Abstract 1683: A comparative evaluation of immunotherapy responses in murine colon carcinoma
Authors: Barnes Sheri R. , Urs Sumithra , Meade Mary Anne , Draper David , Evens Hillary , Saims Daniel , Wise Scott , Franklin Maryland Rosenfeld 
Published: August 2018

With the drive in oncology to develop molecules targeting the immune system, there is a need for reliable and well-characterized preclinical models. To this end, the impact of checkpoint inhibitors, such as anti-PD-1 and anti-PD-L1, has been extensively investigated preclinically, and the landscape of available models varies greatly in response to these molecules. With several recent checkpoint inhibitor-based drug approvals, the focus of immuno-oncology drug development has shifted to immunometabolism targets and costimulatory molecules, particularly with combination strategies. Comparative preclinical tumor model validation with respect to these targets is generally lacking; however, the same level of granularity as was afforded anti-PD-1 and anti-PD-L1 would be needed with these molecules to allow confidence in designing preclinical proof of concept studies for future clinical development.

To better understand the utility of these agents in preclinical development, we examined the response of two murine colon carcinoma models, CT26 and MC38, against a panel of costimulatory molecules and epacadostat, an IDO inhibitor, using in vivo tumor growth delay studies. Our data demonstrate that CT26 tumors are sensitive to the costimulatory molecules, anti-GITR, anti-CD137, and anti-OX40, resulting in 6/10, 7/10, and 2/10 complete responses (CRs), respectively. In contrast, the response of MC38 tumors to these agents was modest with no CRs and times to evaluation size (TES) extending only 1.4 to 6.9 days beyond control. Epacadostat treatment did not impact growth of CT26 or MC38, with TES's extended by 4.4 or 2.3 days, respectively, compared to control. Interestingly, addition of epacadostat did not improve the response of anti-PD-1 in either model.

To determine whether the changes in response could be related to differences in immune infiltration of these tumors, immunophenotyping from untreated CT26 and MC38 tumors was evaluated. We found that immune cell populations also highlighted potential differences in these models. CT26 tumors were well infiltrated with a mean of 25.2% CD45+ cells, with 54.8% of CD3+ cells being CD8+ T cells. Comparatively, MC38 tumors were weakly infiltrated with CD45+ cells (5.3%) with 35.9% of CD3+ cells being CD8+ T cells. Macrophage and MSDC infiltrates, as a percent of CD11b+ cells, in CT26 tumors were generally double that found in MC38 tumors.

Our results indicate that CT26 is more sensitive to the costimulatory molecules tested than MC38. Further, epacadostat as monotherapy or in combination with anti-PD-1 did not elicit clinically meaningful tumor growth delay in either model. Stark differences were also seen in overall lymphocyte infiltrate and composition between CT26 and MC38. The differences in baseline immune infiltrate and efficacy allow us to determine which models and immunotherapies are best suited for rational drug combination approaches.

Citation Format: Sheri R. Barnes, Sumithra Urs, Mary Anne Meade, David Draper, Hillary Evens, Daniel Saims, Scott Wise, Maryland Rosenfeld Franklin. A comparative evaluation of immunotherapy responses in murine colon carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1683.