Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy

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Abstract
Exploration for biomarkers for drugs that block immune checkpoints should be rationally conducted based on knowledge of the mechanism of action of the targeted pathway. The programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte associated antigen 4 (CTLA4) pathways are unique, and there are special considerations based on mechanisms of action for developing biomarkers for drugs blocking each of these pathways. Biomarkers for immune checkpoint-blocking drugs currently fall into three major categories: immunological, genetic and virological. Future work may reveal additional markers related to metabolism and the microbiome. Immunological biomarkers offer the advantage of applicability across multiple tumour types amenable to immune checkpoint blockade. In the case of anti-PD1 drugs, tumour PD1 ligand 1 (PDL1) expression is a pretreatment biomarker that predicts a greater likelihood of response to therapy. Despite technical pitfalls that make clinical application challenging, two PDL1 immunohistochemistry tests are currently approved by the US Food and Drug Administration for guiding treatment decisions in patients with non-small-cell lung cancer and melanoma. Although no specific oncogene or driver mutation has yet been correlated with clinical response to immune checkpoint blockade, overall tumour mutational burden reflecting neoantigenic diversity may have predictive value. This is exemplified by the high anti-PD1 response rate in DNA mismatch repair deficient colorectal cancers (which have a large mutational burden and which account for ∼15% of all colon cancers), whereas mismatch repair proficient colon cancers are unlikely to respond. Virus-associated cancers, which account for more than 20% of cancers worldwide, express viral neoantigens that are strongly immunogenic. Early evidence demonstrates expression of PD1–PDL1 in these cancers, and suggests responsiveness to anti-PD1 therapies. Combination treatment regimens based on immune checkpoint-blocking drugs are emerging as the next step in clinical development to improve efficacy and response durability. Biomarker considerations for these regimens are complex and are likely to involve multifactorial assessments.

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