Abstract 4091: Evaluating the efficacy of a STING agonist in a murine model of prostate cancer

Abstract

Abstract Despite the promise of checkpoint inhibitor therapy, prostate cancer has remained resistant to this treatment. Innate immune agonists, however, have been shown to have anti-tumor effects in various cancer types, such as melanoma and colon cancer, and have been nominated to be used in combination with approved anti-PD1/PD-L1 drugs. For instance, STING agonist + anti-PD-1 combination therapy has been demonstrated in a syngeneic mouse model of melanoma. Other innate immune agonists, such as TLR7/8 and TLR9 have also been shown to have potential anti-tumor effects. We hypothesized that innate immune agonists may be effective in the MycCaP syngeneic mouse model of prostate cancer. To compare the efficacy of three innate agonists targeting the STING (3’3’ cGAMP), TLR7/8 (CL097), and TLR9 (ODN2395) pathways, FVB mice were first injected bilaterally with MycCaP subcutaneous tumors. Upon establishment of tumors, mice were administered 3 doses of a single-sided intratumoral injection of each drug. The injected tumors had responses of 50% (6/12), 23% (3/13), and 8% (1/13) for the STING, TLR7/8 and, TLR8 agonists, respectively. Contralateral tumors showed no significant regression. Published data have reported inherent resistance of MycCaP tumors to anti-PD-1 treatment in vivo. Given our results, we hypothesize that the addition of a STING agonist could enhance efficacy of anti-PD-1 therapy in this model. Mice with MycCaP tumors were administered anti-PD1 alone (n=10) or in combination with bilateral injections of the STING agonist (n=14). Combined therapy resulted in significant reduction in tumor size (71%) compared to anti-PD1 alone (9%). Additionally, there was a significant increase in the Ifnb1 (p=.04), Ifng (p=.008), Tnf-α (p=.006), IRF3 (p=.003) and II6 (p<.0001) gene expression in the combination group showing enhancement of the STING pathway genes. Combined, these findings suggest that targeting the STING pathway may have a modest local anti-tumor effect when compared to other innate immune pathways in prostate cancer. The efficacy of anti-PD-1 therapy was significantly enhanced when combined with a STING agonist, possibly through enhancement STING pathway genes. Our data suggest that combination therapy with a STING agonist and anti-PD1 therapy may have potential anti-tumor efficacy in prostate cancer. Future studies will examine these effects on both local and abscopal tumors. Citation Format: Jonathan Gurkan, Jae Eun Choi, Jean Tien, Marcin Cieślik, Luigi Franchi, Arul M. Chinnaiyan. Evaluating the efficacy of a STING agonist in a murine model of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4091.