasms ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
The impact of liver metastases on immune checkpoint-inhibitor effectiveness in patients with solid-tumor malignancies has been the focus of several recent clinical and translational studies. We review the literature describing the immune functions of the liver and particularly the mechanistic observations in these studies. The initial clinical observation was that pembrolizumab appeared to be much less effective in melanoma and non-small cell lung cancer (NSCLC) patients with liver metastasis. Subsequently other clinical studies have extended and reported similar findings with programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) inhibitors in many cancers. Two recent translational studies in animal models have dissected the mechanism of this systemic immune suppression. In both studies CD11b+ suppressive macrophages generated by liver metastasis in a two-site MC38 model appear to delete CD8+ T cells in a FasL-dependent manner. In addition, regulatory T-cell (Treg) activation was observed and contributed to the distal immunosuppression. Finally, we discuss some of the interventions reported to address liver immune suppression, such as radiation therapy, combination checkpoint blockade, and Treg depletion.
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- 2022
8. Discovering dominant tumor immune archetypes in a pan-cancer census
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Combes, Alexis J, Samad, Bushra, Tsui, Jessica, Chew, Nayvin W, Yan, Peter, Reeder, Gabriella C, Kushnoor, Divyashree, Shen, Alan, Davidson, Brittany, Barczak, Andrea J, Adkisson, Michael, Edwards, Austin, Naser, Mohammad, Barry, Kevin C, Courau, Tristan, Hammoudi, Taymour, Argüello, Rafael J, Rao, Arjun Arkal, Olshen, Adam B, Consortium, The Immunoprofiler, Spitzer, Matthew, Fong, Lawrence, Nelson, Amanda, Kumar, Raj, Lee, Justin, Burra, Arun, Hsu, Joy, Hackett, Caroline, Tolentino, Karen, Sjarif, Jasmine, Johnson, Peter, Shao, Evans, Abrau, Darrell, Lupin, Leonard, Shaw, Cole, Collins, Zachary, Lea, Tasha, Corvera, Carlos, Nakakura, Eric, Carnevale, Julia, Alvarado, Michael, Loo, Kimberley, Chen, Lawrence, Chow, Melissa, Grandis, Jennifer, Ryan, Will, El-Sayed, Ivan, Jablons, David, Woodard, Gavitt, Meng, Maxwell W, Porten, Sima P, Okada, Hideho, Tempero, Margaret, Ko, Andrew, Kirkwood, Kim, Vandenberg, Scott, Guevarra, Denise, Oropeza, Erica, Cyr, Chris, Glenn, Pat, Bolen, Jennifer, Morton, Amanda, Eckalbar, Walter, Cai, Cathy, Zhan, Jenny, Davis, Katelyn C, Kelley, Robin K, Chapman, Jocelyn S, Atreya, Chloe E, Patel, Amar, Daud, Adil I, Ha, Patrick, Diaz, Aaron A, Kratz, Johannes R, Collisson, Eric A, Fragiadakis, Gabriela K, Erle, David J, Boissonnas, Alexandre, Asthana, Saurabh, Chan, Vincent, and Krummel, Matthew F
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Genetics ,Cancer ,Cancer Genomics ,Human Genome ,Biomarkers ,Tumor ,Censuses ,Cluster Analysis ,Cohort Studies ,Computational Biology ,Flow Cytometry ,Gene Expression Regulation ,Neoplastic ,Humans ,Neoplasms ,RNA-Seq ,San Francisco ,Transcriptome ,Tumor Microenvironment ,Universities ,Immunoprofiler Consortium ,Pan Cancer analysis ,immune profiling ,solid tumor microenvironement ,system immunology ,tumor immunology ,unsupervised clustering ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
Cancers display significant heterogeneity with respect to tissue of origin, driver mutations, and other features of the surrounding tissue. It is likely that individual tumors engage common patterns of the immune system-here "archetypes"-creating prototypical non-destructive tumor immune microenvironments (TMEs) and modulating tumor-targeting. To discover the dominant immune system archetypes, the University of California, San Francisco (UCSF) Immunoprofiler Initiative (IPI) processed 364 individual tumors across 12 cancer types using standardized protocols. Computational clustering of flow cytometry and transcriptomic data obtained from cell sub-compartments uncovered dominant patterns of immune composition across cancers. These archetypes were profound insofar as they also differentiated tumors based upon unique immune and tumor gene-expression patterns. They also partitioned well-established classifications of tumor biology. The IPI resource provides a template for understanding cancer immunity as a collection of dominant patterns of immune organization and provides a rational path forward to learn how to modulate these to improve therapy.
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- 2022
9. Tissue-specific Tregs in cancer metastasis: opportunities for precision immunotherapy.
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Huppert, Laura A, Green, Michael D, Kim, Luke, Chow, Christine, Leyfman, Yan, Daud, Adil I, and Lee, James C
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Humans ,Neoplasms ,Immunotherapy ,Autoimmunity ,Immune Tolerance ,T-Lymphocytes ,Regulatory ,Cancer ,Metastasis ,Organ-specific tolerance ,Tissue Tregs ,Vaccine Related ,Immunization ,Inflammatory and immune system ,Biochemistry and Cell Biology ,Immunology - Abstract
Decades of advancements in immuno-oncology have enabled the development of current immunotherapies, which provide long-term treatment responses in certain metastatic cancer patients. However, cures remain infrequent, and most patients ultimately succumb to treatment-refractory metastatic disease. Recent insights suggest that tumors at certain organ sites exhibit distinctive response patterns to immunotherapy and can even reduce antitumor immunity within anatomically distant tumors, suggesting the activation of tissue-specific immune tolerogenic mechanisms in some cases of therapy resistance. Specialized immune cells known as regulatory T cells (Tregs) are present within all tissues in the body and coordinate the suppression of excessive immune activation to curb autoimmunity and maintain immune homeostasis. Despite the high volume of research on Tregs, the findings have failed to reconcile tissue-specific Treg functions in organs, such as tolerance, tissue repair, and regeneration, with their suppression of local and systemic tumor immunity in the context of immunotherapy resistance. To improve the understanding of how the tissue-specific functions of Tregs impact cancer immunotherapy, we review the specialized role of Tregs in clinically common and challenging organ sites of cancer metastasis, highlight research that describes Treg impacts on tissue-specific and systemic immune regulation in the context of immunotherapy, and summarize ongoing work reporting clinically feasible strategies that combine the specific targeting of Tregs with systemic cancer immunotherapy. Improved knowledge of Tregs in the framework of their tissue-specific biology and clinical sites of organ metastasis will enable more precise targeting of immunotherapy and have profound implications for treating patients with metastatic cancer.
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- 2022
10. Current Role and Status for Intratumoral Injection Therapies in Metastatic Melanoma
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Haugh, Alexandra M. and Daud, Adil I.
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- 2024
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11. Pembrolizumab and Ipilimumab as Second-Line Therapy for Advanced Melanoma
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Huppert, Laura A and Daud, Adil I
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Antibodies ,Monoclonal ,Humanized ,Humans ,Ipilimumab ,Melanoma ,Clinical Sciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Published
- 2021
12. Single-cell analyses identify circulating anti-tumor CD8 T cells and markers for their enrichment
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Pauken, Kristen E, Shahid, Osmaan, Lagattuta, Kaitlyn A, Mahuron, Kelly M, Luber, Jacob M, Lowe, Margaret M, Huang, Linglin, Delaney, Conor, Long, Jaclyn M, Fung, Megan E, Newcomer, Kathleen, Tsai, Katy K, Chow, Melissa, Guinn, Samantha, Kuchroo, Juhi R, Burke, Kelly P, Schenkel, Jason M, Rosenblum, Michael D, Daud, Adil I, Sharpe, Arlene H, and Singer, Meromit
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Cancer ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Adenocarcinoma ,Animals ,Biomarkers ,Tumor ,CD8-Positive T-Lymphocytes ,Cell Line ,Tumor ,Colonic Neoplasms ,Female ,Humans ,Melanoma ,Mice ,Mice ,Inbred C57BL ,Programmed Cell Death 1 Receptor ,Receptors ,Antigen ,T-Cell ,Single-Cell Analysis ,Skin Neoplasms ,Transcriptome ,Medical and Health Sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
The ability to monitor anti-tumor CD8+ T cell responses in the blood has tremendous therapeutic potential. Here, we used paired single-cell RNA and TCR sequencing to detect and characterize "tumor-matching" (TM) CD8+ T cells in the blood of mice with MC38 tumors or melanoma patients using the TCR as a molecular barcode. TM cells showed increased activation compared with nonmatching T cells in blood and were less exhausted than matching cells in tumors. Importantly, PD-1, which has been used to identify putative circulating anti-tumor CD8+ T cells, showed poor sensitivity for identifying TM cells. By leveraging the transcriptome, we identified candidate cell surface markers for TM cells in mice and patients and validated NKG2D, CD39, and CX3CR1 in mice. These data show that the TCR can be used to identify tumor-relevant cells for characterization, reveal unique transcriptional properties of TM cells, and develop marker panels for tracking and analysis of these cells.
