6 results on '"Tilakawardane, Dileshni"'
Search Results
2. Nonsignaling extracellular spacer regulates tumor antigen selectivity of CAR T cells
- Author
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Kennewick, Kelly T., Yamaguchi, Yukiko, Gibson, Jackson, Gerdts, Ethan A., Jeang, Brook, Tilakawardane, Dileshni, Murad, John P., Chang, Wen-Chung, Wright, Sarah L., Thiel, Michalina S., Forman, Stephen J., Stern, Lawrence A., and Priceman, Saul J.
- Published
- 2024
- Full Text
- View/download PDF
3. Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer.
- Author
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Priceman, Saul J., Gerdts, Ethan A., Tilakawardane, Dileshni, Kennewick, Kelly T., Murad, John P., Park, Anthony K., Jeang, Brook, Yamaguchi, Yukiko, Yang, Xin, Urak, Ryan, Weng, Lihong, Chang, Wen-Chung, Wright, Sarah, Pal, Sumanta, Reiter, Robert E., Wu, Anna M., Brown, Christine E., and Forman, Stephen J.
- Subjects
PROSTATE cancer treatment ,CANCER stem cells ,TUMOR antigens - Abstract
Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with “on-target off-tumor” activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robustin vivoanti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
4. Pre-conditioning modifies the TME to enhance solid tumor CAR T cell efficacy and endogenous protective immunity.
- Author
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Murad JP, Tilakawardane D, Park AK, Lopez LS, Young CA, Gibson J, Yamaguchi Y, Lee HJ, Kennewick KT, Gittins BJ, Chang WC, Tran CP, Martinez C, Wu AM, Reiter RE, Dorff TB, Forman SJ, and Priceman SJ
- Subjects
- Animals, Antigens, Neoplasm genetics, Apoptosis, Cell Proliferation, GPI-Linked Proteins antagonists & inhibitors, GPI-Linked Proteins genetics, Humans, Male, Mice, Mice, Inbred C57BL, Myeloablative Agonists pharmacology, Neoplasm Proteins genetics, Pancreatic Neoplasms immunology, Pancreatic Neoplasms pathology, Prostatic Neoplasms immunology, Prostatic Neoplasms pathology, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Cyclophosphamide pharmacology, Immunotherapy, Adoptive methods, Neoplasm Proteins antagonists & inhibitors, Pancreatic Neoplasms therapy, Prostatic Neoplasms therapy, Tumor Microenvironment
- Abstract
Chimeric antigen receptor (CAR) T cell therapy has led to impressive clinical responses in patients with hematological malignancies; however, its effectiveness in patients with solid tumors has been limited. While CAR T cells for the treatment of advanced prostate and pancreas cancer, including those targeting prostate stem cell antigen (PSCA), are being clinically evaluated and are anticipated to show bioactivity, their safety and the impact of the immunosuppressive tumor microenvironment (TME) have not been faithfully explored preclinically. Using a novel human PSCA knockin (hPSCA-KI) immunocompetent mouse model, we evaluated the safety and therapeutic efficacy of PSCA-CAR T cells. We demonstrated that cyclophosphamide (Cy) pre-conditioning significantly modified the immunosuppressive TME and was required to uncover the efficacy of PSCA-CAR T cells in metastatic prostate and pancreas cancer models, with no observed toxicities in normal tissues with endogenous expression of PSCA. This combination dampened the immunosuppressive TME, generated pro-inflammatory myeloid and T cell signatures in tumors, and enhanced the recruitment of antigen-presenting cells, as well as endogenous and adoptively transferred T cells, resulting in long-term anti-tumor immunity., Competing Interests: Declaration of interests S.J.P. and S.J.F. are scientific advisors to and receive royalties from Mustang Bio. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
5. Regional Delivery of Chimeric Antigen Receptor-Engineered T Cells Effectively Targets HER2 + Breast Cancer Metastasis to the Brain.
- Author
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Priceman SJ, Tilakawardane D, Jeang B, Aguilar B, Murad JP, Park AK, Chang WC, Ostberg JR, Neman J, Jandial R, Portnow J, Forman SJ, and Brown CE
- Subjects
- Animals, Brain Neoplasms therapy, Breast Neoplasms genetics, Breast Neoplasms immunology, Breast Neoplasms metabolism, CD28 Antigens genetics, Cytokines metabolism, Cytotoxicity, Immunologic, Disease Models, Animal, Female, Humans, Inflammation Mediators metabolism, Lymphocyte Activation genetics, Lymphocyte Activation immunology, Receptor, ErbB-2 genetics, Receptors, Chimeric Antigen genetics, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Tumor Necrosis Factor Receptor Superfamily, Member 9 genetics, Xenograft Model Antitumor Assays, Brain Neoplasms immunology, Brain Neoplasms secondary, Breast Neoplasms pathology, Immunotherapy, Adoptive methods, Receptors, Antigen, T-Cell metabolism, Receptors, Chimeric Antigen metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism
- Abstract
Purpose: Metastasis to the brain from breast cancer remains a significant clinical challenge, and may be targeted with CAR-based immunotherapy. CAR design optimization for solid tumors is crucial due to the absence of truly restricted antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we have optimized HER2-CAR T cells for the treatment of breast to brain metastases, and determined optimal second-generation CAR design and route of administration for xenograft mouse models of breast metastatic brain tumors, including multifocal and leptomeningeal disease. Experimental Design: HER2-CAR constructs containing either CD28 or 4-1BB intracellular costimulatory signaling domains were compared for functional activity in vitro by measuring cytokine production, T-cell proliferation, and tumor killing capacity. We also evaluated HER2-CAR T cells delivered by intravenous, local intratumoral, or regional intraventricular routes of administration using in vivo human xenograft models of breast cancer that have metastasized to the brain. Results: Here, we have shown that HER2-CARs containing the 4-1BB costimulatory domain confer improved tumor targeting with reduced T-cell exhaustion phenotype and enhanced proliferative capacity compared with HER2-CARs containing the CD28 costimulatory domain. Local intracranial delivery of HER2-CARs showed potent in vivo antitumor activity in orthotopic xenograft models. Importantly, we demonstrated robust antitumor efficacy following regional intraventricular delivery of HER2-CAR T cells for the treatment of multifocal brain metastases and leptomeningeal disease. Conclusions: Our study shows the importance of CAR design in defining an optimized CAR T cell, and highlights intraventricular delivery of HER2-CAR T cells for treating multifocal brain metastases. Clin Cancer Res; 24(1); 95-105. ©2017 AACR ., (©2017 American Association for Cancer Research.)
- Published
- 2018
- Full Text
- View/download PDF
6. Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer.
- Author
-
Priceman SJ, Gerdts EA, Tilakawardane D, Kennewick KT, Murad JP, Park AK, Jeang B, Yamaguchi Y, Yang X, Urak R, Weng L, Chang WC, Wright S, Pal S, Reiter RE, Wu AM, Brown CE, and Forman SJ
- Abstract
Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robust in vivo anti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies.
- Published
- 2017
- Full Text
- View/download PDF
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