CAR Macrophages Well-Tolerated, May Reprogram Tumor Microenvironments


The first in-human study of CAR macrophages has dosed 2 participants so far.

A phase 1, first in-human study (NCT04660929) of CT-0508, a chimeric antigen receptor (CAR) macrophage, has demonstrated that the therapy is well-tolerated and has promising preliminary efficacy in reprogramming the tumor microenvironment (TME).

“CAR-T cell therapies have shown success in numerous hematologic malignancies, but solid tumors remain a major challenge in the field. Macrophages are actively recruited into solid tumors and are abundant in the solid TME and typically evince immunosuppressive behavior. Macrophages are capable of direct anti-tumor activity and antigen presentation to T cells,” investigator Kim A. Reiss Binder, MD, assistant professor of medicine, University of Pennsylvania, and colleagues wrote.

The study is evaluating the safety, tolerability, manufacturing feasibility, pharmacokinetics, and mechanism of action of CT-0508 in 18 participants with advanced solid tumors overexpressing HER2 who have progressed on prior therapies, not excluding HER2 targeted therapies if indicated. Data were presented at the 36th Annual Meeting of the Society for Immunotherapy of Cancer (SITC), November 10-14, 2021.

CT-0508 is an autologous monocyte-derived pro-inflammatory engineered macrophage cell therapy. It is engineered with Ad5f35 to express an anti-HER2 CAR. The therapy previously demonstrated safety and efficacy in preclinical studies.

READ MORE: Tmod CAR T-Cell Therapy Offers Precise Targeting of Solid Tumors

“Non-engineered macrophages did not achieve meaningful efficacy, as these cells did not have the ability to recognize and attack tumor cells and were not phenotypically locked into the pro-inflammatory M1 phenotype. To address these shortcomings, we have developed CAR macrophages (CAR-M) and demonstrated that these engineered myeloid cells kill tumor cells through phagocytosis, reprogram the TME, and induce a broad anti-tumor adaptive immune response in pre-clinical models of HER2 overexpressing solid tumors,” Reiss wrote.

During the study, participants are dosed with filgrastim for monocyte mobilization before apheresis. Investigators manufacture CT-0508 CAR-M with the autologous apheresis products. Patients are dosed with the therapy in 2 schemes, 1 an intra-patient fractionated dose-escalation regimen in which patients are dosed on days 1, 3, and 5, and the other in with patients receive the full dose on day 1. Investigators collect biopsies and blood samples to assess biomarkers of safety and efficacy. These include serum cytokines and chemokines, pharmacokinetics, TME modulation, and induction of an adaptive anti-tumor immune response.

The study has dosed 2 participants, one with esophageal adenocarcinoma and the other with extrahepatic cholangiocarcinoma, with CT-0508 so far. The cell product was successfully manufactured.

In terms of safety, CT-0508 was well-tolerated, with no dose-limiting toxicities or major organ toxicities observed. There was a case of grade 2 cytokine release syndrome (CRS) on day 3 which resolved same-day, as well as grade 3 adverse events (AEs) including anemia (present at baseline) and lymphopenia (present at baseline in 1/2). One patient experienced an unrelated serious AE of grade 4 tumor bleeding 88 days post-infusion.

In terms of efficacy, CAR-M was incorporated into tissues within hours after each infusion and transient cytokine/chemokine elevations did occur. Investigators observed dynamic TME reprogramming via single cell RNAseq analysis of dissociated tumor samples at baseline, day 8, and week 4. Analysis at day 8 revealed inflammatory innate immune cells and naïve T cell recruitment and analysis at week 4 revealed significant CD8+ T cell infiltration, activation, and proliferation.

"In summary, the early data from this phase 1 safety and feasibility study show that patient material was successfully manufactured at least preliminarily there were no concerning safety signals. Biopsy analyses from the first 2 treated patients demonstrated broad activation of the TME with signs of an adaptive immune response with signs of T-cell expansion activation and proliferation," Reiss said during her presentation. "This data is undoubtably very early and the study remains active and is enrolling at multiple sites. We anticipate that additional data will be available in 2022 and given the signifiant impact in the TME and synergy in preclinical tumor models, a combination study with CT-0508 and PD1 is currently being planned."

For more coverage of SITC 2021, click here.

Reiss K, Yuan Y, Barton D, et al. A phase 1 first in human study of adenovirally transduced anti-HER2 CAR macrophages in subjects with HER2 overexpressing solid tumors: preliminary safety, pharmacokinetics, and TME reprogramming data. Presented at: 2021 SITC Annual Meeting; November 10-14, 2021; Washington, DC. Poster 951
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