1517 Mutant-p53 amplifies Cxcl1 expression from distal enhancers blunting immune checkpoint inhibition efficacy in pancreatic cancer

• DOI: 10.1136/jitc-2023-sitc2023.1517
• Publication Date: 2023-10-31T11:01:43Z
• Authors: Dig Bijay Mahat; Heena Kumra; Emily Metcalf; Sarah Castro; Kim Nguyen; William W Ho; Ivy Chen; Brandon Sullivan; Leon K Yim; Vikash Chauhan; Arjun Bhutkar; Hernandez Moura S...; Stefani Spranger; Rakesh K Jain; Phillip A Sharp
• Keywords: Immune checkpoint

<h3>Background</h3> Myeloid cells, unlike other immune cells such as T or NK are known residents in the solid tumor microenvironment (TME). In absence of checkpoints and proinflammatory conditions, M1 macrophages to be capable direct phagocytosis can present tumor-associated antigens host system. However, immunosuppressive conditions within TME restrict limit anti-tumor response associated (TAMs), including their ability recruit activate against tumor. Engineered CAR-Monocytes serve a unique function cell therapy by bridging key gap treatment tumors. We developing an autologous engineered CAR-M product targeting Glypican-3 treat hepatocellular carcinoma. The CAR serves homing 'GPS' signal for trafficking directly site, directs specifically at targeted cells. Our proprietary M83.CAR molecule contains macrophage-specific costimulatory domain that significantly increases Furthermore, we have demonstrated M83.CAR-M not inhibited prevalent CD47 'do eat me' checkpoint, which is myeloid TME. <h3>Methods</h3> Primary hematopoietic stem (HSCs) were harvested express lentivirus transduction generating CAR-HSCs. CAR-HSCs underwent our ex-vivo HSC differentiation process yield CAR-Monocytes. <h3>Results</h3> Effective central subsequent mechanisms actions elicit robust immunity patient-specific neoantigens. first barrier overcome effective infiltration into from periphery. CAR-Monocyte drug successfully home specifically, Subsequent <i>in situ</i> CAR-monocytes CAR-macrophages enables phagocytosis, mechanism results following: 1) shift TME, 2) recruitment APCs 3) activation T-cells <h3>Conclusions</h3> above summarizes outcome action capitulated CAR-T CAR-NK Leveraging further enhancing could lead rejection its metastases, particularly combination with immune-modulating therapies. HSC-derived platform yields demonstrates durability superior function, expect translate clinic.