Carisma Therapeutics and Moderna are also collaborating to develop CAR-M cell therapies.
CT-0508, Carisma Therapeutics’ chimeric antigen receptormacrophage (CAR-M) cell therapy, is being evaluated in a first-in-human, phase 1 study (NCT04660929) for the potential treatment of solid tumors.1
An overview of the study was presented at the 2022 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers (GI) Symposium, January 20-22, 2022, by Kim A. Reiss Binder, assistant professor of medicine, University of Pennsylvania Hospital.
“Adoptive T cell therapies have led to remarkable advances among patients with hematologic malignancies, but not in those with solid tumors. Macrophages are actively recruited into, and are abundantly present in the solid tumor microenvironment (sTME). Tumor- associated macrophages typically display immunosuppressive behavior, but when engineered to be proinflammatory, may be an ideal vector to administer adoptive cellular therapy in solid tumors,” Reiss Binder and colleagues wrote.1
The phase 1 study is evaluating the safety, tolerability, feasibility, and efficacy of the cell therapy. CT-0508 consists of HER2-targeted CAR autologous monocyte-derived pro-inflammatory macrophages. CT-0508 previously demonstrated efficacy in preclinical studies and were safe in a semi-immunocompetent mouse model of HER2+ ovarian cancer.
READ MORE: CAR-Macrophage Receives Fast Track Designation for Solid Tumors
The study has dosed 2 participants, one with esophageal adenocarcinoma and the other with extrahepatic cholangiocarcinoma, with CT-0508 so far.2 The cell product was successfully manufactured. CT-0508 has been well-tolerated, with no dose-limiting toxicities or major organ toxicities observed. There was a case of grade 2 cytokine release syndrome (CRS) on day 3 which resolved same-day, as well as grade 3 adverse events (AEs) including anemia (present at baseline) and lymphopenia (present at baseline in 1/2). One patient experienced an unrelated serious AE of grade 4 tumor bleeding 88 days post-infusion.
Participants continue to be monitored for AEs, including CRS, immune effector cell-associated neurotoxicity syndrome, and other toxicities. Investigators will collect blood samples and biopsies before and after treatment to examine immunogenicity, trafficking, engagement, TME modulation, CT-0508 persistence, immune response, and others.
"To address... shortcomings, we have developed CAR macrophages and demonstrated that these engineered myeloid cells traffic to tumors, reduce tumor burden, reprogram the TME, and induce a broad anti-tumor adaptive immune response in pre-clinical models of HER2 overexpressing solid tumors,” Reiss Binder and colleagues wrote.1
The study plans to enroll 18 participants with locally advanced or metastatic solid tumors overexpressing HER2 unresponsive to available therapies, including anti-HER2 therapies. Participants will receive filgrastim for monocyte collection by apheresis. There is no preparative chemotherapy before infusion. Nine participants in the first group will receive up to 0.5x109 cells on day 1, up to 1.5x109 cells on day 3, and up to 3.0x109 cells on day 5. Participants in the second group will receive the full infusion on day 1.
The study’s primary outcomes are assessing safety and tolerability via the incidence of AEs, as well as feasibility via the percentage of products that pass release criteria among all manufactured products. Secondary outcomes are measuring the cell therapy’s efficacy via objective response rate and progression-free survival.
Carisma Therapeutics recently announced a collaboration with Moderna to develop CAR-M cell therapies for oncologic targets.3 The collaboration will combine Carisma’s engineered macrophage technology and Moderna’s mRNA and lipid nanoparticle technology to create in vivo CAR-M therapeutics. Carisma will discover and optimize candidates while Moderna will develop and commercialize candidates.
“We are excited to begin this collaboration with Carisma to further expand our oncology pipeline with a differentiated in vivo cell-therapy approach,” Stephen Hoge, president, Moderna, said in a statement.3 “This exemplifies our strategy to partner with companies with deep biological expertise while leveraging Moderna’s core mRNA and LNP capabilities to further expand the reach of Moderna’s technology.”