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Sept 26th: Alizadeh DARYA
26 September @ 11 h 00 min - 12 h 30 min UTC+1
Assistant Research Professor
Department of Hematology & Hematopoietic Cell Transplantation
City of Hope
Title: Advancing CAR T cell Therapy for the Treatment of Brain Tumors
Abstract: Chimeric antigen receptor (CAR)-T cell therapy has led to encouraging clinical outcomes, especially against hematological malignancies. However, CAR-T cell therapy for solid tumors, including brain tumors, faces many challenges, including tumor heterogeneity, a suppressive tumor microenvironment and the lack of T cell persistence. We have developed a research program with the overarching goal of improving the quality and efficacy of CAR-T cell products in the context of this hostile glioma microenvironment.
Our team was the first to clinically develop CAR-T cells for the treatment of human brain tumors, our lead target being the glioma-associated protein, interleukin 13 receptor alpha 2 (IL13Rα2), an ideal tumor-specific antigen. Incorporating the 4-1BB co-stimulatory domain in the IL13Rα2-CAR-T cell design led to superior antitumor activity and persistence of CAR-T cells in glioma models. We further determined that less-differentiated CAR-T lymphocytes were more potent therapeutically, and that the inclusion of IL15 during the manufacturing process promoted the generation of cells exhibiting a stem-cell memory, less exhausted and anti-apoptotic phenotype. Furthermore, CAR-T cells exposed to IL15 were characterized by decreased mTORC1 activity, reduced expression of glycolytic enzymes and improved mitochondrial respiratory capacity, overall resulting in a more metabolically fit CAR-T product.
A second research axis has focused on the development of a syngeneic immunocompetent mouse model, which recapitulates glioma microenvironment (TME) in patients to further comprehend the impact of tumor-promoting immunosuppressive networks on CAR-T cell therapies. Analogous to the human IL13Rα2-CAR being evaluated in our clinical trials, murine IL13Rα2-CAR-T cells (mIL13Rα2-CAR-T) are composed of a mouse IL-13 tumor-targeting domain, murine 4-1BB and CD3ζ signaling domains. The mIL13Rα2-CAR-T cells efficiently target IL13Rα2+ murine gliomas in vitro and in vivo. Characterization of the tumor microenvironment post-CAR-T therapy reveals activation of endogenous immune cells such as cytotoxic CD8 T and myeloid cells, and reduction of the frequency of T regulatory cells. Studies are ongoing to elucidate the interplay between CAR-T cells and host immune cells and identify factors that may impair CAR-T efficacy in the glioma microenvironment. This syngeneic immunocompetent platform will provide fundamental information for the development of potential combination therapies that may overcome the immunosuppressive glioma TME, with the goal of enhancing CAR T cell antitumor activity and subsequently to improve survival of GBM patients.
1. Alizadeh D, Wong RA, Yang X, Wang D, Pecoraro JR, Kuo CF, Aguilar B, Qi Y, Ann DK, Starr R, Urak R, Wang X, Forman SJ, Brown CE. IL15 Enhances CAR-T Cell Antitumor Activity by Reducing mTORC1 Activity and Preserving Their Stem Cell Memory Phenotype. Cancer Immunol Res. 2019 May;7(5):759-772.
2. Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, Ostberg JR, Blanchard MS, Kilpatrick J, Simpson J, Kurien A, Priceman SJ, Wang X, Harshbarger TL, D’Apuzzo M, Ressler JA, Jensen MC, Barish ME, Chen M, Portnow J, Forman SJ, Badie B. Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy. N Engl J Med. 2016 Dec 29;375(26):2561-9.
3. Wang D, Aguilar B, Starr B, Alizadeh D, Brito A, Sarkissian A, Ostberg JR, Forman SJ, Brown CE. Glioblastoma-targeted CD4+ CAR T Cells Mediate Superior Antitumor Activity. JCI Insight. Advance online publication. 2018 May 17:3(10):e99048.
4. Brown CE, Aguilar B, Starr R, Yang X, Chang WC, Weng L, Chang B, Sarkissian A, Brito A, Sanchez JF, Ostberg JR, D’Apuzzo M, Badie B, Barish ME, Forman SJ. Optimization of IL13Rα2-Targeted Chimeric Antigen Receptor T Cells for Improved Anti-tumor Efficacy against Glioblastoma. Mol Ther. 2017 Oct 5: S1525-0016(17)30467-7.