Purpose: Abscopal responses during radiotherapy are rare, especially for immunologically cold tumors like Castration resistant prostate cancer. Here we investigate a new approach called radio-immunotherapy dose-painting (RAID), which specifically targets tumor sub-volumes with radiotherapy and in-situ delivered immunoadjuvant to boost abscopal responses. The study is conducted in metastatic castration-resistant prostate cancer animal model with and without check-point inhibitors.
Methods: Syngeneic murine model of castration registrant prostate adenocarcinoma (CRPA) was generated in both flanks of wild C57/BL6 background mice using androgen deprived TRAMP-C1 cell lines. The palpable sized tumor of one of the flanks was treated as four different randomized cohorts: control with no treatment, direct treatment with 5 Gy of radiation, intra-tumor treatment with Immunogenic Biomaterial (IBM) loaded with AntiCD40, and in combination. Tumor growth was measured on both sides. The highest responded treatment method (RT+IBM) was rechallenged by adding checkpoint inhibitors, AntiPD1 and CTLA4, for survival study. Checkpoint inhiitors were given in systemic doses for 3 consequent administrations. Image Guided Radiotherapy (IGRT) targeting tumor and tumor sub-volumes was administered with the small animal radiation research platform.
Results: We demonstrate that the RAID approach substantially boosts abscopal responses for prostate cancer. Adding checkpoint inhibitors with 5 Gy of IGRT+IBM, further increases the survival duration, where the combination treatment with (RT+IBM) demonstrates enhancement of abscopal effect (p<0.001) compares with only RT, and only IBM. Adding AntiPD-1 (p<0.001) and CTLA4 (p<0.01) with the combination of RT+IBM, show significant increase in the survival duration. whereas, AntiPD-1 shows the longest duration of survival (>250 days), compared to others (<50 days) for at least one third of the treated mice.
Conclusion: RAID with IBM represents a promising new approach to significantly boost abscopal response rates for immunologically cold tumors like prostate cancer. Moreover, Checkpoint inhibitors like AntiPD-1 can further boost treatment outcomes.