Evaluation of the Tumor Immunoenvironment in Clinical Trials

Abstract

Monitoring of immunotherapeutic clinical trials has undergone a considerable change in the last decade resulting in a general agreement that immune monitoring should guide the development of cancer vaccines. The emphasis on immune cell functions and the quantitation of antigen-specific T cells has played a major role in the attempts to establish meaningful correlations between therapy-induced alterations in immune responses and clinical endpoints. However, one significant unresolved issue in modern immunotherapy is that when a tumor-specific cellular immune response is observed following a course of immunotherapy, it does not always lead to clinically proven cancer regression. This disappointing lack of a correlation between the tumor-specific cytotoxic immune responses and the therapeutic benefit may be explained in part by the notion that the analysis of any single immunological parameter is not sufficient to provide detailed information about the complex interactions between different cell subsets in the peripheral blood or immune, tumor, and stromal cells in the tumor milieu itself. Therefore, following administration of vaccines or immunomodulators, a systemic approach is required to improve the quality of a serial monitoring to ensure that it adequately and reliably measures crucial beneficial immunological changes induced in patients. Comprehensive evaluation of the balance between the immunostimulatory and immunosuppressive compartments of the immune system could be critical for obtaining a better understanding of why a given immunotherapy does or does not work in a particular clinical trial. New approaches to characterize tumor-infiltrating leukocytes, including their phenotypic, biochemical and genetic characteristics within the tumor microenvironment need to be developed, validated and standardized for reliability and consistency in order to establish the rigorous performance standards that should additionally complement current monitoring techniques.