On April 17, 2023 Precigen, Inc. (Nasdaq: PGEN), a biopharmaceutical company specializing in the development of innovative gene and cell therapies to improve the lives of patients, reported preclinical data for the next generation UltraCAR-T platform utilizing MSLN CAR from Precigen’s library of non-viral plasmids at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 (Press release, Precigen, APR 17, 2023, View Source [SID1234630184]). The abstract titled, "Next Generation UltraCAR-T Cells with Intrinsic Checkpoint Inhibition and Overnight Manufacturing Overcome Suppressive Tumor Microenvironment Leading to Sustained Antitumor Activity" will be presented as a poster presentation on Monday, April 17, 2023 from 9:00 AM to 12:30 PM ET (Abstract #1791).
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Next Generation MSLN UltraCAR-T
UltraCAR-T cells are engineered to co-express a CAR, membrane bound IL-15 (mbIL15), and kill switch genes using non-viral gene transfer via the high-throughput UltraPorator system. UltraCAR-T cells offer the potential for enhanced potency, safety and scalability. Next generation MSLN UltraCAR-T cells also incorporate a novel mechanism for blockade of PD-1, to potentially supersede the need for combination therapy with checkpoint inhibitors and mitigating classic T cell exhaustion that occurs from chronic stimulation, thereby expanding the therapeutic window for efficacy. MSLN has limited expression in normal healthy tissue but is commonly overexpressed on multiple solid tumors such as mesothelioma, ovarian cancer and pancreatic cancer and is associated with poor prognosis making it an attractive anti-tumor target.
Preclinical Summary Results
Next generation MSLN UltraCAR-T cells were successfully engineered using a single multicistronic non-viral transposon and overnight manufacturing process to simultaneously express a CAR, mbIL15, a kill switch, and a novel mechanism for intrinsic PD-1 blockade. Next generation MSLN UltraCAR-T cells showed specific and significant downregulation of PD-1 leading to significant increase in cytotoxicity of MSLN+ PD-L1+ tumor cells in vitro at low effector to target cell ratios compared to control MSLN CAR-T cells lacking PD-1 blockade. Next generation MSLN UltraCAR-T cells exhibited markedly enhanced polyfunctionality as well as enhanced inflammatory cytokine production in the presence of MSLN+ PD-L1+ tumor cells.
In two different in vivo xenograft models, MSLN+ PD-L1+ ovarian cancer and MSLN+ PD-L1+ mesothelioma, a single administration of next generation MSLN UltraCAR-T cells to tumor bearing mice resulted in robust UltraCAR-T cell expansion and durable persistence leading to significant antitumor efficacy. Moreover, rechallenging the previously treated mice who became tumor-free for a second time with mesothelioma tumors to simulate tumor relapse led to the significant reduction in tumor burden without additional MSLN UltraCAR-T treatment demonstrating the durable persistence and functionality of UltraCAR-T cells in vivo.
In mice, the next generation MSLN UltraCAR-T cells demonstrated significant downregulation of PD-1 and preferred CAR-T phenotype that was most similar to T central memory (TCM) and stem cell memory (TSCM). These data demonstrate the potential of UltraCAR-T cells to persist long-term in vivo, prevent CAR-T cell exhaustion, and mount a durable anti-tumor response with the ability for continued response upon tumor rechallenge.
"Precigen has built one of the most comprehensive clinical and preclinical CAR-T portfolios with antigen-specific targets spanning both hematological and solid tumors, including CD33, MUC16, ROR1, CD19, BCMA and MSLN," said Helen Sabzevari, PhD, President and CEO of Precigen. "MSLN is the second target for the next generation UltraCAR-T incorporating intrinsic checkpoint inhibition, following our recently initiated Phase 1/1b study for PRGN-3007. With every milestone, we move closer to our ultimate vision to transform the personalized cell therapy landscape using Precigen’s library approach to target tumor-associated antigens to address unmet medical needs for cancer patients."