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Immunotherapy for Microsatellite Stable Colorectal Cancers: Challenges and Novel Therapeutic Avenues
Ibrahim Halil Sahin1, Kristen K Ciombor2, Luis A Diaz3
1H. Lee Moffitt Cancer Center and Research Institute, Tampa FL.
Abstract:
With the development of immune checkpoint inhibitors, immunotherapy researchers have facilitated substantial progress for patients with mismatch repair deficient/microsatellite instability-high colorectal cancer, which has led to practice changes at a head-spinning pace. However, this benefit has not been translated into microsatellite stable colorectal cancer, which carries the hallmarks of chromosomal instability. So far, clinical trials have not shown any substantial clinical benefits of immune checkpoint inhibitor therapy for patients with microsatellite stable colorectal cancer, which has been disappointing. Recently, combinations of immune checkpoint inhibitors with tyrosine kinase inhibitors and targeted therapies have been investigated for potential synergistic effects that may increase antitumor activity in the tumor microenvironment and achieve more substantial clinical and radiologic responses. In this article, we discuss the current state of the science for the use of immune checkpoint inhibitors in microsatellite stable colorectal cancers, and we review the molecular underpinnings of inherited physiologic barriers for the delivery of effective immunotherapy. We also elaborate on existing therapeutic opportunities to convert microsatellite stable colorectal cancer into an "immune hot" cancer, which may define the future treatment paradigm of colorectal cancer for which there is a great unmet need.
Insights
Immune checkpoint inhibitors benefit mismatch repair deficient colorectal cancer, but not microsatellite stable types. Research explores combining therapies to improve outcomes for microsatellite stable colorectal cancer.
Area of Science:
- Oncology
- Immunotherapy
- Gastrointestinal Cancers
Background:
- Immune checkpoint inhibitors (ICIs) have revolutionized treatment for mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC).
- Microsatellite stable (MSS) CRC, characterized by chromosomal instability, has shown limited response to current ICI therapy.
- Significant unmet need exists for effective immunotherapies in MSS CRC.
Purpose of the Study:
- To review the current landscape of ICI use in MSS CRC.
- To explore molecular barriers hindering immunotherapy efficacy in MSS CRC.
- To discuss strategies for converting MSS CRC into an immunogenic tumor type.
Main Methods:
- Review of current scientific literature on immunotherapy in colorectal cancer.
- Analysis of molecular characteristics of MSS CRC and their impact on the tumor microenvironment.
- Exploration of combination therapies involving ICIs, tyrosine kinase inhibitors, and targeted agents.
Main Results:
- Current ICI monotherapy offers minimal benefit for MSS CRC patients.
- Investigating combination strategies aims to enhance antitumor activity and clinical responses.
- Understanding molecular barriers is crucial for developing novel therapeutic approaches.
Conclusions:
- Novel therapeutic strategies are urgently needed for MSS CRC.
- Combination therapies hold promise for improving outcomes in MSS CRC.
- Converting MSS CRC to an "immune hot" phenotype may represent a future treatment paradigm.
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