Investigational CAR macrophage cell therapy shown to infiltrate solid tumors
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A novel monocyte-derived cell therapy showed evidence of migrating from the blood to the tumor microenvironment for several solid tumor types, according to phase 1 study results.
Data from the trial presented at Society for Immunotherapy of Cancer Annual Meeting suggest that the experimental therapy continues to be a safe and feasible approach for the treatment of solid tumors.
Background
CT-0508 (Carisma Therapeutics) is an autologous, gene-edited, HER2-targeted chimeric antigen receptor macrophage therapy. Carisma Therapeutics and University of Pennsylvania collaborated to develop the technology, which capitalizes on previous cell therapies by using monocyte-derived macrophages genetically modified to express a CAR.
Kim A. Reiss, MD, assistant professor of medicine at Perelman School of Medicine at University of Pennsylvania and member of the Abramson Cancer Center, presented initial results from the first three patients to receive the therapy at last year’s SITC Annual Meeting. Her group has now treated nine patients and, in addition to its continued safety and feasibility to generate the product, researchers have learned a great deal about how the agent behaves within the body to target solid tumor tissue.
“By obtaining serial biopsies from the treated patients, we have learned that CT-0508 almost always gets into the tumor cells and has the ability to manipulate the [tumor microenvironment] to generate an antitumor T-cell response,” Reiss told Healio.
Methodology
Reiss and colleagues treated nine patients (median age, 58 years; range, 45-73; 33% male) as part of a phase 1 multicenter study to evaluate the safety, tolerability and feasibility of CT-0508 for patients with HER2-positive solid tumors who experienced disease progression on previous therapy.
The study included four patients with breast cancer (44%), two with esophageal cancer (22%) and one patient each with cholangiocarcinoma, ovarian cancer or salivary carcinoma.
Participants had received a median three (range, 2-11) prior lines of therapy, including previous HER2-targeted agents in eight of nine patients.
Researchers reported results from group 1 of the study, which received three fractionated doses on days 1, 3 and 5 of the treatment regimen without preconditioning lymphodepletion typically used for adoptive cellular therapy. Group 2 from the study will treat another nine patients with a single dose of CT-0508.
Safety and manufacturing feasibility served as the study’s primary endpoints. Secondary endpoints included best overall response and cell kinetics.
Key findings
Investigators reported stable disease as the best overall response to therapy in five of nine patients (55.6%).
Successful manufacturing of CT-0508 occurred for all patients.
Meanwhile, researchers reported no dose-limiting toxicities during the study.
Cytokine release syndrome occurred in six patients (66%), but investigators reported no cases of grade 3 or higher.
“We were able to detect CT-0508 in tumor biopsies performed post-infusion in eight of nine patients, meaning that the CAR macrophages are getting to their targets,” Reiss told Healio. “Analysis of serial biopsies also confirmed that CT-0508 can activate and remodel the tumor microenvironment and lead to increased T-cell clonality, with expansion of new T-cell clones and CD8 activation within the tumor microenvironment.”
Clinical implications
Researchers did not design this phase 1 study to evaluate treatment efficacy, and despite the small number of patients treated thus far, Reiss said is “an encouraging sign” that five of the first nine patients to receive CT-0508 have maintained stable disease.
“The key takeaways are that CAR macrophages are feasible to generate, even from heavily pretreated patients, and that viable product can be manufactured,” she told Healio.
Further study of CT-0508 will include a new study cohort examining its use in concert with pembrolizumab (Keytruda, Merck) — a PD1 inhibitor — based on preclinical data suggesting increased efficacy with the combination therapy, according to Reiss.
Additionally, some patients treated at University of Pennsylvania will have their CAR macrophage cells tagged with zirconium-89 and undergo serial post infusion scans, she added.
“This will help us track CT-0508 throughout the body and understand its distribution within tumors more completely,” Reiss said.
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Reiss KA, et al. Abstract 634. Presented at: Society for Immunotherapy of Cancer Annual Meeting; Nov. 8-12, 2022; Boston.
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