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- 2021
13. Long-term safety of pembrolizumab monotherapy and relationship with clinical outcome: A landmark analysis in patients with advanced melanoma
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Robert, Caroline, Hwu, Wen-Jen, Hamid, Omid, Ribas, Antoni, Weber, Jeffrey S, Daud, Adil I, Hodi, F Stephen, Wolchok, Jedd D, Mitchell, Tara C, Hersey, Peter, Dronca, Roxana, Joseph, Richard W, Boutros, Celine, Min, Le, Long, Georgina V, Schachter, Jacob, Puzanov, Igor, Dummer, Reinhard, Lin, Jianxin, Ibrahim, Nageatte, Diede, Scott J, Carlino, Matteo S, and Joshua, Anthony M
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Cancer ,Vaccine Related ,Immunization ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Adult ,Aged ,Aged ,80 and over ,Antibodies ,Monoclonal ,Humanized ,Antineoplastic Agents ,Immunological ,Clinical Trials as Topic ,Drug-Related Side Effects and Adverse Reactions ,Female ,Follow-Up Studies ,Humans ,Male ,Melanoma ,Meta-Analysis as Topic ,Middle Aged ,Prognosis ,Young Adult ,Pembrolizumab ,Advanced melanoma ,Immune-related adverse events ,Immune-checkpoint inhibitors ,PD-1 inhibitors ,Immunomodulating drugs ,Corticosteroid use ,Oncology and Carcinogenesis ,Public Health and Health Services ,Oncology & Carcinogenesis - Abstract
ObjectiveLong-term safety of pembrolizumab in melanoma was analyzed in KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006.Patients and methodsAnalysis involved patients who received ≥1 pembrolizumab dose. Lead-time bias was addressed via landmark analyses in patients who were progression-free before day 147.ResultsAdverse events (AEs) were analyzed for 1567 patients (median follow-up, 42.4 months). Most AEs were mild/moderate; grade 3/4 treatment-related AEs occurred in 17.7% of patients. Two pembrolizumab-related deaths occurred. Any-grade immune-mediated AEs (imAEs) occurred in 23.0%, most commonly hypothyroidism (9.1%), pneumonitis (3.3%), and hyperthyroidism (3.0%); grade 3/4 imAEs occurred in 6.9% of patients. Most imAEs occurred within 16 weeks of treatment. In landmark analysis, patients who did (n = 79) versus did not (n = 384) develop imAEs had similar objective response rates (ORRs) (64.6% versus 63.0%); median time to response (TTR), 5.6 months for both; median duration of response (DOR), 20.0 versus 25.3 months; median progression-free survival (PFS), 17.0 versus 17.7 months; median overall survival (OS), not reached (NR) versus 43 months (p = 0.1104). Patients who did (n = 17) versus did not (n = 62) receive systemic corticosteroids had similar ORRs (70.6% vs. 62.9%) and median TTR (6.4 vs. 5.6 months) but numerically shorter median PFS (9.9 vs. 17.0 months); median DOR, 14.2 months versus NR; median OS, NR for both.ConclusionsThese results enhance the knowledge base for pembrolizumab in advanced melanoma, with no new toxicity signals after lengthy follow-up of a large population. In landmark analyses, pembrolizumab efficacy was similar regardless of imAEs or systemic corticosteroid use.Clinical trial registryNCT01295827, NCT01704287, NCT01866319.
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- 2021
14. Treatment of Metastatic Melanoma With Leptomeningeal Disease Using Intrathecal Immunotherapy.
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Huppert, Laura A, Melisko, Michelle E, Glastonbury, Christine M, Khanafshar, Elham, and Daud, Adil I
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Humans ,Immunotherapy ,Melanoma ,Meningeal Neoplasms ,Neoplasms ,Second Primary ,Oncology and carcinogenesis - Published
- 2020
15. Continuous versus intermittent BRAF and MEK inhibition in patients with BRAF-mutated melanoma: a randomized phase 2 trial
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Algazi, Alain P, Othus, Megan, Daud, Adil I, Lo, Roger S, Mehnert, Janice M, Truong, Thach-Giao, Conry, Robert, Kendra, Kari, Doolittle, Gary C, Clark, Joseph I, Messino, Michael J, Moore, Dennis F, Lao, Christopher, Faller, Bryan A, Govindarajan, Rangaswamy, Harker-Murray, Amy, Dreisbach, Luke, Moon, James, Grossmann, Kenneth F, and Ribas, Antoni
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Clinical Trials and Supportive Activities ,Clinical Research ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Administration ,Oral ,Adult ,Aged ,Antineoplastic Combined Chemotherapy Protocols ,Drug Administration Schedule ,Female ,Humans ,Imidazoles ,MAP Kinase Kinase Kinases ,Male ,Melanoma ,Middle Aged ,Mutation ,Missense ,Oximes ,Protein Kinase Inhibitors ,Proto-Oncogene Proteins B-raf ,Pyridones ,Pyrimidinones ,Skin Neoplasms ,Survival Analysis ,Treatment Outcome ,Young Adult ,Medical and Health Sciences ,Immunology ,Biomedical and clinical sciences ,Health sciences - Abstract
Preclinical modeling suggests that intermittent BRAF inhibitor therapy may delay acquired resistance when blocking oncogenic BRAFV600 in melanoma1,2. We conducted S1320, a randomized, open-label, phase 2 clinical trial (NCT02196181) evaluating whether intermittent dosing of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib improves progression-free survival in patients with metastatic and unresectable BRAFV600 melanoma. Patients were enrolled at 68 academic and community sites nationally. All patients received continuous dabrafenib and trametinib during an 8-week lead-in period, after which patients with non-progressing tumors were randomized to either continuous or intermittent dosing of both drugs on a 3-week-off, 5-week-on schedule. The trial has completed accrual and 206 patients with similar baseline characteristics were randomized 1:1 to the two study arms (105 to continuous dosing, 101 to intermittent dosing). Continuous dosing yielded a statistically significant improvement in post-randomization progression-free survival compared with intermittent dosing (median 9.0 months versus 5.5 months, P = 0.064, pre-specified two-sided α = 0.2). Therefore, contrary to the initial hypothesis, intermittent dosing did not improve progression-free survival in patients. There were no differences in the secondary outcomes, including overall survival and the overall incidence of treatment-associated toxicity, between the two groups.
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- 2020
16. ASO Author Reflections: Tumor Immune Profiling-Based Neoadjuvant Immunotherapy for Locally Advanced Melanoma
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Mahuron, Kelly M, Levine, Lauren S, and Daud, Adil I
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Good Health and Well Being ,Humans ,Immunotherapy ,Melanoma ,Neoadjuvant Therapy ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Published
- 2020
17. Tumor Immune Profiling-Based Neoadjuvant Immunotherapy for Locally Advanced Melanoma
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Levine, Lauren S, Mahuron, Kelly M, Tsai, Katy K, Wu, Clinton, Mattis, Daiva M, Pauli, Mariela L, Oglesby, Arielle, Lee, James C, Spitzer, Matthew H, Krummel, Matthew F, Algazi, Alain P, Rosenblum, Michael D, Alvarado, Michael, and Daud, Adil I
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Patient Safety ,Cancer ,Immunization ,Clinical Research ,Vaccine Related ,CTLA-4 Antigen ,Humans ,Immune Checkpoint Inhibitors ,Immunotherapy ,Kaplan-Meier Estimate ,Melanoma ,Neoadjuvant Therapy ,Programmed Cell Death 1 Receptor ,Tumor Microenvironment ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundThe frequency of "exhausted" or checkpoint-positive (PD-1+CTLA-4+) cytotoxic lymphocytes (Tex) in the tumor microenvironment is associated with response to anti-PD-1 therapy in metastatic melanoma. The current study determined whether pretreatment Tex cells in locally advanced melanoma predicted response to neoadjuvant anti-PD-1 blockade.MethodsPretreatment tumor samples from 17 patients with locally advanced melanoma underwent flow cytometric analysis of pretreatment Tex and regulatory T cell frequency. Patients who met the criteria for neoadjuvant checkpoint blockade were treated with either PD-1 monotherapy or PD-1/CTLA-4 combination therapy. Best overall response was evaluated by response evaluation criteria in solid tumors version 1.1, with recurrence-free survival (RFS) calculated by the Kaplan-Meier test. The incidence and severity of adverse events were tabulated by clinicians using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.ResultsOf the neoadjuvant treated patients, 10 received anti-PD-1 monotherapy and 7 received anti-CTLA-4/PD-1 combination therapy. Of these 17 patients, 12 achieved a complete response, 4 achieved partial responses, and 1 exhibited stable disease. Surgery was subsequently performed for 11 of the 17 patients, and 8 attained a complete pathologic response. Median RFS and overall survival (OS) were not reached. Immune-related adverse events comprised four grade 3 or 4 events, including pneumonitis, transaminitis, and anaphylaxis.ConclusionThe results showed high rates of objective response, RFS, and OS for patients undergoing immune profile-directed neoadjuvant immunotherapy for locally advanced melanoma. Furthermore, the study showed that treatment stratification based upon Tex frequency can potentially limit the adverse events associated with combination immunotherapy. These data merit further investigation with a larger validation study.
