Through multiple pathways, tumors suppress immune activity during all phases of growth and dissemination, and enhancement of antitumor immunity is a major goal of cancer treatment. Attractive immunotherapy targets include Toll-like receptors, which activate the innate immune system and play an important role in adaptive immune responses, and immune-checkpoint pathways, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), which regulate T cell activity. Agents directed against these targets alone or in combination have the potential to break immune tolerance and enhance antitumor immune responses. IMO-2055 is a potent and selective TLR 9 agonist designed to stimulate an immune response, and in previous studies it demonstrated synergistic or additive effects when combined with tyrosine-kinase inhibitors and monoclonal antibodies (mAb). In multiple clinical studies, IMO-2055 has been generally well tolerated in more than 300 healthy volunteers and patients with renal, lung, colon, or head and neck cancer.
In the present studies, we studied IMO-2055 alone and in combination with ipilimumab, an approved mAb against CTLA-4, in a CT26 colon carcinoma model to evaluate antitumor immune activity and effects on treated and distant tumors. In the first study, BALB/c mice were s.c. implanted with 106 CT26 and CT26.CL25 cells, a subclone of CT26 expressing a model antigen β-galactosidase (β-gal), on right and left flanks, respectively. Treatment was initiated when tumor nodules reached 200 mm3. Treated mice received 2.5 mg/kg IMO-2055 by intratumoral injections only in CT26 implanted right tumor twice per week for total 5 times. A similar experiment with IMO-2055 was conducted in the MB-49 bladder cancer mouse model. In the second study, BALB/c mice were s.c. implanted with 7.5 x 105 CT26 on right flank and the same mice were i.v. implanted with 4 x 105 CT26.CL25 to generate lung metastases. Coinjections of 2.5 mg/kg IMO-2055 and 0.5 mg/kg ipilimumab into CT26 solid tumors on the right flank were initiated on day 8 when tumor nodules reached 200 to 300 mm3. IMO-2055 was given on days 8, 11, 13 and 15 while ipilimumab was administered on days 8 and 13.
IMO-2055 monotherapy resulted in tumor growth inhibition in both treated and distant tumors. Distant tumors grew when treatment stopped, indicating the possible role of immune tolerance. Similar results were observed in the MB-49 bladder cancer model. In situ IMO-2055 injections elicited statistically significant differences in tumor-specific cytotoxic T cells against CT26 associated antigen AH1 (p<0.0001) and β-gal presented only in remote CT26.CL25 tumors (p=0.0003) versus PBS control. IMO-2055 and ipilimumab combination therapy resulted in improved tumor growth inhibition versus IMO-2055 or ipilimumab alone. The cytotoxic T cells against β-gal presented in the systemic lung metastasis sites were dramatically increased (p<0.01) compared to either monotherapy alone. The antitumor immune response generated by the combination of IMO-2055 and ipilimumab eradicated disseminated lung metastases in 6 of 8 tumor-bearing mice.
In conclusion, IMO-2055 monotherapy and IMO-2055 and ipilimumab combination therapy showed potent antitumor activity in preclinical models. In addition, combination therapy overcame immune tolerance and demonstrated improved antitumor activity versus monotherapy with either agent, supporting further evaluation of combination regimens with IMO-2055 and CTLA-4 mAbs or possibly other checkpoint inhibitors.
Citation Format: Daqing Wang, Dong Yu, Sudhir Agrawal. Intratumoral injection of IMO-2055, a novel Toll-like receptor 9 agonist, with ipilimumab induces a systemic tumor-specific immune response. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A56.
- ©2015 American Association for Cancer Research.