Novel PSCA-Targeting Adapter Molecules for Late-Stage RevCAR-T Cell Therapy in Prostate Cancer

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor (CAR) T-cell therapies offer a novel treatment strategy for metastatic castration-resistant prostate cancer (PCa), independent of the androgen receptor pathway.
• Adapter CAR-T platforms, like RevCAR, provide enhanced therapeutic control and tumor targeting using small, quickly cleared adapters.
• Developing methods for discontinuous infusion of adapter CAR-T therapy components is crucial for convenient late-stage treatment in PCa patients.

Purpose of the Study:

• To develop and evaluate novel, larger IgG4-based reverse target modules (RevTMs) targeting prostate stem cell antigen (PSCA) for the RevCAR system.
• To benchmark these new IgG4-based RevTMs against previously described smaller adapter formats for PCa treatment.
• To assess the efficacy, safety profile, and pharmacokinetic properties of PSCA-IgG4 RevTMs in preclinical models.

Main Methods:

• Development of novel IgG4-based RevTMs targeting PSCA.
• In vitro assessment of PCa cell killing mediated by PSCA-IgG4 RevTMs at varying effector-to-target ratios and RevTM concentrations.
• Evaluation of cytokine release profiles in response to RevTM treatment.
• In vivo anti-tumor activity assessment in a short-term mouse model.
• Preliminary positron emission tomography (PET) studies to evaluate blood elimination and tumor accumulation of IgG4-RevTMs.

Main Results:

• PSCA-IgG4 RevTMs demonstrated effective PCa cell killing at low effector-to-target ratios and low concentrations in an antigen-dependent manner.
• Treatment induced rapid and significant release of proinflammatory cytokines, beneficial for immunologically "cold" tumors like PCa.
• Anti-tumor activity was confirmed in a preclinical mouse model.
• Preliminary PET data indicated slow blood clearance and specific tumor accumulation of the IgG4-RevTMs.

Conclusions:

• Novel PSCA-IgG4 RevTMs are effective and promising candidates for stepwise RevCAR-T therapy in prostate cancer.
• The ability to use larger IgG4-based RevTMs allows for controlled, discontinuous infusion, potentially improving safety and convenience.
• This approach, combining short-lived adapters for safety and larger ones for sustained effect, represents a significant advancement in CAR-T therapy for PCa.