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- 2020
18. Layilin augments integrin activation to promote antitumor immunity
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Mahuron, Kelly M, Moreau, Joshua M, Glasgow, Jeff E, Boda, Devi P, Pauli, Mariela L, Gouirand, Victoire, Panjabi, Luv, Grewal, Robby, Luber, Jacob M, Mathur, Anubhav N, Feldman, Renny M, Shifrut, Eric, Mehta, Pooja, Lowe, Margaret M, Alvarado, Michael D, Marson, Alexander, Singer, Meromit, Wells, Jim, Jupp, Ray, Daud, Adil I, and Rosenblum, Michael D
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Cancer ,Aetiology ,Underpinning research ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Animals ,CD8-Positive T-Lymphocytes ,Carrier Proteins ,Cell Adhesion ,Cell Proliferation ,Clone Cells ,Cytokines ,Cytotoxicity ,Immunologic ,Gene Editing ,Humans ,Immunity ,Integrins ,Lectins ,C-Type ,Lymphocyte Activation ,Lymphocyte Function-Associated Antigen-1 ,Lymphocytes ,Tumor-Infiltrating ,Melanoma ,Membrane Glycoproteins ,Mice ,Inbred C57BL ,Neoplasm Metastasis ,Neoplasms ,Protein Binding ,Talin ,Medical and Health Sciences ,Immunology - Abstract
Tumor-infiltrating CD8+ T cells mediate antitumor immune responses. However, the mechanisms by which T cells remain poised to kill cancer cells despite expressing high levels of inhibitory receptors are unknown. Here, we report that layilin, a C-type lectin domain-containing membrane glycoprotein, is selectively expressed on highly activated, clonally expanded, but phenotypically exhausted CD8+ T cells in human melanoma. Lineage-specific deletion of layilin on murine CD8+ T cells reduced their accumulation in tumors and increased tumor growth in vivo. Congruently, gene editing of LAYN in human CD8+ T cells reduced direct tumor cell killing ex vivo. On a molecular level, layilin colocalized with integrin αLβ2 (LFA-1) on T cells, and cross-linking layilin promoted the activated state of this integrin. Accordingly, LAYN deletion resulted in attenuated LFA-1-dependent cellular adhesion. Collectively, our results identify layilin as part of a molecular pathway in which exhausted or "dysfunctional" CD8+ T cells enhance cellular adhesiveness to maintain their cytotoxic potential.
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- 2020
19. Phase II Trial of IL-12 Plasmid Transfection and PD-1 Blockade in Immunologically Quiescent Melanoma
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Algazi, Alain P, Twitty, Christopher G, Tsai, Katy K, Le, Mai, Pierce, Robert, Browning, Erica, Hermiz, Reneta, Canton, David A, Bannavong, Donna, Oglesby, Arielle, Francisco, Murray, Fong, Lawrence, Pittet, Mikael J, Arlauckas, Sean P, Garris, Christopher, Levine, Lauren P, Bifulco, Carlos, Ballesteros-Merino, Carmen, Bhatia, Shailender, Gargosky, Sharron, Andtbacka, Robert HI, Fox, Bernard A, Rosenblum, Michael D, and Daud, Adil I
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Clinical Research ,Cancer ,Clinical Trials and Supportive Activities ,Adult ,Aged ,Antibodies ,Monoclonal ,Humanized ,Antineoplastic Combined Chemotherapy Protocols ,Case-Control Studies ,Female ,Follow-Up Studies ,Humans ,Interleukin-12 ,Male ,Melanoma ,Middle Aged ,Prognosis ,Programmed Cell Death 1 Receptor ,Prospective Studies ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
PurposeTumors with low frequencies of checkpoint positive tumor-infiltrating lymphocytes (cpTIL) have a low likelihood of response to PD-1 blockade. We conducted a prospective multicenter phase II trial of intratumoral plasmid IL-12 (tavokinogene telseplasmid; "tavo") electroporation combined with pembrolizumab in patients with advanced melanoma with low frequencies of checkpoint positive cytotoxic lymphocytes (cpCTL).Patients and methodsTavo was administered intratumorally days 1, 5, and 8 every 6 weeks while pembrolizumab (200 mg, i.v.) was administered every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST, secondary endpoints included duration of response, overall survival and progression-free survival. Toxicity was evaluated by the CTCAE v4. Extensive correlative analysis was done.ResultsThe combination of tavo and pembrolizumab was well tolerated with adverse events similar to those previously reported with pembrolizumab alone. Patients had a 41% ORR (n = 22, RECIST 1.1) with 36% complete responses. Correlative analysis showed that the combination enhanced immune infiltration and sustained the IL-12/IFNγ feed-forward cycle, driving intratumoral cross-presenting dendritic cell subsets with increased TILs, emerging T cell receptor clones and, ultimately, systemic cellular immune responses.ConclusionsThe combination of tavo and pembrolizumab was associated with a higher than expected response rate in this poorly immunogenic population. No new or unexpected toxicities were observed. Correlative analysis showed T cell infiltration with enhanced immunity paralleling the clinical activity in low cpCTL tumors.
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- 2020
20. Prognostic Biomarkers for Melanoma Immunotherapy
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Twitty, Christopher G, Huppert, Laura A, and Daud, Adil I
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Immunization ,Vaccine Related ,Cancer ,Good Health and Well Being ,Antineoplastic Agents ,B7-H1 Antigen ,Biomarkers ,Tumor ,CTLA-4 Antigen ,Gastrointestinal Microbiome ,Humans ,Immune Checkpoint Inhibitors ,Immunotherapy ,Melanoma ,Prognosis ,Programmed Cell Death 1 Receptor ,T-Lymphocytes ,Tumor Escape ,Tumor Microenvironment ,Immune checkpoint inhibitors ,Programmed death-1 ,Programmed death ligand-1 ,Exhausted T cells ,Tumor microenvironment ,Memory T cells ,Tumor mutation burden ,Circulating tumor DNA ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
Purpose of reviewRecent developments in immunotherapy have transformed the landscape of melanoma therapy. Here, we review markers for response to immunotherapy.Recent findingsCurrent immunotherapies disable immune checkpoints on T cells and other immune cells and allow immune rejection of tumor. This process depends crucially on a preexisting response to the development of the melanoma. Here we describe the complexity of the anti-tumor immune response and the links to the development of markers that are currently used or under investigation in the clinic. We describe immune response biomarkers along with new developments that could translate into advances.
- Published
- 2020
21. Intratumoral Delivery of Plasmid IL12 Via Electroporation Leads to Regression of Injected and Noninjected Tumors in Merkel Cell Carcinoma
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Bhatia, Shailender, Longino, Natalie V, Miller, Natalie J, Kulikauskas, Rima, Iyer, Jayasri G, Ibrani, Dafina, Blom, Astrid, Byrd, David R, Parvathaneni, Upendra, Twitty, Christopher G, Campbell, Jean S, Le, Mai H, Gargosky, Sharron, Pierce, Robert H, Heller, Richard, Daud, Adil I, and Nghiem, Paul
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Biotechnology ,Patient Safety ,Stem Cell Research - Nonembryonic - Non-Human ,Cancer ,Clinical Trials and Supportive Activities ,Rare Diseases ,Stem Cell Research ,Vaccine Related ,Clinical Research ,Aged ,Aged ,80 and over ,CD8-Positive T-Lymphocytes ,Carcinoma ,Merkel Cell ,Cohort Studies ,Electroporation ,Female ,Gene Transfer Techniques ,Humans ,Immunotherapy ,Interleukin-12 ,Male ,Middle Aged ,Neoplasm Metastasis ,Pilot Projects ,Plasmids ,Skin Neoplasms ,Treatment Outcome ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
PurposeIL12 promotes adaptive type I immunity and has demonstrated antitumor efficacy, but systemic administration leads to severe adverse events (AE), including death. This pilot trial investigated safety, efficacy, and immunologic activity of intratumoral delivery of IL12 plasmid DNA (tavo) via in vivo electroporation (i.t.-tavo-EP) in patients with Merkel cell carcinoma (MCC), an aggressive virus-associated skin cancer.Patients and methodsFifteen patients with MCC with superficial injectable tumor(s) received i.t.-tavo-EP on days 1, 5, and 8 of each cycle. Patients with locoregional MCC (cohort A, N = 3) received one cycle before definitive surgery in week 4. Patients with metastatic MCC (cohort B, N = 12) received up to four cycles total, administered at least 6 weeks apart. Serial tumor and blood samples were collected.ResultsAll patients successfully completed at least one cycle with transient, mild (grades 1 and 2) AEs and without significant systemic toxicity. Sustained (day 22) intratumoral expression of IL12 protein was observed along with local inflammation and increased tumor-specific CD8+ T-cell infiltration, which led to systemic immunologic and clinical responses. The overall response rate was 25% (3/12) in cohort B, with 2 patients experiencing durable clinical benefit (16 and 55+ months, respectively). Two cohort A patients (1 with pathologic complete remission) were recurrence-free at 44+ and 75+ months, respectively.ConclusionsI.t.-tavo-EP was safe and feasible without systemic toxicity. Sustained local expression of IL12 protein and local inflammation led to systemic immune responses and clinically meaningful benefit in some patients. Gene electrotransfer, specifically i.t.-tavo-EP, warrants further investigation for immunotherapy of cancer.
