Cancer immunotherapy aims to stimulate host antitumor immune responses or break tumor-related immune tolerance or both with the potential of curative treatment. Potential immunotherapy targets include Toll-like receptors (TLRs), which are key receptors of the innate immune system and play an important role in regulating adaptive immune responses. IMO-2125 is a potent and selective agonist of endosomal TLR9 which significantly induces IFN-α, and the maturation of dendritic cells (DC). In the setting of cancer immunotherapy, we hypothesize that intratumoral (i.t.) administration of IMO-2125 has the potential to stimulate DC maturation and T-cell activation in the tumor microenvironment, leading to increased local and systemic antitumor immune responses and tumor regression, and may potentiate the activity of checkpoint inhibitors.
In the present study, we evaluated the antitumor immune activity of i.t. IMO-2125 in murine syngeneic colon carcinoma models. BALB/c mice were s.c. implanted with 3 x 106 CT26 and CT26.CL25 cells, a subclone of CT26 expressing a model antigen beta-galactosidase (beta-gal), on the right and left flanks, respectively. Treatment was initiated when tumor nodules reached 200 mm3. Treated mice received IMO-2125 at doses of 10, 50 and 100 µg per injection, placebo, or a control compound (n=8 each), by i.t. injection only in the CT26 tumor implanted in the right flank twice weekly for two weeks. To evaluate IMO-2125 in combination with an anti-CTLA-4 mAb, 50 µg IMO-2125 and 10 µg anti-mouse CTLA-4 mAb were co-injected into the right tumor. Over two weeks, IMO-2125 was administered five times and the anti-mouse CTLA-4 mAb was administered four times.
Results showed that i.t. IMO-2125 treatment led to dose-dependent inhibition of both treated and distant tumor growth. In mice treated with 100 µg, there were reductions in tumor volume of 95.2% (p = 0.0058) and 91.2% (p = 0.0048) in the treated and distant tumors, respectively. At this dose, there was complete tumor regression in 5 out 8 mice (63%). Control compound showed no anti-tumor activity. Antitumor activity was correlated with increased CD8+ T cell infiltration into both treated and distant tumors. In vivo depletion of T cells showed that IMO-2125 i.t mediated antitumor effects depended on CD8+ T cells, while depletion of CD4+ T cells enhanced IMO-2125 mediated tumor regression through elimination of Tregs. Furthermore, treatment elicited tumor-specific cytotoxic T cells not only to CT26 associated antigen AH1 in the injected tumor and also to beta-gal presented only in distant CT26.CL25 tumors. The mice with complete regression were rechallenged with CT26/CT26.CL25 and rejected the implantation; however, they were not protected from rechallenge with A20 lymphoma, indicating IMO-2125 i.t. treatment resulted in persistent tumor memory. Treatment with a combination of i.t. IMO-2125 and i.t. anti CTLA-4 mAb resulted in more potent antitumor activity than either agent alone.
In conclusion, i.t. administration of IMO-2125 changes the local tumor microenvironment by inducing Th1 type cytokines, thereby modulating levels of immune checkpoint expression, and exerting potent local and systemic antitumor activity. In addition, IMO-2125 treatment in combination with an anti-CTLA-4 mAb demonstrated more potent antitumor activity compared to either agent alone. IMO-2125 has been well tolerated and showed induction of systemic IFN-α in a human trial. Planning for a clinical trial of a combination of i.t. IMO-2125 and ipilumimab is ongoing.
Citation Format: Daqing Wang, Fugang Zhu, Xianzhi Mao, Sudhir Agrawal. Intratumoral administration of IMO-2125, a novel TLR9 agonist, modulates the tumor microenvironment and exerts systemic antitumor activity alone and in combination with an anti-CTLA-4 mAb. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B094.
- ©2016 American Association for Cancer Research.