Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential

Abstract

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.

Figure 1

Depiction of tumor cells dying as a result of genomically-targeted therapies with release of tumor antigens. Tumor antigens are taken up by antigen-presenting cells (APCs) and presented in the context of B7 costimulatory molecules to T cells. T cells recognize antigens on APCs to become activated. Activated T cells also upregulate inhibitory checkpoints such as CTLA-4 and PD-1. Immune checkpoint therapy prevents attenuation of T cell responses thereby allowing T cells to kill tumor cells. Development of memory T cells that can reactivate in the presence of recurrent tumor.

Figure 2

Depiction of Kaplan-Meier survival curve with genomically-targeted agents (blue line) as compared to standard therapies (purple line) indicating an improvement in median overall survival but lack of durable responses; improved median overall survival and durable responses in a fraction of patients treated with immune checkpoint therapy (green line); possibility for improved median overall survival with durable responses for the majority of patients in the setting of combination treatment with genomically-targeted agents and immune checkpoint therapy (red line)