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- 2020
22. Intratumoral Plasmid IL12 Electroporation Therapy in Patients with Advanced Melanoma Induces Systemic and Intratumoral T-cell Responses
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Greaney, Samantha K, Algazi, Alain P, Tsai, Katy K, Takamura, Kathryn T, Chen, Lawrence, Twitty, Christopher G, Zhang, Li, Paciorek, Alan, Pierce, Robert H, Le, Mai H, Daud, Adil I, and Fong, Lawrence
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Clinical Trials and Supportive Activities ,Cancer ,Clinical Research ,Inflammatory and immune system ,Adjuvants ,Immunologic ,Antigens ,Neoplasm ,Biomarkers ,CD8-Positive T-Lymphocytes ,Electroporation ,Humans ,Immunity ,Cellular ,Immunotherapy ,Interferon-gamma ,Interleukin-12 ,Melanoma ,Neoplasm Staging ,Patient Safety ,Plasmids ,Skin Neoplasms ,Treatment Outcome ,Tumor Microenvironment ,Immunology ,Oncology and Carcinogenesis ,Pharmacology and Pharmaceutical Sciences - Abstract
Whereas systemic IL12 is associated with potentially life-threatening toxicity, intratumoral delivery of IL12 through tavokinogene telseplasmid electroporation (tavo) is safe and can induce tumor regression at distant sites. The mechanism by which these responses are mediated is unknown but is presumed to result from a cellular immune response. In a phase II clinical trial of tavo (NCT01502293), samples from 29 patients with cutaneous melanoma with in-transit disease were assessed for immune responses induced with this treatment. Within the blood circulating immune cell population, we found that the frequencies of circulating PD-1+ CD4+ and CD8+ T cells declined with treatment. Circulating immune responses to gp100 were also detected following treatment as measured by IFNγ ELISpot. Patients with a greater antigen-specific circulating immune response also had higher numbers of CD8+ T cells within the tumor. Clinical response was also associated with increased intratumoral CD3+ T cells. Finally, intratumoral T-cell clonality and convergence were increased after treatment, indicating a focusing of the T-cell receptor repertoire. These results indicated that local treatment with tavo can induce a systemic T-cell response and recruit T cells to the tumor microenvironment.
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- 2020
23. Immunotherapy in Melanoma and Merkel Cell Cancer
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Chow, Melissa, Sangalang, Elizabeth A., Chow, Christine, Daud, Adil I., Leong, Stanley P., editor, Nathanson, S. David, editor, and Zager, Jonathan S., editor
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- 2022
- Full Text
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24. Unleashing Type-2 Dendritic Cells to Drive Protective Antitumor CD4+ T Cell Immunity
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Binnewies, Mikhail, Mujal, Adriana M, Pollack, Joshua L, Combes, Alexis J, Hardison, Emily A, Barry, Kevin C, Tsui, Jessica, Ruhland, Megan K, Kersten, Kelly, Abushawish, Marwan A, Spasic, Marko, Giurintano, Jonathan P, Chan, Vincent, Daud, Adil I, Ha, Patrick, Ye, Chun J, Roberts, Edward W, and Krummel, Matthew F
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Cancer ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Antigens ,Neoplasm ,CD4-Positive T-Lymphocytes ,Cell Differentiation ,Cell Line ,Tumor ,Cytokines ,Dendritic Cells ,Diphtheria Toxin ,Forkhead Transcription Factors ,Humans ,Lectins ,C-Type ,Lymph Nodes ,Lymphocyte Activation ,Melanoma ,Experimental ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Receptors ,Chemokine ,T-Lymphocytes ,Regulatory ,Tumor Microenvironment ,CD4(+) T cells ,T cell priming ,checkpoint blockade ,dendritic cells ,immunotherapy ,regulatory T cells ,tumor immunology ,tumor microenvironment ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
Differentiation of proinflammatory CD4+ conventional T cells (Tconv) is critical for productive antitumor responses yet their elicitation remains poorly understood. We comprehensively characterized myeloid cells in tumor draining lymph nodes (tdLN) of mice and identified two subsets of conventional type-2 dendritic cells (cDC2) that traffic from tumor to tdLN and present tumor-derived antigens to CD4+ Tconv, but then fail to support antitumor CD4+ Tconv differentiation. Regulatory T cell (Treg) depletion enhanced their capacity to elicit strong CD4+ Tconv responses and ensuing antitumor protection. Analogous cDC2 populations were identified in patients, and as in mice, their abundance relative to Treg predicts protective ICOS+ PD-1lo CD4+ Tconv phenotypes and survival. Further, in melanoma patients with low Treg abundance, intratumoral cDC2 density alone correlates with abundant CD4+ Tconv and with responsiveness to anti-PD-1 therapy. Together, this highlights a pathway that restrains cDC2 and whose reversal enhances CD4+ Tconv abundance and controls tumor growth.
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- 2019
25. Successful Anti-PD-1 Cancer Immunotherapy Requires T Cell-Dendritic Cell Crosstalk Involving the Cytokines IFN-γ and IL-12.
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Garris, Christopher S, Arlauckas, Sean P, Kohler, Rainer H, Trefny, Marcel P, Garren, Seth, Piot, Cécile, Engblom, Camilla, Pfirschke, Christina, Siwicki, Marie, Gungabeesoon, Jeremy, Freeman, Gordon J, Warren, Sarah E, Ong, SuFey, Browning, Erica, Twitty, Christopher G, Pierce, Robert H, Le, Mai H, Algazi, Alain P, Daud, Adil I, Pai, Sara I, Zippelius, Alfred, Weissleder, Ralph, and Pittet, Mikael J
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Dendritic Cells ,T-Lymphocytes ,Animals ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Humans ,Neoplasms ,NF-kappa B ,Interleukin-12 ,Antibodies ,Monoclonal ,Immunotherapy ,Signal Transduction ,Adult ,Aged ,Aged ,80 and over ,Middle Aged ,Female ,Male ,Interferon-gamma ,Programmed Cell Death 1 Receptor ,IFN-γ ,IL-12 ,anti-PD-1 ,cancer ,checkpoint ,dendritic cell ,immunotherapy ,non-canonical NF-κB ,Vaccine Related ,Cancer ,Immunization ,Aetiology ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,Immunology - Abstract
Anti-PD-1 immune checkpoint blockers can induce sustained clinical responses in cancer but how they function in vivo remains incompletely understood. Here, we combined intravital real-time imaging with single-cell RNA sequencing analysis and mouse models to uncover anti-PD-1 pharmacodynamics directly within tumors. We showed that effective antitumor responses required a subset of tumor-infiltrating dendritic cells (DCs), which produced interleukin 12 (IL-12). These DCs did not bind anti-PD-1 but produced IL-12 upon sensing interferon γ (IFN-γ) that was released from neighboring T cells. In turn, DC-derived IL-12 stimulated antitumor T cell immunity. These findings suggest that full-fledged activation of antitumor T cells by anti-PD-1 is not direct, but rather involves T cell:DC crosstalk and is licensed by IFN-γ and IL-12. Furthermore, we found that activating the non-canonical NF-κB transcription factor pathway amplified IL-12-producing DCs and sensitized tumors to anti-PD-1 treatment, suggesting a therapeutic strategy to improve responses to checkpoint blockade.
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- 2018
26. In-field and abscopal response after short-course radiation therapy in patients with metastatic Merkel cell carcinoma progressing on PD-1 checkpoint blockade: a case series
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Xu, Melody J, Wu, Susan, Daud, Adil I, Yu, Siegrid S, and Yom, Sue S
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Immunization ,Cancer ,Vaccine Related ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Aged ,Antibodies ,Monoclonal ,Humanized ,Antineoplastic Agents ,Immunological ,Carcinoma ,Merkel Cell ,Combined Modality Therapy ,Drug Resistance ,Neoplasm ,Humans ,Male ,Positron Emission Tomography Computed Tomography ,Programmed Cell Death 1 Receptor ,Skin Neoplasms ,Treatment Outcome ,Metastatic Merkel cell carcinoma ,Abscopal response ,PD-1 inhibition ,Single-fraction radiation therapy ,Stereotactic body radiation therapy ,Oncology and carcinogenesis - Abstract
BACKGROUND:Patients with metastatic Merkel cell carcinoma (mMCC) who experience disease progression on immunotherapy have limited additional standard options. Given evidence of synergism between radiation therapy (RT) and immunotherapy, two patients progressing on PD-1 inhibition were referred for short-course RT. CASE PRESENTATION:Two patients were found to have progressive mMCC on PD-1 inhibitor therapy and were treated with single-fraction palliative RT. Both patients were observed to have local control at irradiated regions, as well as durable abscopal response at unirradiated, out-of-field, sites of metastatic disease. CONCLUSIONS:Short-course RT is a compelling strategy that could be a means to augment response in patients with mMCC who show progression on immune checkpoint blockade. Ongoing clinical trials are investigating the relationship between RT and immunotherapy in mMCC.
