Combination immunotherapy and radiotherapy causes an abscopal treatment response in a mouse model of castration resistant prostate cancer

Abstract

Background Prostate cancer is poorly responsive to immune checkpoint inhibition, yet a combination with radiotherapy may enhance the immune response. In this study, we combined radiotherapy with immune checkpoint inhibition (iRT) in a castration-resistant prostate cancer (CRPC) preclinical model. Methods Two Myc-CaP tumor grafts were established in each castrated FVB mouse. Anti-PD-1 or anti-PD-L1 antibodies were given and one graft was irradiated 20 Gy in 2 fractions. Results In CRPC, a significant increase in survival was found for radiation treatment combined with either anti-PD-1 or anti-PD-L1 compared to monotherapy. The median survival for anti-PD-L1 alone was 13 days compared to 30 days for iRT ( p = 0.0003), and for anti-PD-1 alone was 21 days compared to 36 days for iRT ( p = 0.0009). Additional treatment with anti-CD8 antibody blocked the survival effect. An abscopal treatment effect was observed for iRT in which the unirradiated graft responded similarly to the irradiated graft in the same mouse. At 21 days, the mean graft volume for anti-PD-1 alone was 2094 mm 3 compared to iRT irradiated grafts 726 mm 3 ( p = 0.04) and unirradiated grafts 343 mm 3 ( p = 0.0066). At 17 days, the mean graft volume for anti-PD-L1 alone was 1754 mm 3 compared to iRT irradiated grafts 284 mm 3 ( p = 0.04) and unirradiated grafts 556 mm 3 ( p = 0.21). Flow cytometry and immunohistochemistry identified CD8+ immune cell populations altered by combination treatment in grafts harvested at the peak effect of immunotherapy, 2–3 weeks after starting treatment. Conclusions These data provide preclinical evidence for the use of iRT targeting PD-1 and PD-L1 in the treatment of CRPC. Immune checkpoint inhibition combined with radiotherapy treats CPRC with significant increases in median survival compared to drug alone: 70% longer for anti-PD-1 and 130% for anti-PD-L1, and with an abscopal treatment effect. Precis Castration-resistant prostate cancer in a wild-type mouse model is successfully treated by X-ray radiotherapy combined with PD-1 or PD-L1 immune checkpoint inhibition, demonstrating significantly increased median overall survival and robust local and abscopal treatment responses, in part mediated by CD8 T-cells. Electronic supplementary material The online version of this article (10.1186/s40425-019-0704-z) contains supplementary material, which is available to authorized users.

Radiotherapy-Mediated Immunomodulation and Anti-Tumor Abscopal Effect Combining Immune Checkpoint Blockade

“…CD8+ T cells obtained using flow cytometry were then re-stimulated with anti-CD3/CD28 in vitro, and CD8+ cells in the combination treatment group expressed higher INF-γ and Tbet [ 65 ]. Of note, similar results have been elaborated in mouse models of lung cancer, glioblastoma, breast cancer, prostate cancer, and osteosarcoma [ 66 , 67 , 68 , 69 , 70 ]. Clinical trials have also clarified abscopal effects.…”

Modulation of Determinant Factors to Improve Therapeutic Combinations with Immune Checkpoint Inhibitors

“…However, this TI-AIR mechanism can be disrupted by the co-administration of anti-PD-1 blocking antibodies to prevent the dysfunction of specific ICP + CD8 T cell induced by Folfox, thus resulting in complete tumor regressions in most mice [34]. A similar mechanism and antitumor benefit were described in tumor-bearing mice treated with radiotherapy plus ICPi [37][38][39]. Indeed, localized radiotherapy can enhance tumor antigenicity, adjuvanticity, and immunogenicity through the increase of MHC (Major Histocompatibility Complex) class-I expression, the induction of cGas (cyclic GMP-AMP synthase)/ STING (stimulator of interferon genes)/ IFN-I (type-I interferon) pathways, and the induction of ICD.…”

Dramatic response to combination pembrolizumab and radiation in metastatic castration resistant prostate cancer

“…One preclinical study demonstrated that combination therapy in a CRPC subcutaneous tumor graft mouse model enhanced tumor shrinkage and increased survival compared with single agent anti-PD-1 or PD-L1 therapy. 20 A retrospective case series found that 7/10 patients treated with pembrolizumab and SBRT had either a response or stable disease, although it is unclear whether this significant response is superior to single agent pembrolizumab alone. 21 There are ongoing prospective trials in mCRPC investigating anti-PD-1/PD-L1 therapy combined with different forms of radiation therapies, including SBRT (ClinicalTrials.gov identifier: NCT03477864), brachytherapy (ClinicalTrials.gov identifier: NCT03543189), alpha-radiation from Radium-223 preferentially absorbed by the bone (ClinicalTrials.gov identifiers: NCT04071236, NCT03093428, NCT04109729, NCT03795207) and the targeted radio-ligand to the PSMA lutetium-177-PSMA-617 (ClinicalTrials.gov identifier: NCT03805594).…”