Leveraging PSMA-targeted radioligand therapy induced vulnerabilities by STING activation in prostate cancer

Introduction: Prostate-specific membrane antigen (PSMA), a plasma membrane glycoprotein highly expressed in metastatic castration-resistant prostate cancer (mCRPC), can be engaged with high-specificity by radiolabeled PSMA-617, a targeted radiation-based therapeutic that has recently been validated as an alternative treatment for mCRPC. Results from the VISION phase 3 clinical trial showed that ¹⁷⁷Lu-PSMA-617 radioligand therapy (RLT) led to reduction in serum prostate specific antigen levels in 71.5% of patients. However, relapses occurred uniformly after delays in disease progression. Thus, there is an urgent unmet need to identify mechanisms that can both enhance and prolong the efficacy of RLT. Emerging anticancer combination therapies are exploring synergies between immunotherapy and radiation. Several studies have shown that STING signaling is essential for antitumor immunity by inducing the production of type I interferons and activating both innate and adaptive immunity. Therefore, the combination of PSMA-RLT with STING activation could be a promising approach for leveraging profound synergistic anti-cancer effects in mCRPC. In this study, we evaluated whether RLT induced anti-tumor effects synergize with systemic STING activation in a murine model of mCRPC and how immune memory was affected by such combination.

Methods: <h2>C57BL/6 mice were subcutaneously inoculated with 0.1 x 10⁶ RM1-PGLS cells in 100 µl PBS/Matrigel (1:1). PSMA expression was quantified in vivo by PET/CT 1h after i.v. administration of 1.1 MBq ⁶⁸Ga-PSMA-617. In a preliminary study, doses escalation with STING agonist (diABZI, 1.0mg/kg to 1.5mg/kg) showed potent effects of diABZI on mice bearing RM1-PGLS tumors without side effects at 1.5mg/kg. On day 8 p.i. (average tumor volume: 100 mm³), animals received 40 kBq ²²⁵Ac-PSMA-617 and/or STING agonist (diABZI 1.5 mg/kg, i.v.) (n=12/group). Therapeutic efficacy was assessed by tumor volumetry (CT), time to progression (TTP) and survival. Naïve mice and animals with complete tumor regression were re-challenged with either 0.1 x 10⁶ cells of RM1-PGLS or the parental RM1 cell line on the contralateral side. Tumor growth was monitored by weekly tumor volumetry (CT) for evaluation of immune memory responses. OsiriX Software was used for PET/CT analysis and CT volumetry. GraphPad Prism was used for statistical analysis.</h2>

Results: <h2>In a syngeneic setting, low doses of the systemic STING agonist diABZI combined with PSMA-RLT produced significant tumor growth-inhibitory effects. Compared to untreated controls each monotherapy showed moderate tumor growth delay, recapitulating for PSMA-RLT the clinical findings from the VISION trial; however, the combination of RLT and systemic STING agonist completely abolished tumor growth and induced immune memory. RM1-PGLS re-challenged mice showed an immune memory rate of 75% (3/4) for the RLT group and 90% (9/10) for the combination group. All mice re-challenged with parental RM1 cells developed tumors.</h2>

Conclusions: With this study we have shown that the anti-cancer effects of PSMA-RLT can be amplified by the combination with STING activation, which induced long-lasting immune memory responses.