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- 2018
27. Quantitative Spatial Profiling of PD-1/PD-L1 Interaction and HLA-DR/IDO-1 Predicts Improved Outcomes of Anti-PD-1 Therapies in Metastatic Melanoma.
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Johnson, Douglas B, Bordeaux, Jennifer, Kim, Ju Young, Vaupel, Christine, Rimm, David L, Ho, Thai H, Joseph, Richard W, Daud, Adil I, Conry, Robert M, Gaughan, Elizabeth M, Hernandez-Aya, Leonel F, Dimou, Anastasios, Funchain, Pauline, Smithy, James, Witte, John S, McKee, Svetlana B, Ko, Jennifer, Wrangle, John M, Dabbas, Bashar, Tangri, Shabnam, Lameh, Jelveh, Hall, Jeffrey, Markowitz, Joseph, Balko, Justin M, and Dakappagari, Naveen
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Cell Line ,Tumor ,Humans ,Melanoma ,Neoplasm Metastasis ,HLA-DR Antigens ,Biopsy ,Neoplasm Staging ,Prognosis ,Treatment Outcome ,Retreatment ,Immunohistochemistry ,Protein Binding ,Models ,Biological ,Adult ,Aged ,Middle Aged ,Female ,Male ,Indoleamine-Pyrrole 2 ,3 ,-Dioxygenase ,Programmed Cell Death 1 Receptor ,Biomarkers ,Tumor ,Antineoplastic Agents ,Immunological ,B7-H1 Antigen ,Cancer ,Prevention ,Clinical Research ,2.1 Biological and endogenous factors ,Aetiology ,4.2 Evaluation of markers and technologies ,Detection ,screening and diagnosis ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Purpose: PD-1/L1 axis-directed therapies produce clinical responses in a subset of patients; therefore, biomarkers of response are needed. We hypothesized that quantifying key immunosuppression mechanisms within the tumor microenvironment by multiparameter algorithms would identify strong predictors of anti-PD-1 response.Experimental Design: Pretreatment tumor biopsies from 166 patients treated with anti-PD-1 across 10 academic cancer centers were fluorescently stained with multiple markers in discovery (n = 24) and validation (n = 142) cohorts. Biomarker-positive cells and their colocalization were spatially profiled in pathologist-selected tumor regions using novel Automated Quantitative Analysis algorithms. Selected biomarker signatures, PD-1/PD-L1 interaction score, and IDO-1/HLA-DR coexpression were evaluated for anti-PD-1 treatment outcomes.Results: In the discovery cohort, PD-1/PD-L1 interaction score and/or IDO-1/HLA-DR coexpression was strongly associated with anti-PD-1 response (P = 0.0005). In contrast, individual biomarkers (PD-1, PD-L1, IDO-1, HLA-DR) were not associated with response or survival. This finding was replicated in an independent validation cohort: patients with high PD-1/PD-L1 and/or IDO-1/HLA-DR were more likely to respond (P = 0.0096). These patients also experienced significantly improved progression-free survival (HR = 0.36; P = 0.0004) and overall survival (HR = 0.39; P = 0.0011). In the combined cohort, 80% of patients exhibiting higher levels of PD-1/PD-L1 interaction scores and IDO-1/HLA-DR responded to PD-1 blockers (P = 0.000004). In contrast, PD-L1 expression was not predictive of survival.Conclusions: Quantitative spatial profiling of key tumor-immune suppression pathways by novel digital pathology algorithms could help more reliably select melanoma patients for PD-1 monotherapy. Clin Cancer Res; 24(21); 5250-60. ©2018 AACR.
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- 2018
28. A natural killer–dendritic cell axis defines checkpoint therapy–responsive tumor microenvironments
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Barry, Kevin C, Hsu, Joy, Broz, Miranda L, Cueto, Francisco J, Binnewies, Mikhail, Combes, Alexis J, Nelson, Amanda E, Loo, Kimberly, Kumar, Raj, Rosenblum, Michael D, Alvarado, Michael D, Wolf, Denise M, Bogunovic, Dusan, Bhardwaj, Nina, Daud, Adil I, Ha, Patrick K, Ryan, William R, Pollack, Joshua L, Samad, Bushra, Asthana, Saurabh, Chan, Vincent, and Krummel, Matthew F
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Cancer ,Vaccine Related ,Immunization ,2.1 Biological and endogenous factors ,Aetiology ,Good Health and Well Being ,Antigens ,Surface ,Cell Communication ,Cell Survival ,Dendritic Cells ,Humans ,Immunotherapy ,Killer Cells ,Natural ,Lymphocytes ,Melanoma ,Membrane Proteins ,Survival Analysis ,Thrombomodulin ,Tumor Microenvironment ,Medical and Health Sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Intratumoral stimulatory dendritic cells (SDCs) play an important role in stimulating cytotoxic T cells and driving immune responses against cancer. Understanding the mechanisms that regulate their abundance in the tumor microenvironment (TME) could unveil new therapeutic opportunities. We find that in human melanoma, SDC abundance is associated with intratumoral expression of the gene encoding the cytokine FLT3LG. FLT3LG is predominantly produced by lymphocytes, notably natural killer (NK) cells in mouse and human tumors. NK cells stably form conjugates with SDCs in the mouse TME, and genetic and cellular ablation of NK cells in mice demonstrates their importance in positively regulating SDC abundance in tumor through production of FLT3L. Although anti-PD-1 'checkpoint' immunotherapy for cancer largely targets T cells, we find that NK cell frequency correlates with protective SDCs in human cancers, with patient responsiveness to anti-PD-1 immunotherapy, and with increased overall survival. Our studies reveal that innate immune SDCs and NK cells cluster together as an excellent prognostic tool for T cell-directed immunotherapy and that these innate cells are necessary for enhanced T cell tumor responses, suggesting this axis as a target for new therapies.
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- 2018
29. Partially exhausted tumor-infiltrating lymphocytes predict response to combination immunotherapy
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Loo, Kimberly, Tsai, Katy K, Mahuron, Kelly, Liu, Jacqueline, Pauli, Mariela L, Sandoval, Priscila M, Nosrati, Adi, Lee, James, Chen, Lawrence, Hwang, Jimmy, Levine, Lauren S, Krummel, Matthew F, Algazi, Alain P, Pampaloni, Miguel, Alvarado, Michael D, Rosenblum, Michael D, and Daud, Adil I
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Clinical Research ,Immunization ,Vaccine Related ,Cancer ,Cancer immunotherapy ,Dermatology ,Melanoma ,Oncology ,T cells ,Biomedical and clinical sciences ,Health sciences - Abstract
BackgroundProgrammed death 1 (PD-1) inhibition activates partially exhausted cytotoxic T lymphocytes (peCTLs) and induces tumor regression. We previously showed that the peCTL fraction predicts response to anti-PD-1 monotherapy. Here, we sought to correlate peCTL and regulatory T lymphocyte (Treg) levels with response to combination immunotherapy, and with demographic/disease characteristics, in metastatic melanoma patients.MethodsPretreatment melanoma samples underwent multiparameter flow cytometric analysis. Patients were treated with anti-PD-1 monotherapy or combination therapy, and responses determined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria. peCTL and Treg levels across demographic/disease variables were compared. Low versus high peCTL (≤20% vs. >20%) were defined from a previous study.ResultsOne hundred and two melanoma patients were identified. The peCTL fraction was higher in responders than nonresponders. Low peCTL correlated with female sex and liver metastasis, but not with lactate dehydrogenase (LDH), tumor stage, or age. While overall response rates (ORRs) to anti-PD-1 monotherapy and combination therapy were similar in high-peCTL patients, low-peCTL patients given combination therapy demonstrated higher ORRs than those who received monotherapy. Treg levels were not associated with these factors nor with response.ConclusionIn melanoma, pretreatment peCTL fraction is reduced in women and in patients with liver metastasis. In low-peCTL patients, anti-PD-1 combination therapy is associated with significantly higher ORR than anti-PD-1 monotherapy. Fewer tumor-infiltrating peCTLs may be required to achieve response to combination immunotherapy.Trial registrationUCSF IRB Protocol 138510FUNDING. NIH DP2-AR068130, K08-AR062064, AR066821, and Burroughs Wellcome CAMS-1010934 (M.D.R.). Amoroso and Cook Fund, and the Parker Institute for Cancer Immunotherapy (A.I.D.).
