Abstract B001: Double targeted therapy PSCA-CAR-T cells and PSMA-radioligand in metastatic castration-resistant prostate cancer
Authors: Fajnorova Iveta , Jeanjean Pauline , Azrour Ines Camille , Fakharpour Ava , Liu Venna Jiangyue , Czernin Johannes , Radu Caius , Priceman Saul , Mona Christine 
Published: January 2025

Abstract
Targeted radioligand therapy (PSMA-RLT) extends survival in advanced castration-resistant prostate cancer (CRPC) (Sartor et al., 2021), yet half of patients experiences limited responses or relapse with additional metastases (Stuparu et al., 2020). Given that metastatic CRPC has a tumor environment lacking immune infiltration and resisting immune checkpoint therapies, combination strategies that actively bring immune cells into the tumor are urgently needed (Choudhury et al., 2024). Prostate stem cell antigen (PSCA) is another promising target, as it is frequently overexpressed in advanced CRPC. PSCA-CAR-T cells, engineered to specifically attack PSCA-expressing tumors, may complement PSMA-RLT by overcoming immune resistance (Dorff et al., 2024; Murad et al., 2021). This study explores the therapeutic potential of combining PSMA-RLT with PSCA-CAR-T cells to strengthen immune response and increase response rates and survival. For this reasons, PC3-PIP human metastatic prostate cancer cells expressing PSMA were transfected to express human PSCA. PSMA and PSCA expression was confirmed by flow cytometry. Double positive PSMA-PSCA cells were inoculated by intracardiac injection in NSG mice under ultrasound guidance. Tumor progression was followed up twice a week by bioluminescence imaging. Mice were randomized before treatment into 5 groups: (1) Control NT (2) 225Ac-PSMA-617 (15 kBq) alone (3) CAR-T (0.2 x 106 cells) alone (4) Combo 225Ac-PSMA-617 (15 kBq) + CAR-T (0.2 x 106 cells) (day 4 post-RLT) (5) Combo 225Ac-PSMA-617 (15 kBq) + CAR-T (0.2 x 106 cells) (day 6 post-RLT). 4 mice per group were used to determine blood toxicity of RLT and 8 mice in each group were followed up until the end point for efficacy study. No blood toxicity related to RLT was observed in treated mice. Compared to control group, the Combo 225Ac-PSMA-617 and PSCA-CAR-T demonstrated a synergistic effect with a significant delay in tumor growth. Comparison between 68Ga-PSMA-11 PET and bioluminescence imaging showed heterogenous localization in 3 mice randomized to Combo groups and CAR-T alone group. In conclusion, our study shows promising results from combining PSMA-RLT with PSCA-CAR-T cell therapy. In a dual prostate cancer expressing in vivo model (PC3-PIP PSMA-PSCA), we observed a delay in tumor growth. However, the increase of survival rates in combo groups compared to CAR-T alone was limited. Additional studies are required to improve overall survival. Thus, we plan to extend our study to test the combination of PSCA-CAR-T with PluvictoTM, a recent FDA approved theranostics agent for metastatic CRPC (Hennrich & Eder, 2022). Moreover, we will modify the expression of PSCA to mimic the heterogeneity expression observed in patients, to validate the performance of the combination.
Citation Format: Iveta Fajnorova, Pauline Jeanjean, Ines Camille Azrour, Ava Fakharpour, Venna Jiangyue Liu, Johannes Czernin, Caius Radu, Saul Priceman, Christine Mona. Double targeted therapy PSCA-CAR-T cells and PSMA-radioligand in metastatic castration-resistant prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B001.