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.

Keywords: Biomarkers; Cytotoxic T-lymphocyte antigen 4 (CTLA-4); DNA damage response (DDR); Immunotherapy; Mismatch repair deficiency (MMR); Programmed death 1 (PD-1); Tumor mutation burden (TMB).

Fig. 1

Cancer cell biomarkers and checkpoint inhibitor response. (1) Mutations in tumor cells, mostly related to smoking, generate neo-antigens, (2) neo-antigens are expressed on the cancer cell surface, (3) antigen presenting cells (APCs) recognize neo-antigens, and present them to CD8⁺ T-cells, inducing cytotoxic T-cell responses. (4) Cytotoxic CD8⁺ T-cell activation occurs, resulting in robust neo-antigen-dependent tumor cell death. Checkpoint inhibitors are effective against tumors with high PD-L1, MMR-positive tumors, or TMB-high tumors that reach a threshold for robust CD8⁺ cytotoxic T-cell activation. MHC major histocompatibility complex, TCR T-cell receptor. B7.1/CD80 and B7.2/CD86 are proteins expressed on APC that bind to CTLA-4 on cytotoxic CD8⁺ T-cells

Fig. 2

Correlation between tumor mutational burden and objective response rate with anti-PD-1 or anti-PD-L1 therapy in 27 tumor types. [Reprinted with permission from https://www.nejm.org/doi/10.1056/NEJMc1713444]. Shown are the median numbers of coding somatic mutations per megabase (MB) of DNA in 27 tumor types or subtypes among patients who received inhibitors of programmed death 1 (PD-1) protein or its ligand (PD-L1), as described in published studies for which data regarding the objective response rate are available. The number of patients who were evaluated for the objective response rate is shown for each tumor type (size of the circle), along with the number of tumor samples that were analyzed to calculate the tumor mutational burden (degree of shading of the circle). Data on the x axis are shown on a logarithmic scale. MMRd denotes mismatch repair-deficient, MMRp mismatch repair-proficient, and NSCLC non-small cell lung cancer. A significant correlation between the tumor mutational burden and the objective response rate (P < 0.001) to the IO was demonstrated by the above study [75]