Precigen Presents Preclinical Data for the Next Generation Mesothelin UltraCAR-T® with Intrinsic PD-1 Blockade at the AACR Annual Meeting 2023
– First preclinical data presented for the next generation of the UltraCAR-T platform utilizing a mesothelin (MSLN) chimeric antigen receptor (CAR) –
– MSLN is overexpressed on multiple solid tumors such as mesothelioma, ovarian cancer and pancreatic cancer –
– Proprietary technology for checkpoint blockade intrinsic to UltraCAR-T cells has the potential for an improved safety profile and reduced cost by eliminating the need for checkpoint inhibitor combination –
– Single administration of next generation MSLN UltraCAR-T incorporating intrinsic PD-1 blockade resulted in robust UltraCAR-T cell expansion and durable persistence leading to strong antitumor efficacy, even upon tumor rechallenge after three months –
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.
UltraCAR-T is a multigenic autologous CAR-T platform that utilizes
UltraCAR-T® Clinical Program
The UltraCAR-T platform has shifted the autologous CAR-T manufacturing paradigm using an advanced non-viral multigene delivery system and an overnight, decentralized manufacturing process for administration of autologous CAR-T cells one day after gene transfer to reduce vein-to-vein time.
UltraCAR-T® Library Approach
The UltraPorator system is an exclusive device and proprietary software solution for the scale-up of rapid and cost-effective manufacturing of UltraCAR-T therapies and potentially represents a major advancement over current electroporation devices by significantly reducing the processing time and contamination risk. The UltraPorator device is a high-throughput, semi-closed electroporation system for modifying T cells using
Cautionary Statement Regarding Forward-Looking Statements
Some of the statements made in this press release are forward-looking statements. These forward-looking statements are based upon the Company's current expectations and projections about future events and generally relate to plans, objectives, and expectations for the development of the Company's business, including the timing and progress of preclinical studies, clinical trials, discovery programs and related milestones, the promise of the Company's portfolio of therapies, and in particular its CAR-T and AdenoVerse therapies. Although management believes that the plans and objectives reflected in or suggested by these forward-looking statements are reasonable, all forward-looking statements involve risks and uncertainties, including the possibility that the timeline for the Company's clinical trials might be impacted by the COVID-19 pandemic, and actual future results may be materially different from the plans, objectives and expectations expressed in this press release. The Company has no obligation to provide any updates to these forward-looking statements even if its expectations change. All forward-looking statements are expressly qualified in their entirety by this cautionary statement. For further information on potential risks and uncertainties, and other important factors, any of which could cause the Company's actual results to differ from those contained in the forward-looking statements, see the section entitled "Risk Factors" in the Company's most recent Annual Report on Form 10-K and subsequent reports filed with the
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