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Carisma Therapeutics Begins Phase I Trial of HER2 CAR-Monocyte Therapy

NEW YORK – Carisma Therapeutics on Thursday said the first patient with a HER2-overexpressing solid tumor received its investigational cell therapy CT-0525 in a Phase I trial.

The milestone comes on the heels of a pipeline reprioritization that the Philadelphia-based drug developer announced last month, which resulted in a 37 percent workforce reduction in Q2. As part of the reorganization, Carisma discontinued patient recruitment in a Phase I trial of the CAR-macrophage CT-0508 in patients with HER2-positive tumors (immunohistochemistry 3+ scores) and stopped developing the anti-mesothelin CAR-monocyte CT-1119 until it receives additional financing.

The changes will allow Carisma to focus on advancing CT-0525, also a CAR-monocyte therapy, as its lead anti-HER2 product. The company believes that CAR-monocytes have the potential for a 2,000-fold increase in patient exposure compared to CAR-macrophages and that CT-0525 can improve on the anti-tumor activity observed in the now discontinued Phase I trial of CT-0508.

In April, Carisma reported preliminary results from that earlier trial of CT-0508 in combination with Merck's PD-1 inhibitor Keytruda (pembrolizumab), showing that the therapy was well-tolerated and caused no dose-limiting toxicities. Two out of three patients responded, and one had stable disease.

"Our preclinical data leads us to believe that this next-generation approach of our [CAR-monocyte] platform has the potential to have a greater impact on patients than our initial CAR-macrophage program, particularly through faster manufacturing, higher dosing, and increased potency, persistence, and tumor infiltration," Carisma Chief Medical Officer Eugene Kennedy said in a statement.

Carisma's CAR-macrophage (CAR-M) platform is designed to treat solid tumors by overcoming the mechanistic heterogeneity of cancer cells that allows them to bypass the immune response triggered by single-antigen therapies. CAR-M therapy differs from CAR T-cell therapy in that macrophages are harvested and engineered instead of T cells. CAR-monocytes are a further refinement of the CAR-macrophage approach that makes use of monocytes, which are macrophage precursor cells. According to Carisma, preclinical models showed that, with CAR-monocytes, five times more cells can be produced from a single apheresis with 40-fold higher tumor infiltration and 10-fold increased persistence compared to CAR-macrophages.

In the Phase I trial of CT-0525 that's now underway, Carisma researchers are enrolling six patients with locally advanced unresectable or metastatic solid tumors overexpressing HER2 that have progressed on standard therapy. The company's goal is to evaluate the safety and tolerability of CT-0525 and gauge the feasibility of manufacturing the product. Secondarily, investigators will be tracking patients' overall response rates and duration of response on CT-0525.

To be eligible for the study, patients' tumors must have IHC 3+ or 2+ scores for HER2 overexpression with confirmation by in situ hybridization. Patients with HER2-positive breast cancer must have received at least two US Food and Drug Administration-approved anti-HER2 therapies in the advanced or metastatic setting. They may also have received checkpoint inhibitors and other targeted therapies for actionable molecular alterations. For patients with other HER2-positive tumor types, they must have progressed on at least two prior standard-of-care therapies.

Carisma is expecting to report initial data from this trial in Q4 2024.