Immunotherapy combination approaches: mechanisms, biomarkers and clinical observations

The approval of the first immune checkpoint inhibitors provided a paradigm shift for the treatment of malignancies across a broad range of indications. Whereas initially, single-agent immune checkpoint inhibition was used, increasing numbers of patients are now treated with combination immune checkpoint blockade, where non-redundant mechanisms of action of the individual agents generally lead to higher response rates. Furthermore, immune checkpoint therapy has been combined with various other therapeutic modalities, including chemotherapy, radiotherapy and other immunotherapeutics such as vaccines, adoptive cellular therapies, cytokines and others, in an effort to maximize clinical efficacy. Currently, a large number of clinical trials test combination therapies with an immune checkpoint inhibitor as a backbone. However, proceeding without inclusion of broad, if initially exploratory, biomarker investigations may ultimately slow progress, as so far, few combinations have yielded clinical successes based on clinical data alone. Here, we present the rationale for combination therapies and discuss clinical data from clinical trials across the immuno-oncology spectrum. Moreover, we discuss the evolution of biomarker approaches and highlight the potential new directions that comprehensive biomarker studies can yield.