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- 2017
30. Programmed Death-Ligand 1 Expression and Response to the Anti–Programmed Death 1 Antibody Pembrolizumab in Melanoma
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Daud, Adil I, Wolchok, Jedd D, Robert, Caroline, Hwu, Wen-Jen, Weber, Jeffrey S, Ribas, Antoni, Hodi, F Stephen, Joshua, Anthony M, Kefford, Richard, Hersey, Peter, Joseph, Richard, Gangadhar, Tara C, Dronca, Roxana, Patnaik, Amita, Zarour, Hassane, Roach, Charlotte, Toland, Grant, Lunceford, Jared K, Li, Xiaoyun Nicole, Emancipator, Kenneth, Dolled-Filhart, Marisa, Kang, S Peter, Ebbinghaus, Scot, and Hamid, Omid
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Cancer ,Brain Disorders ,Clinical Research ,Clinical Trials and Supportive Activities ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Antibodies ,Monoclonal ,Humanized ,Antineoplastic Agents ,B7-H1 Antigen ,Biomarkers ,Tumor ,Drug Administration Schedule ,Female ,Humans ,Immunohistochemistry ,Male ,Melanoma ,Middle Aged ,Neoplasm Staging ,Programmed Cell Death 1 Receptor ,Survival Rate ,Treatment Outcome ,Clinical Sciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Purpose Expression of programmed death-ligand 1 (PD-L1) is a potential predictive marker for response and outcome after treatment with anti-programmed death 1 (PD-1). This study explored the relationship between anti-PD-1 activity and PD-L1 expression in patients with advanced melanoma who were treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Patients and Methods Six hundred fifty-five patients received pembrolizumab10 mg/kg once every 2 weeks or once every 3 weeks, or 2 mg/kg once every 3 weeks. Tumor response was assessed every 12 weeks per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by independent central review. Primary outcome was objective response rate. Secondary outcomes included progression-free survival (PFS) and overall survival (OS). Membranous PD-L1 expression in tumor and tumor-associated immune cells was assessed by a clinical trial immunohistochemistry assay (22C3 antibody) and scored on a unique melanoma (MEL) scale of 0 to 5 by one of three pathologists who were blinded to clinical outcome; a score ≥ 2 (membranous staining in ≥ 1% of cells) was considered positive. Results Of 451 patients with evaluable PD-L1 expression, 344 (76%) had PD-L1-positive tumors. Demographic and staging variables were equally distributed among PD-L1-positive and -negative patients. An association between higher MEL score and higher response rate and longer PFS (hazard ratio, 0.76; 95% CI, 0.71 to 0.82) and OS (hazard ratio, 0.76; 95% CI, 0.69 to 0.83) was observed ( P < .001 for each). Objective response rate was 8%, 12%, 22%, 43%, 57%, and 53% for MEL 0, 1, 2, 3, 4, and 5, respectively. Conclusion PD-L1 expression in pretreatment tumor biopsy samples was correlated with response rate, PFS, and OS; however, patients with PD-L1-negative tumors may also achieve durable responses.
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- 2016
31. Increased FDG avidity in lymphoid tissue associated with response to combined immune checkpoint blockade
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Tsai, Katy K, Pampaloni, Miguel H, Hope, Charity, Algazi, Alain P, Ljung, Britt-Marie, Pincus, Laura, and Daud, Adil I
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Immunization ,Biomedical Imaging ,Cancer ,4.2 Evaluation of markers and technologies ,Detection ,screening and diagnosis ,Immunotherapy ,Biomarker ,PD-1 ,CTLA-4 ,PET/CT - Abstract
BackgroundAntibodies against programmed death 1 (PD-1) receptor and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) have transformed the systemic treatment of melanoma and many other cancers. Understanding the spectrum of benign findings and atypical response patterns seen in immune checkpoint blockade is important for accurately assessing treatment response as these immunotherapies become more widely used.Case presentationWe report a 63-year-old man with metastatic melanoma successfully treated with combination CTLA-4 and PD-1 blockade (ipilimumab and nivolumab), after non-response to pembrolizumab monotherapy. The initial impression of disease progression, based on cutaneous and PET/CT findings of increased fluoro-2-deoxy-D-glucose (FDG) uptake in benign lymphoid tissue, proved to be erroneous after assiduous review of radiographic imaging and correlative pathology.ConclusionsThese findings indicate that increased FDG uptake in benign lymphoid tissue seen on PET/CT may be a surrogate marker of immune activation and treatment response. Prospective studies will be invaluable in validating immune-related radiographic findings as a prognostic biomarker of response in cancer patients being treated with immune checkpoint blockade.
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- 2016
32. Clinical outcomes in metastatic uveal melanoma treated with PD‐1 and PD‐L1 antibodies
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Algazi, Alain P, Tsai, Katy K, Shoushtari, Alexander N, Munhoz, Rodrigo R, Eroglu, Zeynep, Piulats, Josep M, Ott, Patrick A, Johnson, Douglas B, Hwang, Jimmy, Daud, Adil I, Sosman, Jeffrey A, Carvajal, Richard D, Chmielowski, Bartosz, Postow, Michael A, Weber, Jeffrey S, and Sullivan, Ryan J
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Prevention ,Rare Diseases ,Clinical Research ,Cancer ,Clinical Trials and Supportive Activities ,Evaluation of treatments and therapeutic interventions ,6.2 Cellular and gene therapies ,6.1 Pharmaceuticals ,Adult ,Aged ,Aged ,80 and over ,Antibodies ,Monoclonal ,Antibodies ,Monoclonal ,Humanized ,Antineoplastic Combined Chemotherapy Protocols ,B7-H1 Antigen ,Female ,Follow-Up Studies ,Humans ,Male ,Melanoma ,Middle Aged ,Mucous Membrane ,Neoplasm Staging ,Nivolumab ,Prognosis ,Programmed Cell Death 1 Receptor ,Retrospective Studies ,Skin Neoplasms ,Survival Rate ,Uveal Neoplasms ,atezolizumab ,immunotherapy ,nivolumab ,pembrolizumab ,uveal melanoma ,Oncology and Carcinogenesis ,Public Health and Health Services ,Oncology & Carcinogenesis - Abstract
BackgroundAntibodies inhibiting the programmed death receptor 1 (PD-1) have demonstrated significant activity in the treatment of advanced cutaneous melanoma. The efficacy and safety of PD-1 blockade in patients with uveal melanoma has not been well characterized.MethodsFifty-eight patients with stage IV uveal melanoma received PD-1 or PD-1 ligand (PD-L1) antibodies between 2009 and 2015 at 9 academic centers. Patients who were evaluable for response were eligible for the analysis. Imaging was performed every 12 weeks and at the investigators' discretion. Safety and clinical efficacy outcomes, including the best overall response, progression-free survival (PFS), and overall survival (OS), were retrospectively determined.ResultsOf 56 eligible patients, 48 (86%) had received prior therapy, and 35 (63%) had received treatment with ipilimumab. Three patients had an objective response to ipilimumab, and 8 had stable disease as their best response. Thirty-eight patients (68%) received pembrolizumab, 16 (29%) received nivolumab, and 2 (4%) received atezolizumab. Objective tumor responses were observed in 2 patients for an overall response rate of 3.6% (95% confidence interval [CI], 1.8%-22.5%). Stable disease (≥6 months) was observed in 5 patients (9%). The median PFS was 2.6 months (95% CI, 2.4-2.8 months), and the median OS was 7.6 months (95% CI, 0.7-14.6 months). There was no association between prior treatment with ipilimumab or liver-directed therapy and PFS or OS. Treatment was well tolerated, and only 1 patient discontinued treatment because of toxicity.ConclusionsPD-1 and PD-L1 antibodies rarely confer durable remissions in patients with metastatic uveal melanoma. Clinical trial enrollment should be prioritized in this population. Cancer 2016;122:3344-3353. © 2016 American Cancer Society.
