Immune Checkpoint Targeting in Cancer Therapy: Toward Combination Strategies with Curative Potential

Research in two fronts has enabled the development of therapies that provide significant benefit to cancer patients. One area stems from a detailed knowledge of mutations that activate or inactivate signaling pathways that drive cancer development. This work triggered the development of targeted therapies that lead to clinical responses in the majority of patients bearing the targeted mutation, although responses are often of limited duration. In the second front are the advances in molecular immunology that unveiled the complexity of the mechanisms regulating cellular immune responses. These developments led to the successful targeting of immune checkpoints to unleash anti-tumor T cell responses, resulting in durable long-lasting responses but only in a fraction of patients. In this Review, we discuss the evolution of research in these two areas and propose that intercrossing them and increasing funding to guide research of combination of agents represent a path forward for the development of curative therapies for the majority of cancer patients. Pam Sharma and Jim Allison present a comprehensive Review of the basic and clinical research that has established immunotherapy as one of the chief breakthroughs in medicine in the last decade, and they discuss what the next steps will be in order to develop curative therapies for the majority of patients with cancer.