A phase 1, first-in-human study of autologous monocytes engineered to express an anti-HER2 chimeric antigen receptor (CAR) in participants with HER2-overexpressing solid tumors.

TPS2682 Background: Myeloid cells are actively recruited to the solid tumor microenvironment (TME) and have the potential to mediate tumor control via phagocytosis, TME remodeling, and T cell activation. We previously developed human chimeric antigen receptor macrophages (CAR-M) and have shown potent anti-tumor activity in pre-clinical solid tumor models. The anti-HER2 CAR-M cell therapy product, CT-0508, is currently being evaluated in a Phase I trial as a monotherapy and in combination with pembrolizumab. Early clinical data have shown feasibility, safety, and validated the mechanism of action. We have developed a next-generation CAR monocyte (CAR-Mono) platform to increase the dose, improve tumor trafficking and engraftment, and shorten the manufacturing and vein-to-vein time as compared to CAR-M therapy. CT-0525 is an autologous anti-HER2 CAR-Mono cell therapy based on CD14+ monocytes engineered with an Ad5f35 adenoviral vector to express an anti-HER2 CAR. Pre-clinical studies have demonstrated the feasibility, phenotype, pharmacokinetics, durable CAR expression, cellular fate, antigen specificity, and anti-tumor activity of CT-0525. Pre-clinical studies have shown that CT-0525 differentiated into pro-inflammatory CAR-M in vivo and controlled tumor growth. The CT-0525 manufacturing process takes one day and enables the production of up to 10 billion cells from a single apheresis. CT-0525 is being investigated in a first-in-human, open-label, multi-center, Phase I study in patients with HER2 overexpressing solid tumors. Methods: This Phase 1, first-in-human study evaluates the feasibility, safety, tolerability, trafficking, TME activation, and preliminary evidence of efficacy of the investigational CAR-Mono product CT-0525 in 6 participants (pts) with locally advanced unresectable/metastatic solid tumors overexpressing HER2. Pts previously treated with anti-HER2 therapies are eligible. Filgrastim mobilized autologous CD14+ monocytes are collected by apheresis, followed by manufacturing and cryopreservation. The 1 st cohort of pts (n=3) will receive 3 x 10 9 CT-0525 CAR positive monocytes administered IV in one infusion. If tolerated as per the modified toxicity probability interval algorithm (mTPI), the 2 nd cohort of pts (n=3) will receive up to 10 x 10 9 CT-0525 CAR positive monocytes in one infusion. CT-0525 will be administered without conditioning chemotherapy. Primary endpoints include assessment of safety and tolerability, as well as manufacture feasibility. Correlative assessments include pre- and post-treatment biopsies and blood samples for safety, immunogenicity, pharmacokinetics, tumor trafficking, TME modulation, epitope spreading, and other translational biomarkers. Clinical trial information: NCT06254807 .