563TiP - A phase I, first in human (FIH) study of adenovirally transduced autologous macrophages engineered to contain an anti-HER2 chimeric antigen receptor (CAR) in subjects with HER2 overexpressing solid tumors

Background

T cell therapies have led to remarkable advances in hematologic malignancies, but not in solid tumors (ST). Macrophages are actively recruited into, and abundantly present in the solid tumor microenvironment (sTME). Tumor associated macrophages are typically immunosuppressive, but can be engineered with a CAR to be proinflammatory, recognize and phagocytose antigen overexpressing cancer cells, reprogram the sTME and present neoantigens to T cells, leading to epitope spreading and immune memory. HER2 is overexpressed in many cancers, including but not limited to breast and gastroesophageal (table). CT-0508 is comprised of autologous monocyte-derived pro-inflammatory macrophages expressing an anti-HER2 CAR. Pre-clinical studies have shown cancer cell phagocytosis while sparing normal cells, decreased tumor burden and prolonged survival in relevant models, and were safe and effective in a semi-immunocompetent mouse model of human HER2 overexpressing ovarian cancer. Table: 563TiP

HER2 positivity

*References available upon request

Trial design

This is a FIH phase 1 study to evaluate safety, tolerability, manufacturing feasibility, trafficking, and preliminary efficacy of CT-0508 in 18 subjects with locally advanced or metastatic ST overexpressing HER2 who have failed available therapies. G-CSF will be used to mobilize autologous hematopoietic progenitor cells for monocyte collection by apheresis, final CT-0508 product will be cryopreserved. Group 1 subjects will receive CT-0508 infusion over D1, 3 and 5 and will be continually assessed for acute and cumulative toxicity. Dose limiting toxicities will be addressed by a Safety Review Committee. Group 2 subjects will then receive the full dose infusion on D1. Biopsies and blood samples will be collected to investigate correlates of trafficking, persistence, TME modulation, immune response and safety.

Clinical trial identification

NCT04660929.

Editorial acknowledgement

Legal entity responsible for the study

Carisma Therapeutics.

Funding

Carisma Therapeutics.

Disclosure

K.R. Binder: Financial Interests, Personal, Research Grant: Lilly Oncology; Financial Interests, Personal, Research Grant: BMS; Financial Interests, Personal, Research Grant: GSK; Financial Interests, Personal, Research Grant: Tesaro; Financial Interests, Personal, Research Grant: Clovis Oncology. D. Barton: Financial Interests, Personal, Full or part-time Employment: Carisma Therapeutics. A. Ronczka: Financial Interests, Personal, Full or part-time Employment: Carisma Therapeutics. D. Cushing: Financial Interests, Personal, Full or part-time Employment: Carisma Therapeutics. M. Klichinsky: Financial Interests, Personal, Full or part-time Employment: Carisma Therapeutics. C. Dees: Financial Interests, Personal, Research Grant: Carisma Therapeutics; Financial Interests, Personal, Research Grant: Apollomics; Financial Interests, Personal, Research Grant: Boehringer-Ingelheim; Financial Interests, Personal, Research Grant: Debio Pharma; Financial Interests, Personal, Research Grant: G1 Therapeutics; Financial Interests, Personal, Research Grant: H3 Biosciences; Financial Interests, Personal, Research Grant: Meryx; Financial Interests, Personal, Research Grant: Lilly; Financial Interests, Personal, Research Grant: Novartis; Financial Interests, Personal, Research Grant: Pfizer; Financial Interests, Personal, Advisory Role: Strata; Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Personal, Advisory Role: G1 Therapeutics.