Colorectal cancer is the fourth most common cancer diagnosed in the United States. Colorectal cancer represents the third leading cause of cancer-related deaths in women and the second in men. In 2019, over 145,000 estimated new cases of colorectal cancer in the United States will be diagnosed and more than 51,000 patient deaths will occur. Prevention and early detection initiatives over the last several decades, together with improved treatment options, have resulted in reductions in colorectal cancer diagnoses and deaths. These measures have also increased the five-year overall survival rate to 64.9%, but survival drops precipitously for those patients whose cancer is not detected early. For this reason, the development of new treatments for colorectal cancer is a continual need.
The advent of immunotherapy has necessitated syngeneic mouse tumor models with desirable growth kinetics and response to immunomodulatory agents to further advance development of immuno-oncology treatments. One of these colon adenocarcinoma models, MC38, has been characterized by Labcorp to support development of these agents. MC38 was isolated from a colon tumor in a C57BL/6 mouse following long term exposure to the carcinogen DMH (1,2-dimethylhydrazine dihydrochloride). As described below, MC38 has a favorable response profile to immunomodulatory antibodies suggesting a tumor microenvironment amendable to immune activation. Thus, MC38 is well positioned to be a powerful immuno-oncology model with significant utility in drug development
MC38 Tumors Following Checkpoint Inhibitor Therapy
The in vivo doubling time of subcutaneous MC38 tumors is ~4 days, a moderate growth rate which can facilitate up to a three-week dosing window for test agents to elicit their anti-tumor activity. The model was used in a study to evaluate response to commonly utilized checkpoint inhibitor antibodies. Figure 1 demonstrates mean tumor volumes (A) and individual tumor volumes (B-F) of untreated control tumors compared to those treated with isotype control, anti-mCTLA-4, anti-mPD-L1, or anti-mPD-1. Dosing with all test agents began once tumors were established (~100mm3). Anti-mPD-L1 and anti-mPD-1 demonstrated the most meaningful anti-tumor activities, of the three checkpoint inhibitors, with approximately 6 and 8 days of tumor growth delay on day 22, 40% and 50% putative responders, and an increased time to progression of 32 and 29 days, respectively compared to the untreated control group. The clear effect of these treatments can allow for additive or synergistic improvement in combination with candidate molecules.