A multifunctional, theranostic approach for universal CAR T cell therapy, targeted alpha-therapy and imaging of prostate cancer

Background
Chimeric antigen receptor (CAR) T-cells are living drugs successfully applied for treatment of patients with hematological malignancies. However, clinical translation towards solid tumor therapy faces several challenges and does not result in durable responses. In order to improve CAR T-cells´ therapeutic efficiency, combinations with other treatment and imaging modalities are intensively investigated.

Methods
For prostate cancer theranostics we developed a novel, multifunctional IgG4-based antibody construct directed against the prostate stem cell antigen (PSCA). Due to equipment with the UniCAR-tag E5B9 it can be used as a target module (TM) for the well-established UniCAR T-cell approach [1]. Functionality of the PSCA-IgG4 antibody was investigated in vitro by conducting co-cultivation assays with UniCAR T-cells and PSCApos/PSCAneg prostate cancer cells. After radiolabeling with copper-64 or actinium-225, imaging and radioimmunotherapeutic potential of the PSCA-IgG4 antibody were studied using NMRI Foxn1 nu/nu mice.

Results
UniCAR T-cells were specifically activated upon cross-linkage with PSCApos tumor cells via the novel PSCA-IgG4 antibody, which resulted in the secretion of pro-inflammatory cytokines and an efficient tumor cell lysis with EC50 values in the picomolar range. 64Cu- or 225Ac-labeled PSCA-IgG4 antibodies were successfully applied for PET imaging and radioimmunotherapy of prostate tumors in experimental mice. Antibodies specifically enriched at the tumor side whereby maximal tumor accumulation and optimal tumor-to-background ratios were reached after 31 hours. Treatment of tumor-bearing mice with 225Ac-labeled PSCA-IgG4 antibody further resulted in significant lower tumor sizes compared to the control group after 40 days.

Conclusions
We here present a novel, multifunctional PSCA-IgG4 antibody construct for prostate cancer theranostics that facilitates not only UniCAR T-cell immunotherapy, but is also a suitable tool for targeted alpha-therapy and imaging of prostate cancer. This opens the door for a combined radioimmunotherapeutic and imaging approach of prostate cancer that may help to overcome present hurdles in solid tumor therapy.