Abstract CT241: A phase 1, first-in-human (FIH) study of autologous anti-HER2 chimeric antigen receptor macrophage (CAR-M) in participants (pt) with HER2 overexpressing solid tumors
Authors: Abdou Yara , Dees E. Claire , Mortimer Joanne , Ueno Naoto , Johnson Melissa , Maziarz Richard , Specht Jennifer , Yuan Yuan , Puhlman Paula , Angelos Mathew , Gill Saar , Ronczka Amy , Condamine Thomas , Cushing Daniel J. , Klichinsky Michael , Barton Debora , Swaby Ramona F. , Binder Kim Reiss 
Published: April 2023

Abstract
Background: Macrophages are abundant in the solid tumor microenvironment (sTME) and can exhibit both pro- and anti-tumor functions. Macrophages can be redirected by CAR expression to phagocytose cancer cells in an antigen-specific manner. CAR-M can reprogram the sTME and present neoantigens to T cells, leading to epitope spreading and anti-tumor immunity. CT-0508 is comprised of autologous monocyte-derived proinflammatory macrophages expressing an anti-HER2 CAR. Pre-clinical studies showed that CT-0508 induced targeted cancer cell phagocytosis while sparing normal cells, decreased tumor burden, prolonged survival, and was safe and effective. Notably, anti-HER2 CAR-M treatment led to activation of the sTME, with infiltration of CD8+ and CD4+ T cells, NK cells, dendritic cells, and increased activated CD8+ tumor infiltrating lymphocytes. In a pre-clinical model of advanced solid tumor resistant to PD1 blockade, mice treated with anti-HER2 CAR-M combined with a PD1 blocking antibody demonstrated improved tumor control, overall survival, and TME activation compared to either treatment alone, indicating synergy and capacity for CAR-M to sensitize solid tumors to checkpoint blockade.
Methods: This Phase 1, FIH study is evaluating safety, tolerability, cell manufacturing feasibility, trafficking, TME activation, and preliminary evidence of efficacy of investigational product CT-0508 in 18 pt with locally advanced (unresectable)/metastatic solid tumors overexpressing HER2. Pt previously treated with anti-HER2 therapies are eligible. Filgrastim mobilized autologous CD14+ monocytes are collected by apheresis, followed by manufacturing and cryopreservation. Group 1 pt (n = 9; enrollment complete) received fractionated doses over Days 1, 3, and 5. Group 2 pt (n = 9) receive CT-0508 as a single infusion on D1. Additional cohorts include: CT-0508 co-administered with pembrolizumab and CT-0508 monotherapy administered intraperitoneally in pt with peritoneal predominant disease. Correlative assessments include pre- and post-treatment biopsies and blood samples for safety (immunogenicity), trafficking (qPCR, RNA in situ hybridization), CT-0508 persistence in blood and tumor, target antigen engagement, TME modulation (single cell RNA sequencing), immune response (TCR sequencing) and others.
Citation Format: Yara Abdou, E. Claire Dees, Joanne Mortimer, Naoto Ueno, Melissa Johnson, Richard Maziarz, Jennifer Specht, Yuan Yuan, Paula Puhlman, Mathew Angelos, Saar Gill, Amy Ronczka, Thomas Condamine, Daniel J. Cushing, Michael Klichinsky, Debora Barton, Ramona F. Swaby, Kim Reiss Binder. A phase 1, first-in-human (FIH) study of autologous anti-HER2 chimeric antigen receptor macrophage (CAR-M) in participants (pt) with HER2 overexpressing solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT241.