Results and challenges of immune checkpoint inhibitors in colorectal cancer

ABSTRACT

Introduction: Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide and clinical outcome has improved substantially during the last two decades with targeted therapies. The immune system has a major role in cancers, especially the CD8 + T cells specific to tumor antigens. However, tumors can escape immune response by different mechanisms including upregulation of inhibitory immune checkpoint receptors, such as well-known Programmed cell Death protein-1 (PD-1)/Programmed cell Death Ligand 1 (PD-L1) interaction, leading CD8 + T cells to a state of anergy. Immunotherapy, with the so-called immune checkpoint inhibitors (CPIs), has recently been approved in treatment of multiple cancers due to its prolonged disease control and acceptable toxicities. The recent groundbreaking success involving anti-PD-1 CPIs in metastatic CRC with deficient mismatch repair system (dMMR) is promising, with several trials ongoing. Major challenges are ahead in order to determine how, when and for which patients we should use these CPIs in CRC.

Areas covered: This review highlights some promises and challenges concerning personalized immunotherapy in CRC. First results and ongoing breakthrough trials are presented. The crucial role of biomarkers in selecting patient is also discussed.

Expert opinion: As of now, dMMR and POLE mutations (DNA polymerase ε) with ultramutator phenotype are the most powerful predictive biomarkers of CPI efficacy. The most challenging issue is pMMR mCRC and determination of how to convert a ‘nonimmunogenic’ neoplasm into an ‘immunogenic’ neoplasm, a combination of CPIs with radiation or MEK inhibitor probably being the most relevant strategy. Next-generation sequencing (NGS) assays to quantify mutational load could be more reliable predictive biomarkers of CPIs efficacy than PD-L1 expression or immune scores.

KEYWORDS:

• Colorectal cancer
• immunotherapy
• immune checkpoint inhibitors
• programmed cell death protein-1

Article highlights

• Immunoscores are highly prognostic in non-metastatic colorectal cancer but their prospective validation and implementation in clinical practice remains a challenge.

• Groundbreaking success of immunotherapy, with anti-PD1 checkpoint inhibitors, has been observed in metastatic colorectal cancer with deficient mismatch repair system.

• PD-L1 expression is not a good biomarker to predict efficacy of response to anti-PD1 checkpoint inhibitors in colorectal cancer.

• While identification of predictive biomarkers of immune checkpoint inhibitor efficacy in colorectal cancer is still ongoing, microsatellite instability and POLE mutations (DNA polymerase ε) with ultramutator phenotype are now being validated.

• Tumor mutation load and immunoscores are probably the most relevant future biomarkers in colorectal cancer without microsatellite instability but they still need prospective validation, standardization and cost-effectiveness evaluation.

• Immunotherapy combined with other treatment modalities is a major challenge in attempts to convert ‘nonimmunogenic’ proficient mismatch repair colorectal cancer into an ‘immunogenic’ neoplasm and to induce sensitivity to immune checkpoint inhibitors.

This box summarizes key points contained in the article.

Acknowledgments

The authors wish to thank Vanessa Le Berre for her assistance in preparing the submission of the article and Jeffrey Arsham, an American medical translator, for reviewing our original English-language manuscript.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

This paper is not funded