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Biomarkers of therapeutic response with immune checkpoint inhibitors.

ABSTRACT: Immune checkpoint inhibitors (ICPIs) have revolutionized the treatment paradigm of a wide range of malignancies with durable responses seen in even advanced, refractory cancers. Unfortunately, only a small proportion of patients with cancer derive meaningful benefit to ICPI therapy, and its use is also limited by significant immune and financial toxicities. Thus, there is a critical need for the development of biomarkers to reliably predict response to ICPI therapy. Only a few biomarkers are validated and approved for use with currently Food and Drug administration (FDA)-approved ICPIs. The development and broad application of biomarkers is limited by the lack of complete understanding of the complex interactions of tumor-host environment, the effect of immunotherapies on these already complex interactions, a lack of standardization and interpretation of biomarker assays across tumor types. Despite these challenges, the field of identifying predictive biomarkers is evolving at an unprecedented pace leaving the clinician responsible for identifying the patients that may derive optimal benefit from ICPIs. In this review, we provide clinicians with a current and practical update on the key, clinically relevant biomarkers of response to ICPIs. We categorize the current and emerging biomarkers of response to ICPIs in four major categories that govern anticancer response-the inflamed tumor, tumor antigens, immune suppression, and overall host environment.

SUBMITTER: Bindal P

PROVIDER: S-EPMC8267267 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Immune checkpoint inhibitors (ICIs), targeting CTLA-4 or PD-1 molecules, have shown impressive therapeutic results. However, only 20-40% of advanced melanoma patients have durable responses to ICI, and these positive effects must be balanced against severe off-target immune toxicity and high costs. This urges the development of predictive biomarkers for ICI response to select patients with likely clinical benefit from treatment. Although many candidate biomarkers exist, a systematic overview of biomarkers and their usefulness is lacking. OBJECTIVES:Here, we systematically review the current literature of clinical data of ICI treatment to provide an overview of candidate predictive biomarkers for ICI in melanoma patients. METHODS:To identify studies on biomarkers for clinical response or survival to ICI therapy in melanoma patients, we performed a systematic search in OVID MEDLINE and retrieved 429 publications, of which 67 met the eligibility criteria. RESULTS:Blood and genomic biomarkers were mainly studied for CTLA-4 ICI, while tumor tissue markers were analyzed for both CTLA-4 and PD-1 ICI. Blood cytology and soluble factors correlated more frequently to overall survival (OS) than to response, indicating their prognostic rather than predictive nature. Systemic T-cell response and regulation markers correlated to response, but progression-free survival or OS were not analyzed. Tumor tissue analyses revealed response correlations with mutational load, neoantigen load, immune-related gene expression, and CD8+ T-cell infiltration at the invasive margin. The predictive value of PD-L1 varied, possibly due to the influence of T-cell infiltration on tumor PD-L1 expression. Genomic biomarker studies addressed CTLA-4 and other immune-related genes. CONCLUSION:This review outlines all published biomarkers for ICI therapy and highlights potential candidate markers for future research. To date, PD-L1 is the best studied biomarker for PD-1 ICI response. The most promising candidate predictive biomarkers for ICI response have not yet been identified. Variations in outcome parameters, statistical power, and analyses hampered summary of the results. Further investigation of biomarkers in larger patient cohorts using standardized objectives and outcome measures is recommended.

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Biomarkers of therapeutic response with immune checkpoint inhibitors.

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