264 Next-generation off-the-shelf CAR T cell targeting pan-tumor antigen MICA/B and engineered with immune evasion enables treatment across solid tumors without the need for conditioning chemotherapy

Le résumé fourni par la source

Background Successful implementation of chimeric antigen receptor (CAR) T-cell therapies in solid tumors faces multiple obstacles, including challenges in selecting appropriate tumor antigens and ensuring consistent and scaled product manufacturing for on-demand patient treatment. Moreover, both autologous and allogeneic CAR T-cell therapies require conditioning chemotherapy (CCT) to suppress the patient’s immune system and enhance T-cell expansion. However, CCT regimens carry significant risks and specialized healthcare. The limited effectiveness of CAR T cells against solid tumors, combined with toxicity from CCT, highlights the urgent need for (i) innovative strategies for antigen targeting and (ii) the development of approaches that minimize or eliminate the need for CCT.To address these limitations, we have developed FT836, an off-the-shelf iPSC-derived CAR T-cell capable of targeting a broad spectrum of solid tumors without requiring CCT. FT836 employs a novel 3MICA CAR that binds to the conserved α3 domain of MICA and MICB—stress-induced ligands—enabling recognition of a wide array of tumor types.Additionally, FT836 expresses hnCD16 Fc receptor, enabling antibody-dependent cellular cytotoxicity when used with therapeutic antibodies (mAb) targeting secondary antigens (e.g. EGFR, cMET, PD-L1, or HER2).FT836 is also engineered to maintain functional persistence without the need for CCT through the combination of a synthetic alloimmune defense receptor (ADR) that selectively eliminates 4-1BB+ alloreactive immune cells, and deletion of CD58 to disrupt recognition by host immune cells.Methods Method details will be provided in the presentation.Results In xenograft models of prostate, ovarian, lung, and cervical cancers, FT836 achieved tumor growth inhibition rates of 94.5% ± 5.0% ( figure 1). Moreover, the activity and durability of response was further enhanced with the combination of mAb in various stress tumor models. Treatments combining FT836 with chemotherapy, radiotherapy, or antibody-drug conjugates enhanced MICA/B expression on tumor cells, further improving CAR-mediated anti-tumor responses.In serial tumor challenge experiments conducted in base culture or allogeneic environment, the ADR and CD58 knockout edits uniquely enabled sustained functionality and persistence of FT836 even with exposure to alloreactive immune cell attack (figure 2).Conclusions FT836 is a multiplexed engineered, off-the-shelf CAR T-cell therapy targeting the α3 domain of MICA/B, offering applicability across multiple solid tumor types without the need for CCT to facilitate broader clinical application and overcome multiple challenges that limit adoptive cell therapies in treating solid tumor.Abstract 264 Figure 1FT836 demonstrates broad and potent anti-tumor activity in several xenograft settings in vivo, uniquely matching primary CAR-T cell activityAbstract 264 Figure 2FT836 resists allorejection while maintaining durable anti-tumor activity and persistence

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.