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- 2016
33. Combinatorial Approach to Treatment of Melanoma
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Abri, Kamran, Daud, Adil I., Flaherty, Keith T., Section editor, Bastian, Boris C., Section editor, Tsao, Hensin, Section editor, Hodi, F. Stephen, Section editor, Fisher, David E., editor, and Bastian, Boris C., editor
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- 2019
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34. Tumor immune profiling predicts response to anti–PD-1 therapy in human melanoma
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Daud, Adil I, Loo, Kimberly, Pauli, Mariela L, Sanchez-Rodriguez, Robert, Sandoval, Priscila Munoz, Taravati, Keyon, Tsai, Katy, Nosrati, Adi, Nardo, Lorenzo, Alvarado, Michael D, Algazi, Alain P, Pampaloni, Miguel H, Lobach, Iryna V, Hwang, Jimmy, Pierce, Robert H, Gratz, Iris K, Krummel, Matthew F, and Rosenblum, Michael D
- Subjects
Cancer ,Clinical Research ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Aetiology ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,Antibodies ,Monoclonal ,Humanized ,Biopsy ,CD8-Positive T-Lymphocytes ,CTLA-4 Antigen ,Cell Line ,Tumor ,Cohort Studies ,Female ,Flow Cytometry ,Humans ,Immune System ,Leukocyte Common Antigens ,Lymphocyte Activation ,Lymphocytes ,Tumor-Infiltrating ,Male ,Melanoma ,Neoplasm Metastasis ,Phenotype ,Programmed Cell Death 1 Receptor ,Skin Neoplasms ,T-Lymphocyte Subsets ,Tumor Microenvironment ,Medical and Health Sciences ,Immunology - Abstract
BackgroundImmune checkpoint blockade is revolutionizing therapy for advanced cancer, but many patients do not respond to treatment. The identification of robust biomarkers that predict clinical response to specific checkpoint inhibitors is critical in order to stratify patients and to rationally select combinations in the context of an expanding array of therapeutic options.MethodsWe performed multiparameter flow cytometry on freshly isolated metastatic melanoma samples from 2 cohorts of 20 patients each prior to treatment and correlated the subsequent clinical response with the tumor immune phenotype.ResultsIncreasing fractions of programmed cell death 1 high/cytotoxic T lymphocyte-associated protein 4 high (PD-1hiCTLA-4hi) cells within the tumor-infiltrating CD8+ T cell subset strongly correlated with response to therapy (RR) and progression-free survival (PFS). Functional analysis of these cells revealed a partially exhausted T cell phenotype. Assessment of metastatic lesions during anti-PD-1 therapy demonstrated a release of T cell exhaustion, as measured by an accumulation of highly activated CD8+ T cells within tumors, with no effect on Tregs.ConclusionsOur data suggest that the relative abundance of partially exhausted tumor-infiltrating CD8+ T cells predicts response to anti-PD-1 therapy. This information can be used to appropriately select patients with a high likelihood of achieving a clinical response to PD-1 pathway inhibition.FundingThis work was funded by a generous gift provided by Inga-Lill and David Amoroso as well as a generous gift provided by Stephen Juelsgaard and Lori Cook.
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- 2016
35. Nivolumab plus ipilimumab in the treatment of advanced melanoma
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Tsai, Katy K and Daud, Adil I
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Immunization ,Cancer ,Antibodies ,Monoclonal ,Antineoplastic Combined Chemotherapy Protocols ,Clinical Trials ,Phase III as Topic ,Disease-Free Survival ,Double-Blind Method ,Drug Administration Schedule ,Follow-Up Studies ,Humans ,Ipilimumab ,Melanoma ,Multicenter Studies as Topic ,Nivolumab ,Randomized Controlled Trials as Topic ,Skin Neoplasms ,Treatment Outcome ,Immunotherapy ,PD-1 ,CTLA-4 ,Cardiorespiratory Medicine and Haematology ,Oncology and Carcinogenesis - Abstract
Advanced melanoma has historically been a difficult disease to treat due to few effective systemic treatment options. However, over the past few years, scientific advancements in immune checkpoint inhibition have resulted in several novel approaches that have changed front-line management of advanced melanoma. Despite these exciting developments, there remains room for improvement in treatment outcomes. Combination immunotherapy, in particular combined cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) blockade, represents an important first step in this direction.
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- 2015
36. Intratumoral and Combination Therapy in Melanoma and Other Skin Cancers
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Oglesby, Arielle, Algazi, Alain P., and Daud, Adil I.
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- 2019
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37. PD-1 and PD-L1 antibodies for melanoma
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Tsai, Katy K, Zarzoso, Inés, and Daud, Adil I
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Cancer ,Immunization ,Climate-Related Exposures and Conditions ,Antibodies ,Monoclonal ,Antibodies ,Monoclonal ,Humanized ,Antineoplastic Agents ,B7-H1 Antigen ,CTLA-4 Antigen ,Humans ,Immunotherapy ,Lymphocyte Activation ,Melanoma ,Nivolumab ,Programmed Cell Death 1 Receptor ,T-Lymphocytes ,BMS-936559 ,PD-1 ,PD-L1 ,PD-L2 ,immunotherapy ,MPDL3280A ,melanoma ,nivolumab ,pembrolizumab ,AE ,adverse event ,APC ,antigen presenting cell ,ASCO ,American Society of Clinical Oncology ,CTLA-4 ,cytotoxic T-lymphocyte-associated protein 4 ,FDA ,Food and Drug Administration ,gp100 ,glycoprotein 100 vaccine ,Ig ,immunoglobulin ,ITIM ,immunoreceptor tyrosine-based inhibitory motif ,ITSM ,immunoreceptor tyrosine-based switch motif ,MAPK ,mitogen-activated protein kinase ,MHC ,major histocompatibility complex ,NK ,natural killer ,ORR ,objective response rate ,OS ,overall survival ,PD ,progressive disease ,programmed cell death 1 ,programmed cell death ligand 1 ,PFS ,progression free survival ,TCR ,T cell receptor ,TIL ,tumor infiltrating lymphocyte ,AE ,adverse event ,APC ,antigen presenting cell ,ASCO ,American Society of Clinical Oncology ,CTLA-4 ,cytotoxic T-lymphocyte-associated protein 4 ,FDA ,Food and Drug Administration ,ITIM ,immunoreceptor tyrosine-based inhibitory motif ,ITSM ,immunoreceptor tyrosine-based switch motif ,Ig ,immunoglobulin ,MAPK ,mitogen-activated protein kinase ,MHC ,major histocompatibility complex ,NK ,natural killer ,ORR ,objective response rate ,OS ,overall survival ,PD ,progressive disease ,PD-1 ,programmed cell death 1 ,PD-L1 ,programmed cell death ligand 1 ,PFS ,progression free survival ,TCR ,T cell receptor ,TIL ,tumor infiltrating lymphocyte ,gp100 ,glycoprotein 100 vaccine ,Immunology ,Medical Microbiology ,Pharmacology and Pharmaceutical Sciences ,Virology - Abstract
Melanoma is the most serious form of skin cancer. Metastatic melanoma historically carries a poor prognosis and until recently there have been few effective agents available to treat widely disseminated disease. Recognition of the immunogenic nature of melanoma has resulted in the development of various immunotherapeutic approaches, especially with regards to the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1). Antibodies targeting the PD-1 axis have shown enormous potential in the treatment of metastatic melanoma. Here, we will review the immune basis for the disease and discuss approved immunotherapeutic options for advanced melanoma, as well as the current state of development of PD-1 and PD-L1 antibodies and their importance in shaping the future of melanoma treatment.
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- 2014
38. Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo
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Posch, Christian, Moslehi, Homayoun, Feeney, Luzviminda, Green, Gary A, Ebaee, Anoosheh, Feichtenschlager, Valentin, Chong, Kim, Peng, Lily, Dimon, Michelle T, Phillips, Thomas, Daud, Adil I, McCalmont, Timothy H, LeBoit, Philip E, and Ortiz-Urda, Susana
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Biological Sciences ,Pediatric ,Rare Diseases ,Genetics ,Cancer ,Animals ,Antineoplastic Agents ,Apoptosis ,Cell Line ,Tumor ,Drug Synergism ,Female ,GTP Phosphohydrolases ,Humans ,MAP Kinase Signaling System ,Melanoma ,Membrane Proteins ,Mice ,Mice ,Nude ,Mutation ,Phosphoinositide-3 Kinase Inhibitors ,Protein Kinase Inhibitors ,Signal Transduction ,TOR Serine-Threonine Kinases ,Xenograft Model Antitumor Assays - Abstract
Activating mutations in the neuroblastoma rat sarcoma viral oncogene homolog (NRAS) gene are common genetic events in malignant melanoma being found in 15-25% of cases. NRAS is thought to activate both mitogen activated protein kinase (MAPK) and PI3K signaling in melanoma cells. We studied the influence of different components on the MAP/extracellular signal-regulated (ERK) kinase (MEK) and PI3K/mammalian target of rapamycin (mTOR)-signaling cascade in NRAS mutant melanoma cells. In general, these cells were more sensitive to MEK inhibition compared with inhibition in the PI3K/mTOR cascade. Combined targeting of MEK and PI3K was superior to MEK and mTOR1,2 inhibition in all NRAS mutant melanoma cell lines tested, suggesting that PI3K signaling is more important for cell survival in NRAS mutant melanoma when MEK is inhibited. However, targeting of PI3K/mTOR1,2 in combination with MEK inhibitors is necessary to effectively abolish growth of NRAS mutant melanoma cells in vitro and regress xenografted NRAS mutant melanoma. Furthermore, we showed that MEK and PI3K/mTOR1,2 inhibition is synergistic. Expression analysis confirms that combined MEK and PI3K/mTOR1,2 inhibition predominantly influences genes in the rat sarcoma (RAS) pathway and growth factor receptor pathways, which signal through MEK/ERK and PI3K/mTOR, respectively. Our results suggest that combined targeting of the MEK/ERK and PI3K/mTOR pathways has antitumor activity and might serve as a therapeutic option in the treatment of NRAS mutant melanoma, for which there are currently no effective therapies.
