Abstract P012: PSMA-RLT and targeting the cGAS-STING pathway as a combination approach for Prostate Cancer
Authors: Louis Beatrice , Taddio Marco , Garcia Prada Clara Diaz , Richard Mathis , Dove Rachel , Rashid Khalid , Abt Evan , Rosser Ethan , Le Thuc , Lueckerath Katharina , Radu Caius , Czernin Johannes , Mona Christine 
Published: January 2025

Abstract
The VISION trial showed that 177Lu-PSMA-617 radioligand therapy (RLT) effectively reduced PSA levels and improved survival in patients with late-stage prostate cancer1. However, there is still a need to identify strategies to enhance and sustain RLT efficacy. Alpha therapy and combination of immunotherapy and radiation are emerging strategies. Herein, we focused on strategies to amplify the immune system activation to intensify the effects of PSMA-RLT in prostate cancer by combining 225Ac-PSMA-617 RLT with a STING agonist (diABZI). We compared the efficacy of alpha RLT in mice bearing STING-proficient or STING-deficient PC cell line (RM1-PGLS or Myc-CaP) alone or in combination with a STING agonist. Furthermore, we assessed the efficacy of RLT in STING knockout (Sting -/-) mice injected with RM1-PGLS. Method: Male C57BL/6 wt or STING-deficient or FVB mice were subcutaneously injected with 0.1 × 10⁶ RM1-PGLS cells in a 100 µl mixture of PBS and Matrigel (1:1) or 2 × 10⁶ MycCap cells. PSMA expression was assessed in vivo using PET/CT imaging 1h after intravenous injection of 68Ga-PSMA-617 to validate target expression prior to treatment. Once tumors reached 100 mm³, animals were treated intravenously with 30 kBq of 225Ac-PSMA. C57BL/6 mice bearing RM1 PGLS tumors and FVB mice bearing MycCap were treated with RLT alone or in combination with diABZI (1.5 mg/kg), 24h post RLT. Tumor growth and therapeutic efficacy were monitored weekly by CT. Results: In an immunocompetent syngeneic model (C57BL/6 mice bearing RM1-PGLS tumors) we observed a synergistic effect of STING agonist and RLT. At 28 days post-treatment, survival rates were: 0% for NT, 66% for RLT alone, 70% DiABZI and 89% for the combination. Contrastingly, in the MycCap model, the combination of RLT and STING agonist did not improve survival compared to the control group with 0% survival at 22 days. Same survival rate was observed with the STING agonist. Only the RLT group showed 30% of survival at day 22.In the STING-deficient host model, we observed 75% tumor-free mice (6/8). At day 22, the median survival was 50% for the control group compared to 100% for the RLT group. Rechallenged RLT-treated mice did not regrow tumors for more than a year after rechallenging. Conclusion and discussion: STING agonist and RLT synergize in certain models of PCa.Based on our results, STING proficiency in the tumor cells seems to be a critical determinant for RLT-response. Our data in the STING -/- mice suggest that host STING could have deleterious effects. We hypothesize that the acute inflammation triggered by STING activation may stimulate the accumulation of MDSCs (myeloid-derived suppressor cells), which are associated with immune suppression which may restrain the efficacy of RLT. Given this, our next strategy will focus on preventing MDSC activation to maintain the beneficial immune activation within the tumor microenvironment. The dual role of STING in both immune recruitment and activation, as well as in immunosuppression, makes it a complex mechanism that requires further exploration.
Citation Format: Beatrice Louis, Marco Taddio, Clara Diaz Garcia Prada, Mathis Richard, Rachel Dove, Khalid Rashid, Evan Abt, Ethan Rosser, Thuc Le, Katharina Lueckerath, Caius Radu, Johannes Czernin, Christine Mona.PSMA-RLT and targeting the cGAS-STING pathway as a combination approach for 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 P012