Advances in immune checkpoint inhibitor combination strategies for microsatellite stable colorectal cancer
Javier Ros1,2, Francesca Balconi3, Iosune Baraibar1
1Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
Abstract:
Immune checkpoint inhibitors have reshaped the prognostic of several tumor types, including metastatic colorectal tumors with microsatellite instability (MSI). However, 90-95% of metastatic colorectal tumors are microsatellite stable (MSS) in which immunotherapy has failed to demonstrate meaningful clinical results. MSS colorectal tumors are considered immune-cold tumors. Several factors have been proposed to account for this lack of response to immune checkpoint blockade including low levels of tumor infiltrating lymphocytes, low tumor mutational burden, a high rate of WNT/β-catenin pathway mutations, and liver metastases which have been associated with immunosuppression. However, studies with novel combinations based on immune checkpoint inhibitors are showing promising activity in MSS colorectal cancer. Here, we review the underlying biological facts that preclude immunotherapy activity, and detail the different immune checkpoint inhibitor combinations evaluated, along with novel immune-based therapies, to overcome innate mechanisms of resistance in MSS colorectal cancer.
Insights
Immune checkpoint inhibitors show promise for microsatellite-stable (MSS) colorectal cancer, traditionally unresponsive to immunotherapy. Novel combinations are being explored to overcome resistance in these "immune-cold" tumors.
Area of Science:
- Oncology
- Immunotherapy
- Colorectal Cancer Research
Background:
- Immune checkpoint inhibitors (ICIs) have significantly improved outcomes for metastatic colorectal tumors with microsatellite instability (MSI).
- However, the vast majority (90-95%) of metastatic colorectal tumors are microsatellite stable (MSS) and exhibit resistance to current immunotherapies, often characterized as 'immune-cold' tumors.
- Factors contributing to this resistance include low tumor-infiltrating lymphocytes, low tumor mutational burden, frequent WNT/β-catenin pathway mutations, and immunosuppressive liver metastases.
Purpose of the Study:
- To review the biological mechanisms underlying immunotherapy resistance in MSS colorectal cancer.
- To detail current and emerging ICI combination strategies aimed at overcoming this resistance.
- To explore novel immune-based therapies for MSS colorectal cancer treatment.
Main Methods:
- Comprehensive literature review of biological factors impeding immunotherapy efficacy in MSS colorectal cancer.
- Analysis of clinical trial data for various immune checkpoint inhibitor combinations in MSS colorectal cancer.
- Evaluation of novel immunotherapeutic approaches targeting resistance mechanisms.
Main Results:
- MSS colorectal tumors present significant biological barriers to effective immunotherapy.
- Emerging studies indicate promising activity with novel combination therapies involving ICIs in MSS colorectal cancer.
- Various novel immune-based strategies are under investigation to enhance treatment response.
Conclusions:
- Understanding the immune-cold nature of MSS colorectal tumors is crucial for developing effective immunotherapies.
- Combination strategies and novel immune-based therapies hold significant potential to overcome innate resistance mechanisms.
- Further research and clinical trials are warranted to establish the efficacy of these novel approaches in MSS colorectal cancer.
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