The advent of therapies harnessing the intrinsic anti-tumor activity of the immune system against cancer represents a paradigm shift in oncology therapeutics that has permanently changed the future of how we fight cancer.
Colorectal cancer (CRC) is a major contributor to the whole of cancer as a disease, representing 10% of all cases of cancer; over one million new cases of CRC were observed worldwide in 2018 resulting in over half a million deaths1. Clinical treatments involve surgical resection followed by adjuvant chemotherapy for non-metastasized colon cancer with more targeted therapies employed for metastatic CRC2. Recent clinical studies demonstrate strong results for immune checkpoint inhibition in the treatment of patients with unresectable, metastatic with high microsatellite instability (MSI-H), or mismatch repair deficient (dMMR) colorectal cancer3. Clinical benefit was so much so that Keytruda (monoclonal antibody targeting the human PD-1 immune checkpoint protein) was approved as a first line therapy for patients with CRC meeting these three criteria in the summer of 20204. With this new promise of immunotherapy against CRC, highly translational preclinical models of the disease are required to assess the effectiveness of novel immuno-oncology agents.
Assessing the efficacy of therapeutics targeting the immune system require preclinical tumor models with intact immune systems present for manipulation by test agents. Syngeneic tumor models represent such a strategy, in which mouse derived cancer cells are grown to form a tumor in the immune competent mouse strain of the tumor cell origin. We have extensively used CT26.WT murine colon carcinoma as a subcutaneous tumor model in female Balb/c mice to evaluate the efficacy of immuno-oncology agents - see our previous work in the model spotlights below (additional data available upon request):
- CT26 murine colon carcinoma spotlight
- Characterization of proliferation in multiple lymphocyte subsets in the CT26 murine colon carcinoma model by multi-color flow cytometry poster
- Immunophenotypic and Transcriptome Analyses of CT26 and 4T1-Luc Tumor Models Following Anti-mCTLA-4 Treatment poster
We recognize the experimental and translational limitations of subcutaneous tumor models of holding a different tumor microenvironment compared to tumors rising from the organ of origin including, but not limited to, disparate immune cell profiles that can affect response to immunotherapy5,6. Implant of tumor cells into the tissue of origin, known as an orthotopic tumor implant, seeks to rectify the limitations of subcutaneous studies and increase the potential translatability of the model.
In this model spotlight we will provide data that demonstrate a robust and reproducible orthotopic murine tumor model utilizing CT26.WT colon carcinoma, reliable surgical methods for implantation and validating response to checkpoint inhibition.
All animal work was approved by the site Institutional Animal Care and Use Committee and was performed in conformance with the Guide for the Care and Use of Laboratory Animals within an AAALAC-accredited program with humane euthanasia criteria predetermined on all studies.
Orthotopic Growth of CT26.WT-luc Tumors
Figure 1. Growth kinetics of CT26.WT-luc derived tumors orthotopically implanted in Balb/c mice