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CD33 and FLT3 are validated targets for myeloid malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). These malignancies have poor prognosis and high clinical unmet need, and current targeted therapies present ample limitations. One challenge is that untargeted leukemic stem cells (LSCs) can contribute to eventual relapse; however, targeting the LSC markers FLT3 and CD33 can contribute to off-tumor toxicities against normal hematopoietic stem cells and progenitor cells (HSCs/HPCs), leading to bone marrow toxicities such as thrombocytopenia, neutropenia, and infectious complications. SENTI-202 is designed to address these challenges and provide a broader therapeutic window. SENTI-202 is a preclinical CAR-NK cell product candidate engineered with an OR and NOT logic gated gene circuit onto allogeneic healthy adult peripheral blood NK cells along with multi-arming via expression of calibrated release IL-15 (crIL-15) to enhance therapeutic activity and tolerability. The OR gate is implemented using a bivalent CAR (aCAR) that binds both CD33 and FLT3 to target both AML blasts and LSCs. Additionally, the NOT gate is implemented using an inhibitory CAR (iCAR) that recognizes the healthy cell protective antigen endomucin (EMCN) and targets endomucin which is designed to prevent CAR-mediated cytotoxicity against healthy cells, such as HSCs and early HPCs, potentially reducing on-target/off-tumor toxicities. Finally, crIL-15 provides NK cell activation and persistence via simultaneous autocrine, juxtracrine, and paracrine activities. Preclinical studies demonstrated the [antitumor] activity and tolerability of SENTI-202. All SENTI-202 components are stably expressed via a single g-retroviral vector. SENTI-202 preclinical pharmacokinetics and secondary pharmacodynamics demonstrated CAR target engagement, function, as well as mechanism of action for all components in different AML models. SENTI-202 CAR-NK cells demonstrated cytotoxic activity when co-cultured with AML target cells and primary patient-derived samples and had increased antitumor capacity compared to non-engineered NK cells. SENTI-202 induced the production of cytotoxic cytokines and increased expression of activation and cytotoxicity markers consistent with CAR-mediated activation of the NK cells. The presence of EMCN iCAR reduced cytotoxicity in an EMCN-dependent manner in target cells and primary HSCs. crIL-15 expression yielded functional pSTAT5 signaling and increased persistence of SENTI-202 in vitro and in vivo. These results demonstrate the antitumor activity and tolerability of SENTI-202 and warrant further clinical development as a novel therapeutic option for patients with CD33+ and/or FLT3+ tumors. Citation Format: Alba Gonzalez, Enping Hong, Gozde Yucel, Elizabeth Leitner, Pearley Chinta, Han Deng, Ian Li, Alice Lam, Abla Bakir, Brandon Lee, Papia Chakraborty, Carmina Blanco, Chen-Ting Lee, Niran Almudhfar, Mengxi Tian, Wenqi Song, Andrew Banicki, Otto Contreras, Martin Gieldin, Brian Garrison, Timothy K. Lu, Kanya Rajangam. Preclinical development of SENTI-202, an off-the-shelf logic gated CAR-NK cell therapy, for the treatment of CD33/FLT3+ hematologic malignancies including AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3195. |
