Existing and Emerging Biomarkers for Immune Checkpoint Immunotherapy in Solid Tumors

Abstract

In the last few years, immunotherapy has transformed the way we treat solid tumors, including melanoma, lung, head neck, breast, renal, and bladder cancers. Durable responses and long-term survival benefit has been experienced by many cancer patients, with favorable toxicity profiles of immunotherapeutic agents relative to chemotherapy. Cures have become possible in some patients with metastatic disease. Additional approvals of immunotherapy drugs and in combination with other agents are anticipated in the near future. Multiple additional immunotherapy drugs are in earlier stages of clinical development, and their testing in additional tumor types is under way. Despite considerable early success and relatively fewer side effects, the majority of cancer patients do not respond to checkpoint inhibitors. Additionally, while the drugs are generally well tolerated, there is still the potential for significant, unpredictable and even fatal toxicity with these agents. Improved biomarkers may help to better select patients who are more likely to respond to these drugs. Two key biologically important predictive tissue biomarkers, specifically, PD-L1 and mismatch repair deficiency, have been FDA-approved in conjunction with the checkpoint inhibitor, pembrolizumab. Tumor mutation burden, another promising biomarker, is emerging in several tumor types, and may also soon receive approval. Finally, several other tissue and liquid biomarkers are emerging that could help guide single-agent immunotherapy and in combination with other agents. Of these, one promising investigational biomarker is alteration or deficiency in DNA damage response (DDR) pathways, with altered DDR observed in a broad spectrum of tumors. Here, we provide a critical overview of current, emerging, and investigational biomarkers in the context of response to immunotherapy in solid tumors.

Association Between Response to Nivolumab Treatment and Peripheral Blood Lymphocyte Subsets in Patients With Non-small Cell Lung Cancer

“…Finally, it should also be considered that novel immunotherapy-associated biomarkers are emerging in pulmonary oncology; while the determination of tumor mutational burden (TMB) both in tissue and in peripheral blood has achieved mixed results and still needs further evaluations before being considered in clinical practice, the negative role of STK11/LKB1 seems significantly more robust (35,36). When this study started, information involving the clinical role of STK11/LKB1 was not as acknowledged as it is at present date, hence it was not included as a possible covariate.…”

Naturally-Occurring Invasive Urothelial Carcinoma in Dogs, a Unique Model to Drive Advances in Managing Muscle Invasive Bladder Cancer in Humans

“…Sequencing studies have also been used to characterize the immune state in InvUC tissues (13,16,54,59,(170)(171)(172)(173). Whole exome sequencing analyses can be used to determine tumor mutation burden and neoantigen load, factors that are thought to influence the immune attack on the cancer (171)(172)(173).…”

“…Sequencing studies have also been used to characterize the immune state in InvUC tissues (13,16,54,59,(170)(171)(172)(173). Whole exome sequencing analyses can be used to determine tumor mutation burden and neoantigen load, factors that are thought to influence the immune attack on the cancer (171)(172)(173). Patterns in RNA-seq data have been defined to classify tumors broadly as "immune hot" (immune infiltrated) or "immune cold" (noninfiltrated), with mixed patterns also present (13,16,163,170).…”

Defining a Distinct Immunotherapy Eligible Subset of Patients with Cancer of Unknown Primary Using Gene Expression Profiling with the 92-Gene Assay

“…Efforts have been made to identify biomarkers of tumor responsiveness to ICI [17], and such biomarkers have the potential to inform the use of ICI in CUP [15, 18, 19]. The 92‐gene assay is based on collective GEP and is therefore distinct from DNA‐ and protein‐based methods such as next‐generation sequencing (NGS) and measurement of ICI‐related biomarkers such as MSI‐H, TMB‐H, and PD‐L1.…”