Abstract 2322: Intratumoral treatment with a highly interferogenic TLR9 agonist reverts tumor escape from PD-1 blockade
Authors: Wang Shu , Campos Jose , Naik Edwina , Chad Crain , Marilena Gallotta , Robert L. Coffman , Guiducci Cristiana 
Published: July 2016

Abstract
The induction of tumor specific T cell exhaustion by the PD-1/PDL-1 pathway is an important mechanism of immune escape in cancer. Therapies blocking or reversing T cell exhaustion can produce durable responses in metastatic cancers including melanoma, NSCLC, renal carcinoma and bladder cancer. However, only a small subset of patients experience response upon anti-PD-1/PDL-1 treatment, whereas many others are refractory, showing no response at all. Thus, a key challenge is transforming a non-permissive tumor microenvironment into an immunologically competent one, in order to increase the frequency of patients with durable responses to PD-1/PDL-1 blockade.
We have characterized a mouse tumor model with a reproducible dichotomous response to anti-PD-1 treatment analogous to that observed in human cancers. We show that the ability of tumors to be rejected in response to anti-PD-1 treatment is highly correlated with degree of T cell infiltration, expression of Type I IFNs and B cell activation signatures, in whole tumors and in tumor infiltrating leukocytes. We then evaluate whether immunomodulation by intratumoral vaccination with a TLR9 agonist, SD-101, would affect rate of response to anti-PD-1 blockade. SD-101, is a CpG-C class oligonucleotide, optimized to induce both very high levels of IFN-alpha as well as maturation of dendritic cells and B cells. Intratumoral injection of SD-101 in tumor bearing mice undergoing anti-PD-1 therapy leads tumor rejection in 100% of treated mice versus a 20% tumor rejection in mice treated with anti-PD-1 blockade alone. SD-101 alone, although efficacious in reducing tumor growth, did not lead to durable tumor rejection.
Immune cell subset depletion studies implicate CD8, but not CD4, T cells in the rejection of tumors treated with anti-PD1 plus SD-101. T cell response generated in one flank by IT injection of SD-101 synergizes with systemic PD-1 blockade to induce rejection of unvaccinated distal tumors. In addition, we show that mice receiving systemic anti-PD-1 plus SD-101 have a higher percentage of CD8+ T cells infiltrating the tumors when compared to anti-PD-1 responders, anti-PD-1 non-responders or SD-101 given alone. Infiltrating CD4 and CD8 T cells in tumors with combination treatment, show a higher proliferative capacity and a higher frequency of cells producing both TNF-a and IFN-g than tumors responding to anti-PD-1 monotherapy. This demonstrates the potential for SD-101 to significantly enhance the frequency of responders to anti-PD-1 therapy by increasing the number and functionality of anti-tumor T cells within the tumor.
Citation Format: Shu Wang, Jose Campos, Edwina Naik, Crain Chad, Gallotta Marilena, Coffman Robert L., Cristiana Guiducci. Intratumoral treatment with a highly interferogenic TLR9 agonist reverts tumor escape from PD-1 blockade. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2322.