Recently, Carisma Therapeutics, a pioneer in macrophage therapy, announced the first candidate nomination for its solid tumor program in collaboration with Moderna — a targetedGPC3CAR-Macrophage (CAR-M) Therapy in China.
This is the latest effort by Carisma Therapeutics on CAR-M after the company recently announced abandoning the CAR-M project to shift focus to CAR-monocytes.
GPC3-Targeted CAR-M In VivoThis collaboration between Moderna and Carisma Therapeutics can be traced back to January 2022, when a study titled "mRNA LNP directing the in vivo production of CAR-T cells" was featured on the cover of Science, sparking global pharmaceutical interest in in vivo CAR cell therapies.The first nominated candidate drug from the collaboration is an in vivo CAR-M targeting GPC3.This candidate drug simultaneously combines Moderna's LNP mRNA technology and Carisma Therapeutics' engineered monocyte/macrophage technology;Utilizing LNP (lipid nanoparticles) to deliver mRNA into patients, and leveraging the gene-editing function of mRNA to reprogram target cells, transforming them into specific targeted CAR-M cells with the ability to kill tumor cells.According to the report, preclinical data indicate that the candidate drug can directly generate CAR-M in vivo and redirect endogenous myeloid cells to attack cancer cells.In addition, the nomination of this candidate drug will trigger a $2 million milestone payment from Moderna to Carisma.In fact, Carisma Therapeutics itself has abandoned further exploration of the ex vivo solid tumor CAR-M project, focusing instead on the development of CAR-monocytes.In a major strategic update released this April — cutting staff by 37%, abandoning further development of the CAR-M project CT-0508, and suspending the preclinical CAR-monocyte therapy CT-1119,Focusing on the more potentially promising CAR-monocyte therapy CT-0525.However, the official website of Carisma Therapeutics, Inc. does not show the above updates.Abandoning the most leading candidate pipeline CT-0508 and placing all bets on the CAR-monocyte therapy CT-0525 is a无奈之举 driven by Carisma Therapeutics' cash flow困境.At the same time, it is alsoCarisma Therapeutics Sees Greater Potential for CAR-Monocytes in Solid Tumor Treatment——CAR-monocyte therapy has the potential to address some of the challenges in solid tumor cell therapy, including tumor infiltration, immunosuppression in the tumor microenvironment, and antigen heterogeneity.CT-0525 is an ex vivo gene-modified autologous HER2 CAR-singleNuclear cell therapy, currently in Phase 1 clinical trials for the evaluation of treating patients with HER2-overexpressing advanced/metastatic solid tumors. Compared with CAR-macrophages,CT-0525 may have stronger tumor infiltration ability, persistence, and shorter production time.。Currently, CT-0525 has been granted Fast Track designation by the U.S. FDA for the treatment of HER2-overexpressing solid tumors.Fibrotic Development of Engineered MacrophagesDespite the fact that Carisma Therapeutics has abandoned further exploration of CAR-M in the treatment of solid tumors.However, in terms of fibrosis and immunology, Carisma Therapeutics' engineered macrophage therapy has achieved positive preclinical data:Single-dose engineered macrophages co-expressing the anti-fibrotic factor relaxin and IL-10 significantly improved fibrosis in a CCL4-induced liver fibrosis model, with a 116% reduction in fibrosis compared to the control group; in a high-fat diet-induced metabolic dysfunction-associated steatohepatitis (MASH) model, they significantly reduced liver fibrosis, with a 45% reduction in fibrosis compared to the control group.
Moreover, engineered macrophages expressing a dominant-negative TGFβ receptor were able to abrogate pro-fibrotic TGFβ signaling in the lung, preventing pulmonary fibrosis in a mouse model, with a 90% reduction in fibrosis compared to the control group.Carisma Therapeutics, Inc. is expected to nominate a development candidate for its liver fibrosis program in the first quarter of 2025.In recent years, the development of tumor treatments using various types of immune cells has become very popular, including T cells, NK cells, macrophages, γδ-T cells, etc. However, compared to T cells, the progress of other types of cell therapies has not been as rapid.As a pioneer in global macrophage development, Carisma Therapeutics has already abandoned the application of CAR-M in solid tumor treatment, which has had a significant impact on the development of macrophage therapies for solid tumors within the industry.
1.https://ir.carismatx.com/news-releases/news-release-details/carisma-therapeutics-announces-nomination-first-vivo-car-m2.https://ir.carismatx.com/news-releases/news-release-details/carisma-therapeutics-granted-fda-fast-track-designation-ct-05253.https://ir.carismatx.com/news-releases/news-release-details/carisma-therapeutics-reports-first-quarter-2024-financial
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