The safety, tolerability, and preliminary efficacy of the anti-HER2 CAR macrophage therapy, CT-0508, will be investigated in patients with solid tumors and HER2 overexpression, as part of a first-in-human phase 1 study.
The safety, tolerability, and preliminary efficacy of the anti-HER2 CAR macrophage (CAR-M) therapy, CT-0508, will be investigated in patients with solid tumors and HER2 overexpression, as part of a first-in-human phase 1 study (NCT04660929).1
Although CAR T-cell therapies have become a treatment option for those with hematologic malignancies, those with solid tumors have not derived the same benefit from this modality. Because macrophages are abundant in the solid tumor microenvironment, it has been hypothesized that they can be engineered to be proinflammatory, and thus, could serve as an ideal vector for adoptive solid tumor cellular therapy.
Engineered CAR-M can recognize and ingest antigen-overexpressing cancer cells, reprogram the solid tumor microenvironment, and present neoantigens to T cells, which results in epitope spreading and improved immune memory.
CT-0508 is a CAR-M product made from autologous peripheral blood monocyte–derived macrophages, which are transduced with an adenoviral vector that comprises an anti-HER2 CAR and locked into an M1 phenotype. In September 2021, the FDA granted a fast track designation to CT-0508 for use as a potential therapeutic option for patients with solid tumors.2
In a semi-immunocompetent mouse model of human HER2-overexpressing ovarian cancer, CT-0508 was found to elicit targeted cancer cell phagocytosis without harming healthy cells. The CAR-M therapy also decreased tumor burden, improved survival and proved to be safe.
When the a single injection of CAR-M was given to immunodeficient mice with HER2-positive ovarian cancer cells (SKOV3), half of the mice survived to day 100. In the control group, all mice died by day 60. Additionally, in immunocompromised mice that received CT26 HER2-positive tumor cells, CT-0508 reduced the HER2-positive tumors, and 75% of the mice achieved a complete response.3
The ongoing, open-label phase 1 trial will enroll 18 patients with HER2-overexpressing recurrent or metastatic solid tumors, who have at least 1 measurable disease per RECIST criteria, an ECOG performance status of 0 or 1, and who are at least 18 years of age. Patients will be eligible if they have a recurrent or metastatic solid tumor and no curative treatment options available to them, or if they were ineligible to receive or have experienced failure with approved HER2-targeted agents. Patients needed to have acceptable organ function and could not have concurrent infections or the use of chronic steroids.
Once enrolled on the trial, patients will receive filgrastim (Neupogen) to mobilize autologous monocytes into the peripheral blood for collection by apheresis. Subsequently, CT-0508 is prepared, cryopreserved, and released. The first 3 patients in the study will be hospitalized for 8 days following the first infusion of CT-0508, and there will be no preparative chemotherapy prior to infusion of the CAR-M product.
The 18 patients will be divided into 2 groups. The first group of 9 patients will be treated with an intra-subject dose escalation of up to 0.5 x 109 CAR-M cells on day 1, up to 1.5 X 109 cells on day 3, and up to 3.0 x 109 cells on day 5. Patients in the first group will all be treated at least 2 weeks apart. The second group of 9 patients will receive up to 5 x 109 of total manufactured cells on day 1.
Enrolled patients will undergo 1 biopsy prior to treatment, followed by 2 on-treatment biopsies at days 8 to 12 and week 4, respectively. The biopsies will be used to assess trafficking, target antigen engagement, tumor microenvironment reprogramming, epitope spreading, and other pharmacokinetic or pharmacodynamic measures. Blood samples will also be taken over a 52-week period for biomarker evaluation.
The primary end points of the trial are to understand the safety and tolerability of CT-0508, and to assess the feasibility of manufacturing CT-0508. Secondary end points include: to characterize the in vivo cellular kinetics profile of the CT-0508 transgene into peripheral blood and target tissues, to estimate the objective response rate (ORR) per RECIST v1.1 criteria of at least 1 dose of CT-0508, overall survival, progression-free survival (PFS), duration of response (DOR), and 6- and 12-month survival. Exploratory end points include intracranial ORR, PFS, and DOR.
The following 5 clinical sites are currently enrolling patients throughout the United States: University of Pennsylvania, University of North Carolina, City of Hope, the University of Texas MD Anderson Cancer Center, and Sarah Cannon Research Institute.