264 Development of an off-the-shelf, MICA/B-targeted CAR T cell to overcome a pan-tumor escape mechanism for solid tumors
Year: 2024
Type: conference-abstract
Abstract: Background Surface expression of the NKG2D ligands MHC class I related proteins A and B (MICA/B) is regulated by cellular and genotoxic stress in several disease settings including cancer and serves as a critical surveillance axis for effector CD8+ T and NK cells. The NKG2D recognition domains of MICA/B are susceptible to proteolytic cleavage and shedding, enabling immune evasion and disease progression. We have established a novel MICA/B specific CAR that recognizes the highly-conserved and cleavage-resistant α3 domain of MICA/B (3MICA/B CAR), allowing for restoration of the MICA/B immune surveillance by 3MICA/B CAR T cells and near-universal targeting of tumor cells. Methods Here we describe the generation and characterization of FT836, an off-the-shelf, iPSC-derived CAR T cell that incorporates a novel 3MICA/B CAR as well as additional edits specifically designed to promote functional persistence in solid tumor environments without the need for conditioning chemotherapy. iPSCs were engineered to express 3MICA/B CAR and other novel synthetic receptors, including an allo-defense receptor, a TGFβ-signal redirection receptor, a high-affinity, non-cleavable CD16a (hnCD16), and a CXCR2 receptor, and to knock-out CD38, CD58, and T-cell receptor alpha. Engineered iPSCs were differentiated into a uniform population of CD8+ alpha-beta T cells (iT) cells, uniformly expressing all engineered elements. Results FT836 demonstrated potent MICA/B CAR-specific in vitro and in vivo targeting of tumor cells, including lung, gastric, ovarian, and prostate cancer, each with varying levels of surface MICA/B expression. Combination with chemotherapy, radiotherapy, or antibody drug conjugates, such as trastuzumab-deruxtecan, increased MICA/B expression on tumor cells and enhanced FT836 anti-tumor activity. In addition, combination with therapeutic antibodies targeting EGFR, cMET, PDL1, or HER2 promoted antibody-dependent cellular cytotoxicity through hnCD16 and enhanced elimination of heterogenous tumor cell population. Importantly, FT836 sustained anti-tumor activity over multiple rounds of tumor challenge, persisting even in the presence of allogeneic immune cells primed to specifically target FT836. This resistance to immune cell-mediated rejection is a consequence of: (i) CD58 deletion to unidirectionally limit immune synapse formation by allogeneic immune cells, (ii) ADR expression to target and eliminate 4-1BB+ allogeneic immune cells; and (iii) unique and regulated expression of cytokine support. Conclusions FT836 is an off-the-shelf, multiplexed-engineered CAR T cell targeting 3MICA/B, and is designed to overcome a pan-tumor escape mechanism for solid tumors. In preclinical studies, FT836 demonstrates anti-tumor activity in the presence of allogeneic immune cells, suggesting that it may be effectively combined with standard-of-care agents in the absence of conditioning chemotherapy. Ethics Approval These studies were approved by Fate Therapeutics Institutional Animal Care and Use Committee and were carried out in accordance with the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals.
Authors: Alex Garcia, Samad Ibitokou, Spas Markov, Soheila Shirinbak, Shilpi Chandra, Kyla Omilusik, Miguel Meza, Thomas Dailey, Angela Gentile, Mochtar Pribadi, Lauren Fong, Betsy Rezner, Tom T Lee, Ramzey Abujarour, Raedun Clarke, Jode P Goodridge, Kai Wucherpfennig, Martin P Hosking, Bahram Valamehr
Institutions: Fate Therapeutics (United States), Harvard University
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4404063966