Immunologic biomarkers as correlates of clinical response to cancer immunotherapy

Abstract

Over the last few years, several newly developed immune-based cancer therapies have been shown to induce clinical responses in significant numbers of patients. As a result, there is a need to identify immune biomarkers capable of predicting clinical response. If there were laboratory parameters that could define patients with improved disease outcomes after immunomodulation, product development would accelerate, optimization of existing immune-based treatments would be facilitated and patient selection for specific interventions might be optimized. Although there are no validated cancer immunologic biomarkers that are predictive of clinical response currently in widespread use, there is much published literature that has informed investigators as to which markers may be the most promising. Population-based studies of endogenous tumor immune infiltrates and gene expression analyses have identified specific cell populations and phenotypes of immune cells that are most likely to mediate anti-tumor immunity. Further, clinical trials of cancer vaccines and other cancer directed immunotherapy have identified candidate immunologic biomarkers that are statistically associated with beneficial clinical outcomes after immune-based cancer therapies. Biomarkers that measure the magnitude of the Type I immune response generated with immune therapy, epitope spreading, and autoimmunity are readily detected in the peripheral blood and, in clinical trials of cancer immunotherapy, have been associated with response to treatment.

Fig. 1

Characteristics of the ideal immunologic biomarker. Points in the arrow demonstrate the progression of analysis from analyte (bodily fluid) to assay (quantitative/qualitative) to outcome measurement which would reflect mechanism

Fig. 2

Immunologic biomarkers may measure a variety of biologic responses. Shown are examples of three immune biomarkers reported in clinical trials of cancer immune therapy (boxes at top of panel). A cancer vaccine may induce the biologic response of stimulating T cells (blue circles), a demonstration of the potency of the vaccine which was designed to elicit adaptive immunity. The T cells may then traffic to tumor, secreting Type I cytokines, activating APC and stimulating cross-priming (yellow starbursts), inducing epitope spreading the mechanism by which tissue destruction occurs (red lightning bolts). Tissue destruction results in the generation of autoantibodies, which may directly reflect tumor cell death

Fig. 3

Immune biomarkers may be found in differing levels in the peripheral blood. Cancer immunotherapy is often designed to generate cytotoxic T cells (CTL; blue circles) which may have varying levels in the peripheral blood. The majority of induced or infused CTL may be found at the site of the tumor and thus remain undetected. As tumor is destroyed, however, blood-based biomarkers such as antibodies may be present at high levels in the peripheral blood and better reflect tumor destruction (B cells; green circles, antibodies; brown lines)