Abstract 5248: Novel costimulatory domain improves CAR-monocyte activity against tumors

Abstract Myeloid cells, unlike other immune cells such as T cells or NK cells, are known residents in the solid tumor microenvironment (TME). In the absence of checkpoints and in proinflammatory conditions, myeloid cells (particularly M1 macrophages) are known to be capable of direct phagocytosis of tumor cells and can present tumor-associated antigens to the host immune system. However, the immunosuppressive conditions within the TME restrict and limit the anti-tumor response of tumor associated macrophages (TAMs), including their ability to recruit and activate other immune cells against the tumor. Engineered CAR-Monocytes can serve a unique function in cell therapy by bridging a key gap in the treatment of solid tumors. We are developing an autologous engineered CAR-M cell therapy product targeting Glypican-3 (GPC3) to treat hepatocellular carcinoma (HCC). The CAR serves a dual purpose as a homing ‘GPS’ signal for trafficking directly to the tumor site, and for directing phagocytosis specifically at targeted tumor cells. We have designed a proprietary CAR molecule (M83 CAR) which contains a macrophage-specific costimulatory domain that significantly increases the phagocytosis function of the CAR-M cells. Furthermore, we have demonstrated that the M83 CAR-M cells are not inhibited by the prevalent CD47 checkpoint (‘do not eat me’ signal expressed on tumor cells), which is known to restrict myeloid function in the TME. Effective phagocytosis of engineered CAR-M cells is central to subsequent mechanisms of actions that can elicit robust anti-tumor immunity against patient-specific neoantigens. However, the first barrier to overcome is effective infiltration of engineered CAR-M into the tumor from the periphery. We have demonstrated that our engineered CAR-Monocyte drug product can successfully home to the targeted tumor specifically, from the periphery. Subsequent in situ differentiation of CAR-monocytes into CAR-macrophages (M1) enables robust tumor cell phagocytosis, the central mechanism that can result in the following series of events: 1) proinflammatory shift in the TME milieu, 2) recruitment of innate and adaptive immune cells, 3) activation of T-cells against tumor neo-antigens. This is a unique outcome of the CAR-M mechanism of action that is not capitulated by CAR-T or CAR-NK cells. Leveraging and further enhancing CAR-M function could lead to the rejection of the tumor and its metastases, particularly in combination with other immune-modulating therapies. Citation Format: Kevin Carbajal, Warren Anderson, Kilsoo Jeon, Grace Reynolds, Prasanna Ekambaram, Beatrice Breckheimer, Anastasya Birger, Jessica Pafford, Matthew Esquivel, Adam Pecoraro, Sumiti Jain. Novel costimulatory domain improves CAR-monocyte activity against tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5248.