By Erin Harris, Editor-In-Chief, Cell & Gene
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Last year, I caught up with Michael Klichinsky, Ph.D. co-founder and VP of discovery and research at Carisma Therapeutics to discuss its then preclinical findings indicate that CAR-M therapy could overcome the key challenges that cell therapies have encountered with solid tumors — limited trafficking to the tumor site, an immunosuppressive tumor microenvironment, and the heterogeneous expression of tumor-associated antigens. In that article, among other things, Dr. Klichinsky and I discussed the challenges the cell and gene therapy sector faces when it comes to solid tumors. He explained that while it is clear that CAR-T cells are very good at killing hematologic malignancies (for example, B-cell acute lymphoid leukemia and B-cell non-Hodgkin lymphomas) in patients, they have a hard time against solid tumors.
He stated that the three key challenges in targeting solid tumors include trafficking, immunosuppression, and antigen heterogeneity. “Our data shows that macrophages have the unique potential to overcome these challenges because: (i) macrophages are actively recruited to solid tumors, while other immune cells are often actively excluded, (ii) CAR-M are M1 polarized and rather than being corrupted by the suppressive factors of the TME, they exert a ‘warming’ effect on the TME, and (iii) macrophages are professional antigen presenting cells, capable of priming a broad adaptive immune response against the tumor,” Klichinsky states.
Good News for CT-0508
Cut to 18 months later. I had the chance to talk to Carisma’s CMO, Dr. Debora Barton on Cell & Gene: The Podcast, and she shared information about how CAR-Macrophages can eat away at tumors and lead to long-term anti-tumor immunity, giving patients a promising new long term strategy in the fight against cancer. Indeed, Carisma Therapeutics is developing CT-0508 to target HER2-positive solid tumors. While its expression in normal tissues is low, HER2 is highly expressed in a wide range of solid tumors and plays an active role in both malignant transformation and tumor aggressiveness by promoting cancer cell proliferation, invasion, and metastasis.
During the episode, Dr. Barton takes a deep dive into the data that Carisma presented at the 36th Annual Society for Immunotherapy of Cancer (SITC) Annual Meeting. Carisma delivered an oral presentation, which discussed the initial findings from their Phase 1 first-in-human study of adenovirally transduced Anti-HER2 CAR Macrophages in subjects with HER2 overexpressing solid tumors. CT-0508 is the first CAR-Macrophage cell therapy to enter clinical trials. Preclinical trials showed that the treatment has the potential to overcome the key challenges faced by other cell therapies in treating solid tumors. Specifically, the clinical study centers on patients with recurrent or metastatic HER2-overexpressing solid tumors whose cancers do not have approved HER2-targeted therapies or who do not respond to treatment.
Inside the Pipeline
Carisma is developing CT-1119, (Mesothelin), an ex vivo gene-modified autologous CAR-Macrophage cellular therapy to target mesothelin-positive solid tumors. CT-1119 is in pre-clinical development. Carisma is also developing CT-0729, (PSMA), an ex vivo gene-modified autologous CAR-Macrophage cellular therapy to target prostate-specific membrane antigen for treatment of metastatic castration-resistant prostate cancer. To date, CT-0729 is in discovery.