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- 2013
39. Treatment of cutaneous melanoma: current approaches and future prospects.
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Algazi, Alain P, Soon, Christopher W, and Daud, Adil I
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chemotherapy ,clinical trials ,immune modulation ,melanoma ,resection ,small molecule kinase inhibitors ,Oncology and Carcinogenesis - Abstract
Melanoma is the most aggressive and deadly type of skin cancer. Surgical resection with or without lymph node sampling is the standard of care for primary cutaneous melanoma. Adjuvant therapy decisions may be informed by careful consideration of prognostic factors. High-dose adjuvant interferon alpha-2b increases disease-free survival and may modestly improve overall survival. Less toxic alternatives for adjuvant therapy are currently under study. External beam radiation therapy is an option for nodal beds where the risk of local recurrence is very high. In-transit melanoma metastases may be treated locally with surgery, immunotherapy, radiation, or heated limb perfusion. For metastatic melanoma, the options include chemotherapy or immunotherapy; targeted anti-BRAF and anti-KIT therapy is under active investigation. Standard chemotherapy yields objective tumor responses in approximately 10%-20% of patients, and sustained remissions are uncommon. Immunotherapy with high-dose interleukin-2 yields objective tumor responses in a minority of patients; however, some of these responses may be durable. Identification of activating mutations of BRAF, NRAS, c-KIT, and GNAQ in distinct clinical subtypes of melanoma suggest that these are molecularly distinct. Emerging data from clinical trials suggest that substantial improvements in the standard of care for melanoma may be possible.
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- 2010
40. Supplementary Figures from Intratumoral Plasmid IL12 Electroporation Therapy in Patients with Advanced Melanoma Induces Systemic and Intratumoral T-cell Responses
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Greaney, Samantha K., primary, Algazi, Alain P., primary, Tsai, Katy K., primary, Takamura, Kathryn T., primary, Chen, Lawrence, primary, Twitty, Christopher G., primary, Zhang, Li, primary, Paciorek, Alan, primary, Pierce, Robert H., primary, Le, Mai H., primary, Daud, Adil I., primary, and Fong, Lawrence, primary
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- 2023
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41. Supplementary Data from Intratumoral Plasmid IL12 Electroporation Therapy in Patients with Advanced Melanoma Induces Systemic and Intratumoral T-cell Responses
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Greaney, Samantha K., primary, Algazi, Alain P., primary, Tsai, Katy K., primary, Takamura, Kathryn T., primary, Chen, Lawrence, primary, Twitty, Christopher G., primary, Zhang, Li, primary, Paciorek, Alan, primary, Pierce, Robert H., primary, Le, Mai H., primary, Daud, Adil I., primary, and Fong, Lawrence, primary
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- 2023
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- View/download PDF
42. Data from Intratumoral Plasmid IL12 Electroporation Therapy in Patients with Advanced Melanoma Induces Systemic and Intratumoral T-cell Responses
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Greaney, Samantha K., primary, Algazi, Alain P., primary, Tsai, Katy K., primary, Takamura, Kathryn T., primary, Chen, Lawrence, primary, Twitty, Christopher G., primary, Zhang, Li, primary, Paciorek, Alan, primary, Pierce, Robert H., primary, Le, Mai H., primary, Daud, Adil I., primary, and Fong, Lawrence, primary
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- 2023
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43. Data from Intratumoral Electroporation of Plasmid Encoded IL12 and Membrane-Anchored Anti-CD3 Increases Systemic Tumor Immunity
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Han, Mia, primary, Nguyen, Bianca, primary, Lee, Jack Y., primary, Browning, Erica, primary, Zhang, Jun, primary, Mukhopadhyay, Anandaroop, primary, Gujar, Ravindra, primary, Salazar, Jon, primary, Hermiz, Reneta, primary, Svenson, Lauren, primary, Rolig, Annah S., primary, Redmond, William L., primary, Algazi, Alain P., primary, Daud, Adil I., primary, Canton, David A., primary, and Twitty, Christopher G., primary
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- 2023
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- View/download PDF
44. Supplementary Figure from Intratumoral Electroporation of Plasmid Encoded IL12 and Membrane-Anchored Anti-CD3 Increases Systemic Tumor Immunity
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Han, Mia, primary, Nguyen, Bianca, primary, Lee, Jack Y., primary, Browning, Erica, primary, Zhang, Jun, primary, Mukhopadhyay, Anandaroop, primary, Gujar, Ravindra, primary, Salazar, Jon, primary, Hermiz, Reneta, primary, Svenson, Lauren, primary, Rolig, Annah S., primary, Redmond, William L., primary, Algazi, Alain P., primary, Daud, Adil I., primary, Canton, David A., primary, and Twitty, Christopher G., primary
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- 2023
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45. Supplementary Data from Intratumoral Electroporation of Plasmid Encoded IL12 and Membrane-Anchored Anti-CD3 Increases Systemic Tumor Immunity
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Han, Mia, primary, Nguyen, Bianca, primary, Lee, Jack Y., primary, Browning, Erica, primary, Zhang, Jun, primary, Mukhopadhyay, Anandaroop, primary, Gujar, Ravindra, primary, Salazar, Jon, primary, Hermiz, Reneta, primary, Svenson, Lauren, primary, Rolig, Annah S., primary, Redmond, William L., primary, Algazi, Alain P., primary, Daud, Adil I., primary, Canton, David A., primary, and Twitty, Christopher G., primary
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- 2023
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46. Pembrolizumab‐associated chronic rhinosinusitis: A new endotype and management considerations.
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Standiford, Taylor C., Patel, Neil N., Singh, Amritpal, Gochman, Grant, Jamie Wu, Tara, Daud, Adil I., and Goldberg, Andrew N.
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- 2023
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47. Supplementary Figure Legends from Phase II Trial of IL-12 Plasmid Transfection and PD-1 Blockade in Immunologically Quiescent Melanoma
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Algazi, Alain P., primary, Twitty, Christopher G., primary, Tsai, Katy K., primary, Le, Mai, primary, Pierce, Robert, primary, Browning, Erica, primary, Hermiz, Reneta, primary, Canton, David A., primary, Bannavong, Donna, primary, Oglesby, Arielle, primary, Francisco, Murray, primary, Fong, Lawrence, primary, Pittet, Mikael J., primary, Arlauckas, Sean P., primary, Garris, Christopher, primary, Levine, Lauren P., primary, Bifulco, Carlos, primary, Ballesteros-Merino, Carmen, primary, Bhatia, Shailender, primary, Gargosky, Sharron, primary, Andtbacka, Robert H.I., primary, Fox, Bernard A., primary, Rosenblum, Michael D., primary, and Daud, Adil I., primary
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- 2023
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48. Supplementary Materials and Methods from Phase I Study of Bosutinib, a Src/Abl Tyrosine Kinase Inhibitor, Administered to Patients with Advanced Solid Tumors
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Daud, Adil I., primary, Krishnamurthi, Smitha S., primary, Saleh, Mansoor N., primary, Gitlitz, Barbara J., primary, Borad, Mitesh J., primary, Gold, Philip J., primary, Chiorean, Elena G., primary, Springett, Gregory M., primary, Abbas, Richat, primary, Agarwal, Shefali, primary, Bardy-Bouxin, Nathalie, primary, Hsyu, Poe-Hirr, primary, Leip, Eric, primary, Turnbull, Kathleen, primary, Zacharchuk, Charles, primary, and Messersmith, Wells A., primary
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- 2023
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49. Table S1 from Phase II Trial of IL-12 Plasmid Transfection and PD-1 Blockade in Immunologically Quiescent Melanoma
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Algazi, Alain P., primary, Twitty, Christopher G., primary, Tsai, Katy K., primary, Le, Mai, primary, Pierce, Robert, primary, Browning, Erica, primary, Hermiz, Reneta, primary, Canton, David A., primary, Bannavong, Donna, primary, Oglesby, Arielle, primary, Francisco, Murray, primary, Fong, Lawrence, primary, Pittet, Mikael J., primary, Arlauckas, Sean P., primary, Garris, Christopher, primary, Levine, Lauren P., primary, Bifulco, Carlos, primary, Ballesteros-Merino, Carmen, primary, Bhatia, Shailender, primary, Gargosky, Sharron, primary, Andtbacka, Robert H.I., primary, Fox, Bernard A., primary, Rosenblum, Michael D., primary, and Daud, Adil I., primary
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- 2023
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50. Supplementary Data from Potentiation of a Topoisomerase I Inhibitor, Karenitecin, by the Histone Deacetylase Inhibitor Valproic Acid in Melanoma: Translational and Phase I/II Clinical Trial
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Daud, Adil I., primary, Dawson, Jana, primary, DeConti, Ronald C., primary, Bicaku, Elona, primary, Marchion, Douglas, primary, Bastien, Sem, primary, Hausheer, Frederick A., primary, Lush, Richard, primary, Neuger, Anthony, primary, Sullivan, Daniel M., primary, and Munster, Pamela N., primary
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- 2023
- Full Text
- View/download PDF
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