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Emerging Cell Therapies: Realizing the Vision of NextGen Cell Therapeutics | EK15


Engineered Chimeric Antigen Receptors for Nano-optogenetic Control of Therapeutic T-cells (LiCAR T-cells)


Jan 25, 2021 12:00am ‐ Jan 25, 2021 12:00am

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Engineered Chimeric Antigen Receptors for Nano-optogenetic Control of Therapeutic T-cells (LiCAR T-cells) Summary: Chimeric antigen receptor (CAR) T-cell immunotherapy has demonstrated high potential for elimination of tumors, particularly in patients with CD19-positive lymphoma and leukemia. CARs are synthetic receptors engineered onto the surface of T cells, where they can engage specific tumor antigens in a major histocompatibility complex (MHC)-independent manner. The recognition of antigen allows T cells to be activated and subsequently perform their killing/effector activities toward tumor cells. Despite the tremendous success of CAR T-cell therapy in cancer treatment, this type of immunotherapy imposes significant safety challenges, as most notably exemplified by the cytokine release syndrome (CRS) and the “on-target, off-tumor” cytotoxicity due to the lack of control over the dose, location, and timing of T cell activity. As CAR T-cells are activated, they will exponentially proliferate and eventually reach precarious levels where a cytokine response exceeds tolerability. The recently FDA approved CAR T-cell therapies are designed for CD19-positive tumors, but they cannot discriminate between normal CD19+ cells and cancerous CD19+ cells. As such, CAR T-cells will likely attack normal cells/tissues and lead to B cell aplasia or even more devastating consequences in certain patients, thereby posing limitations on the use of the current CAR T-cell therapy. We present herein the design of light-switchable CAR T-cells (designated “LiCAR”), which enables phototunable activation of therapeutic T cells to inducibly kill tumor cells. When coupled with upconversion nanoparticles (UCNPs), LiCAR permits the timing, location, and dosage of T cell-mediated therapeutic activity to be tailored in the dual presence of tumor antigen and light. This nano-optogenetic device sets the stage for the future biomedical application of optogenetic immunotherapy to deliver personalized anti-cancer therapy. Authors and Affiliations: Nhung T. Nguyen1, Kai Huang2, Hongxiang Zeng3, Ji Jing1, Joyce Chen4, Zixian Huang1, Xin Liu5, Anjana Rao4, Yun Huang3,*, Gang Han2,*, Yubin Zhou1,6* 1Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, 2Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, 3Center for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, 4Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA, USA, 5Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas 77030, 6Department of Medical Physiology, College of Medicine, Texas A&M University, Temple, Texas 76504, USA.; *Email: yubinzhou@tamu.edu

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