Background Chimeric Antigen Receptor (CAR)-based cell-therapies have demonstrated clinical benefit in select blood cancers. Unfortunately, their success has yet to be translated to solid tumors. Poor antigen specificity and immune-suppressive mechanisms in the tumor microenvironment (TME) pose key challenges for cell-therapies in the treatment of solid tumors.
Methods SENTI-401, a CAR-NK cell-therapy with NOT Logic Gating and Multi-Arming gene circuits, is designed to overcome the above challenges. SENTI-401 targets CEACAM5 (CEA), a tumor-associated antigen (TAA) highly expressed in solid tumors, including colorectal, pancreatic and lung cancers. SENTI-401 also incorporates NOT Gate technology to overcome on-target off-tumor toxicity from CEA expression by healthy epithelial cells, which has been previously reported when targeting CEA in the clinic.1 Senti is evaluating the effects of multi-arming CAR-NK cells with immunostimulatory payloads to potentially overcome the immunosuppressive TME.
Senti’s novel NOT-Gate technology incorporates an activating (aCAR) targeting a TAA, paired with an inhibitory (iCAR) that recognizes a safety antigen (SA) uniquely expressed on the surface of healthy cells. The NOT-Gate significantly reduces CAR-mediated killing of target cells in a SA-dependent manner, thus mitigating on-target, off-tumor toxicity and allowing targeting of tumor antigens that are broadly expressed by healthy cells.
Results Using our Tumor-Associated Antigen and Safety Antigen Discovery Platform, we discovered and validated VSIG2, a protein on the surface of CEA-expressing healthy epithelial cells and not on tumor cells.
NK cells expressing CEA-targeting aCARs and VSIG2-targeting iCARs receptor pairs had significantly reduced CAR-mediated killing of target cells expressing both CEA and the SA VSIG2, in vitro and in vivo.
To enhance persistence and activity of CAR-NK cells, we developed, calibrated release (cr) technology, which can be coupled to cytokines such as IL-15, resulting in a desired ratio of secreted and surface-bound cytokine to provide autocrine and paracrine functions. The combination of crIL-15 and IL-21 resulted in increased survival and activation of anti-CEA CAR-NK cells, and leading to significantly increased target-cell killing in serial-killing assays. In vivo, anti-CEA CAR-NK cells expressing the both cytokines had superior activity and longer persistence compared to anti-CEA CAR-NK cells. Similarly, we optimized gene-circuits to confer resistance to the immunosuppressive effects of TGFb; anti-CEA CAR-NK cells armed with TGFb-blocking constructs sustained target-cell killing in the continuous presence of TGFb.
Conclusions SENTI-401 incorporates NOT-Gating and Multi-Arming gene-circuits into CAR-NK cells in order to improve the therapeutic window and efficacy of CEA-targeting cell-therapies for the treatment of solid tumors.
Parkhust MR, Yang JC, Langan RC, et al T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther. 2011 Mar;19(3):620-6 [doi: 10.1038/mt.2010.272.]
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