Immunomodulatory antibodies targeting the immune checkpoint receptors CTLA-4, PD-1 and its ligand PD-L1, have resulted in significantly improved clinical benefits over the standard of care in many cancer types. While these immune checkpoint inhibitors have successfully exploited the adaptive immune system to produce remarkable clinical responses in various cancers, a significant number of patient's tumors are either innately resistant or develop resistance, and the disease eventually progresses. For this reason, rational drug combinations with checkpoint inhibitors and other immunomodulating agents are imperative to improve the rate of durable responses and patient survival.
Histone deacetylase inhibitors (HDACi) have been successful as monotherapy for hematologic malignancies, but their clinical effectiveness against solid tumors has been limited to date. The long-held belief that HDACi are immunosuppressive has been challenged recently by data demonstrating the ability of HDACi to enhance anti-tumor immunity through effects on tumor immunogenicity, regulatory T cells, myeloid-derived suppressor cells (MDSCs), as well as effector cell functions. HBI-8000 (chidamide) is a novel, orally bioavailable Class I (HDAC 1,2,3) and Class II (HDAC 10) selective HDACi with a demonstrated positive effects on antitumor immunity, enhancing the activity of CTL and NK cells, as well as having direct activity against tumor cells through reversal of apoptosis resistance. We report here that HBI-8000 enhances the activity of both PD-1 and PD-L1 blocking antibody (Ab) in the MC38 syngeneic mouse model of colon cancer. Combinations of HBI-8000 with PD-1 or PD-L1 Ab resulted in statistically significant decreases in tumor progression and increases in survival compared to single agent therapy. Analysis of tumor infiltrating lymphocytes (TIL) revealed a significant increase in the percentage of intratumoral CD8+ T cells in tumors treated with both HBI-8000/PD-1 Ab and HBI-8000/PD-L1 Ab combinations. The TIL analysis also revealed a trend towards lower percentages of Tregs and granulocytic MDSCs. To evaluate the potential role of this combination as a 2nd line treatment option, i.e., in subjects failing 1st line checkpoint antibody therapy, we developed a model of immune checkpoint antibody failure, where tumor-bearing mice were initially treated (1st line) with either PD-1 or PD-L1 blocking Ab. Mice which had either slow disease progression or stable disease followed by progression, were randomized into one of six 2nd line treatment groups, including combinations of anti PD-1 or PD-L1 blocking Ab with HBI-8000. Fifty percent of mice failing 1st line PD-1 Ab treatment experienced a complete response, and were rescued by treatment with HBI-8000 combined with PD-L1 Ab. Altogether our data suggest that the addition of the HDACi HBI-8000 can improve the anti-tumor response to either PD-1 or PD-L1 blocking antibodies, increase the percentage of intratumoral immune effector cells and potentially counter innate resistance to checkpoint inhibitors. Our data also suggests that combination therapy with HBI-8000 and a checkpoint inhibitor can rescue tumor-bearing mice that have failed 1st line therapy with different checkpoint inhibitor. These results provide a strong rationale for the evaluation of therapeutic regimens utilizing PD-L1 or PD-1 blocking antibodies in combination with HBI-8000.
Citation Format: Reid P. Bissonnette, Alain Rolland, Bob Goodeneow, Mireille Gillings. The HDAC inhibitor HBI-8000 enhances immunotherapy with either PD-1 or PD-L1 blockade in the MC38 model of colon cancer [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B108.