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  • 659 A phase 1, first-in-human study of autologous monocytes engineered to express an anti-HER2 chimeric antigen receptor (CAR) in participants with HER2 overexpressing solid tumors

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Regular and Young Investigator Award Abstracts
Clinical Trials In Progress
659 A phase 1, first-in-human study of autologous monocytes engineered to express an anti-HER2 chimeric antigen receptor (CAR) in participants with HER2 overexpressing solid tumors
  1. Yara Abdou1,
  2. Paula R Pohlmann2,
  3. Richard T Maziarz3,
  4. Hemant S Murthy4,
  5. Yuan Yuan5,
  6. Anuradha Krishnamurthy6,
  7. Kim Reiss7,
  8. James M Isaacs8,9,
  9. Aiwu He10,
  10. Mitchell S Cairo11,
  11. Felicia Cao1,
  12. Pooja Advani4,
  13. Daniel Blumenthal12,
  14. Kenneth Locke12,
  15. Jeanette Wetzel12,
  16. Michael Klichinsky12,
  17. Thomas Condamine12,
  18. Eugene Kennedy12 and
  19. Davendra Sohal13
  1. 1University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
  2. 2The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  3. 3Oregon Health and Science University, Portland, OR, USA
  4. 4Mayo Clinic, Jacksonville, FL, USA
  5. 5Cedars-Sinai, Los Angeles, CA, USA
  6. 6Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
  7. 7University of Pennsylvania, Merion Station, PA, USA
  8. 8Duke University, Durham, NC, USA
  9. 9Cleveland Clinic, Cleveland, OH, USA
  10. 10Medstar Georgetown University Hospital, Washington, DC, USA
  11. 11New York Medical College Maria Fareri Children’s Hospital, Valhalla, NY, USA
  12. 12Carisma Therapeutics, Philadelphia, PA, USA
  13. 13University of Cincinnati Cancer Center, Cincinnati, OH, 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 Myeloid cells are actively recruited to the solid tumor microenvironment (TME) and have the potential to mediate tumor control via phagocytosis, TME remodeling, and T cell activation. We previously developed human chimeric antigen receptor macrophages (CAR-Macrophage) and have shown potent anti-tumor activity in pre-clinical solid tumor models.1 The anti-HER2 CAR-Macrophage cell therapy product, CT-0508, was evaluated in a Phase 1 trial as a monotherapy and in combination with pembrolizumab. Clinical data have demonstrated preliminary safety, feasibility, and validated the mechanism of action. We have developed to increase the available dose, improve tumor trafficking and engraftment, and shorten the manufacturing and vein-to-vein time as compared to CAR-Macrophage therapy. CT-0525 is an autologous anti-HER2 CAR-Monocyte cell therapy based on CD14+ monocytes engineered with an Ad5f35 adenoviral vector to express an anti-HER2 CAR. Pre-clinical studies have demonstrated the feasibility, phenotype, pharmacokinetics, durable CAR expression, cellular fate, antigen specificity, and anti-tumor activity of CT-0525. Pre-clinical studies have shown that CT-0525 differentiated into pro-inflammatory CAR-Macrophages in vivo and controlled tumor growth. The CT-0525 manufacturing process takes one day and enables the production of up to 10 billion cells from a single apheresis. CT-0525 is being investigated in a first-in-human, open-label, multi-center, Phase 1 study in participants (pts) with HER2 overexpressing solid tumors.

Methods This Phase 1, first-in-human study evaluates the preliminary safety, feasibility, tolerability, trafficking, TME activation, and initial evidence of efficacy of the investigational CAR-Monocyte product CT-0525 in pts with locally advanced unresectable/metastatic solid tumors overexpressing HER2. Pts previously treated with anti-HER2 therapies are eligible for this dose escalation study. Filgrastim mobilized autologous CD14+ monocytes are collected by apheresis, followed by manufacturing and cryopreservation. CT-0525 will be administered without conditioning chemotherapy. The 1st cohort of pts will receive 3 x 109 CT-0525 CAR monocytes administered in one infusion intravenously. If tolerated as per the modified toxicity probability interval algorithm (mTPI), the 2nd cohort of pts will receive up to 10 x 109 CT-0525 CAR monocytes in one infusion. A minimum of 3 evaluable pts is required at each dose level. Primary endpoints include assessment of safety and tolerability, as well as manufacturing feasibility. Secondary endpoints include initial evidence of efficacy. Correlative assessments include pre- and post-treatment biopsies and blood samples for safety, immunogenicity, pharmacokinetics, tumor trafficking, TME modulation, epitope spreading, and other translational biomarkers.

Ethics Approval The study has obtained ethics approval with local IRBS at enrolling clinical sites and all participants gave informed consent before being enrolled in the study.

Reference

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

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jitc-2024-SITC2024.0659

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