Background

In the past five years, the field of cancer immunotherapy has been revolutionized by new clinical successes. These improved outcomes for cancer patients are due to several years of development of new drugs, preclinical studies and large scale clinical trials. New immunotherapeutics have been approved by the FDA, including antibodies that block immune checkpoint molecules CTLA-4 and PD-1. Furthermore, very impressive durable responses have been obtained after adoptive transfer of several types of cellular populations, including genetically engineered lymphocytes.

These clinical advances and newly approved therapeutics are moving cancer immunotherapy from a niche approach in limited centers, primarily for melanoma and renal cancer, to a broadly applicable and effective treatment for many common and deadly cancers. Despite the success, the current drugs and early data from their various combinations do not result in durable responses for every patient, and they are not without toxicity. Therefore, a critical roadblock in cancer therapy remains the identification of patients likely to respond to a given immunotherapy who could be pre-selected. In addition, parameters need to be sought to follow patients during therapy to identify those that are benefitting before a clinical response is evident. This is because, contrary to other treatments, evaluable clinical responses to immunotherapy often lag in time due to secondary biologic activity of tumors due to infiltration by inflammatory cells [1].

The Society for Immunotherapy of Cancer (SITC) has been investigating predictive and prognostic biomarkers of response in cancer immunotherapy for many years. The Society has focused on immune biomarkers in several dedicated workshops [2-4]. Between 2008–2011, the SITC Taskforce on Immunotherapy Biomarkers developed a series of recommendations and resources for the field [5-7]. Since then, the field has progressed further. New therapeutics are now in common use and technology has evolved significantly. In addition, a greater understanding of the tumor microenvironment now exists, and characterization of tumor infiltrating cell populations and immune regulatory molecules expressed by both the tumor and TIL is more commonly performed [8-11].

As a field, we still lack the necessary biomarkers that identify the patients who are most likely to respond to a given approach and who will have minimal or acceptable toxicities, nor do we have defined, standardized and validated biomarkers to identify the patients who are responding to a treatment before clinically evident tumor shrinkage is detected. There are, however, many candidate assays and molecules which seem informative in a given trial. These include standardized measures for antigen-specific T cell activation, frequencies of suppressive Treg and MDSC, circulating cytokines and growth factors, antibody titers, and tumor immune cell infiltrate characterization. However, most studies only test one or two readouts, tumor samples are often not available, blood volumes can be limited, and methods for performing assays and interpreting the results vary broadly. Furthermore, none of these tests have definitively proven to date to correlate with clinical outcome across trials.

To address these issues, the SITC Immune Biomarkers Task Force has reconvened under the continuing leadership of the Steering Committee: Lisa H. Butterfield, Mary L. Disis, Bernard A. Fox, Samir N. Khleif and Francesco M. Marincola. In its previous iteration, the Taskforce had two working groups which individually addressed two general areas. Working Group (WG)1, led by Drs. Butterfield and Disis, focused on issues of standardization and validation of immune assays. WG2, led by Drs. Marincola and Peter P. Lee, focused on novel technologies and high throughput approaches.

The recommendations of the Taskforce, published in 2011 [6] could be summarized as follows:“Although specific immune parameters and assays are not yet validated, we recommend following standardized (accurate, precise, and reproducible) protocols and use of functional assays for the primary immunologic readouts of a trial; consideration of central laboratories for immune monitoring of large, multi-institutional trials; and standardized testing of several phenotypic and functional potential potency assays specific to any cellular product. When reporting results, the full QA (quality assessment)/QC (quality control) should be conducted and selected examples of truly representative raw data and assay performance characteristics should be included. Finally, to promote broader analysis of multiple aspects of immunity, and gather data on variability, we recommend that in addition to cells and serum, RNA and DNA samples be banked (under standardized conditions) for later testing. We also recommend that sufficient blood be drawn to allow for planned testing of the primary hypothesis being addressed in the trial, and that additional baseline and post-treatment blood is banked for testing novel hypotheses (or generating new hypotheses) that arise in the field”.