HER2-targeted chimeric antigen receptor macrophages (CAR-M) could be the next cell therapies to treat advanced solid tumors overexpressing HER2, according to data presented by Kim A. Reiss, MD, and colleagues at the Society for Immunotherapy of Cancer (SITC) 2021 Annual Meeting (Abstract 951).
Early results from a phase I, first-in-human safety and feasibility study showed that the patient product was successfully manufactured and that there were no concerning safety signals. Analysis of the first two patients treated with CAR-M also identified T-cell repertoire modulation and reprogramming of the tumor microenvironment consistent with the induction of antitumor immunity.
“Biopsy analyses from the first two treated patients demonstrated broad activation of the tumor microenvironment, with signs of an adaptive immune response based on T-cell expansion, activation, and proliferation,” said lead study author Dr. Reiss, Assistant Professor of Medicine at the Hospital of the University of Pennsylvania.
Biopsy analyses from the first two treated patients demonstrated broad activation of the tumor microenvironment, with signs of an adaptive immune response based on T-cell expansion, activation, and proliferation.— Kim A. Reiss, MD
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As Dr. Reiss reported, in extensive preclinical testing, CAR-M demonstrated the capability to exert targeted phagocytosis, remodel the solid tumor microenvironment by inducing inflammation and recruiting T cells, and prime an adaptive antitumor immune response by presenting antigens and activating antitumor T cells.
The study remains active and is enrolling at multiple sites. For this multi-institutional trial (ClinicalTrials.gov identifier NCT04660929), the primary objectives are to establish the safety and feasibility of CAR-M. Secondary endpoints include cellular pharmacokinetics; response rate; survival; progression-free survival; and immune correlates including serum cytokines, tumor microenvironment dynamics, and T-cell repertoire analysis.
The study will enroll a total of 18 patients with advanced HER2-positive solid tumors. Prior HER2 therapy is permitted, and patients must have good performance status and at least one measurable lesion.
Two Patients Treated With CAR-M
As Dr. Reiss reported, two patients—with esophageal adenocarcinoma and extrahepatic cholangiocarcinoma—have been treated with CAR-M to date. The patient product was successfully manufactured, and the treatment was well tolerated, with no dose-limiting toxicities and no major organ toxicities observed, said Dr. Reiss.
Analysis of the tumor microenvironment in the participants also showed clear myeloid cell and T-cell clusters. At a population level, there was a significant increase in inflammatory myeloid cells at day 8 and a significant increase in T-cell activation by week 4, Dr. Reiss reported.
In addition, neutrophils were enriched in the tumor on day 8 and went back to baseline at week 4, which is consistent with inflammation, commented Dr. Reiss. Monocyte-derived cells were also enriched on therapy at both time points, and tumor-resident macrophages were reduced on therapy.
Changes in lymphocyte population during treatment were also observed. There was overall expansion of CD8-positive T cells in the tumor, for example, with a fraction being enriched from 17% to 28% by week 4. In addition, naive-like CD8-positive T cells were enriched at day 8 and went back to baseline by week 4, suggesting potential recruitment from T cells from the periphery. Finally, activated effector CD8-positive T cells were significantly enriched by week 4, and the same was noted for proliferating Ki67-positive CD8-positive T cells.
“Taken together, these data suggest activation of the myeloid and lymphocyte compartments in the subjects’ tumor microenvironment,” said Dr. Reiss.
Nevertheless, Dr. Reiss also cautioned that data are “undoubtedly very early.”
She noted: “We anticipate that additional data will be available in 2022. Given the significant impact on the tumor microenvironment and synergy in preclinical tumor models, a combination study with CT-0508 and PD-1 is currently being planned.”
CAR-M (CT-0508) was granted Fast Track designation by the U.S. Food and Drug Administration in September of 2021.
Disclosure: Dr. Reiss has received research funding from Lilly Oncology, Bristol Myers Squibb, GlaxoSmithKline, Tesaro, and Clovis Oncology.
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