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635 A phase 1, first in human (FIH) study of autologous macrophages engineered to express an anti-HER2 chimeric antigen receptor (CAR) in participants (pts) with HER2 overexpressing solid tumors
  1. Kim Reiss1,
  2. Joanne Mortimer2,
  3. Paula R Pohlmann3,
  4. Melissa Johnson4,
  5. Richard T Maziarz5,
  6. Jennifer Specht6,
  7. E Claire Dees7,
  8. Yuan Yuan8,
  9. Naoto Ueno3,
  10. Mathew Angelos9,
  11. Saar Gill1,
  12. Thomas Condamine10,
  13. Daniel Cushing10,
  14. Debora Barton11,
  15. Michael Klichinsky10,
  16. Ramona F Swaby10 and
  17. Yara Abdou12
  1. 1University of Pennsylvania, Philadelphia, PA, USA
  2. 2City of Hope, Duarte, CA, USA
  3. 3The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  4. 4Sarah Cannon Research Institute, Nashville, TN, USA
  5. 5Oregon Health and Science University, Portland, OR, USA
  6. 6Fred Hutchinson Cancer Center, Seattle, WA, USA
  7. 7University of North Carolina Lineberger Comprehensive Cancer, Chapel Hill, NC, USA
  8. 8Cedars-Sinai, Los Angeles, CA, USA
  9. 9University of Pennsylvania Abramson Cancer Center, Philadelphia, PA, USA
  10. 10Carisma Therapeutics, Philadelphia, PA, USA
  11. 11TScan, Springfield, NJ, USA
  12. 12University of North Carolina at Chapel Hill, Durham, NC, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.

Abstract

Background Macrophages are abundant in the solid tumor microenvironment (sTME) and can promote tumor growth (M2) or enhance anti-tumor immunity (M1). CAR expression can redirect macrophage function to selectively target and phagocytose antigen overexpressing cancer cells. 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 demonstrated that CT-0508 induced targeted cancer cell phagocytosis while sparing normal cells, decreased tumor burden, prolonged survival, and was safe. 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 anti-PD1 resistant solid tumor model, mice that received anti-HER2 CAR-M and anti-PD1 demonstrated improved tumor control, overall survival, and TME activation compared to single treatment alone, indicating synergy and capacity for CAR-M to sensitize solid tumors to checkpoint blockade.1

Methods This Phase 1, First in Human study evaluates the safety, tolerability, cell manufacturing feasibility, trafficking, TME activation, and preliminary evidence of efficacy of investigational product CT-0508 in 18 participants (pts) with locally advanced (unresectable)/metastatic solid tumors overexpressing HER2. Pts previously treated with anti-HER2 therapies are eligible. Filgrastim mobilized autologous CD14+ monocytes are collected by apheresis, without the need for lymphodepleting chemotherapy, followed by manufacturing and cryopreservation. Group 1 pts (n = 9; enrollment complete) received fractionated doses of CT-0508 over Days 1, 3, and 5. Group 2 pts (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 pts with peritoneal predominant disease. Correlative assessments include pre- and post-treatment biopsies and blood samples for safety (immunogenicity), trafficking (PCR, RNA scope), CT-0508 persistence in blood and tumor, target antigen engagement, TME modulation (single cell RNA sequencing), immune response (TCR sequencing) and others.

Reference

  1. Klichinsky M, et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nature Biotechnology. 2020;38:947–953.

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