Immune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors

Highlights

• CTLA-4, PD-1, and PD-L1 are key negative regulators of anti-tumor T cell reactivity.

• Inhibitors of CTLA-4, PD-1, and PD-L1 can enhance anti-tumor T cell reactivity.

• Immune checkpoint blockade yields significant clinical benefit in cancer patients.

Abstract

Although T lymphocytes have long been appreciated for their role in the immunosurveillance of cancer, it has been the realization that cancer cells may ultimately escape a response from tumor-reactive T cells that has ignited efforts to enhance the efficacy of anti-tumor immune responses. Recent advances in our understanding of T cell immunobiology have been particularly instrumental in informing therapeutic strategies to overcome mechanisms of tumor immune escape, and immune checkpoint blockade has emerged as one of the most promising therapeutic options for patients in the history of cancer treatment. Designed to interfere with inhibitory pathways that naturally constrain T cell reactivity, immune checkpoint blockade releases inherent limits on the activation and maintenance of T cell effector function. In the context of cancer, where negative T cell regulatory pathways are often overactive, immune checkpoint blockade has proven to be an effective strategy for enhancing the effector activity and clinical impact of anti-tumor T cells. Checkpoint inhibitors targeting CTLA-4, PD-1, and PD-L1 have yielded unprecedented and durable responses in a significant percentage of cancer patients in recent years, leading to U.S. FDA approval of six checkpoint inhibitors for numerous cancer indications since 2011. In this review, we highlight the clinical success of these FDA-approved immune checkpoint inhibitors and discuss current challenges and future strategies that must be considered going forward to maximize the efficacy of immune checkpoint blockade therapy for cancer.

Introduction

Immunotherapy has recently emerged as a viable and attractive treatment option for many cancer patients. In particular, monoclonal antibody-based immune checkpoint blockade (ICB) therapies that enhance the function of anti-tumor T lymphocytes have been especially promising, yielding unprecedented results in the clinic. Based on these successes, there is now great optimism that ongoing work in immunooncology will further enhance the efficacy of these revolutionary cancer therapies, which have already led to durable remissions in many cancer patients.

The transition of cancer immunotherapy from hopeful vision to standard-of- care treatment for many tumor types has been driven by years of work in the fields of T cell biology and tumor immunology. Some of the first experimental evidence supporting a role for T cells in tumor immune surveillance was provided by seminal studies in murine models showing that either T lymphocytes or effector molecules released by these cells are critical to the control of spontaneous, inducible, or transplanted tumors [[1], [2], [3], [4], [5], [6], [7]]. Additionally, a role for T lymphocytes in tumor immune surveillance in humans was supported by clinical observations correlating spontaneous tumor regression with either autoimmune reactivity (i.e., melanoma regression in the context of vitiligo) [8] or the detection of tumor-associated CD4+ and CD8+ T cell responses in cancer patients [9, 10]. The significance of such T cell responses to the immunologic control of many tumor types was further highlighted by subsequent studies documenting the recovery of dysfunctional T cells from tumors and tumor-draining lymph nodes of patients with progressive disease [[11], [12], [13]]. During this time, the realization that T cell receptor engagement by itself is insufficient to promote T cell activation [14] propelled significant efforts to understand the nature of signals that regulate T cell responses to a source of antigen. In addition to the discovery that T cell activation requires co-stimulation and cytokine support as 2nd and 3rd signals over and above the “first signal” provided by antigenic stimulation through the T cell receptor [15], the identification of co-inhibitory signaling pathways that negatively regulate T cell activation provided key insights into the complex network of interactions that ultimately control the balance between T cell activation and tolerance [16]. While these co-inhibitory immune checkpoints act as fail-safes to prevent aberrant or chronic activation of the immune system and are thus critical to the maintenance of immune homeostasis, they may be co-opted by cancer cells or tumor-associated antigen-presenting cells (APC) as a means of dampening anti-tumor T cell responses and promoting tumor immune escape. Importantly, checkpoint blockade therapies that target these co-inhibitory pathways in the context of cancer effectively “release the brakes” on the immune system at both the induction and effector phases of anti-tumor T cell responses, thereby overcoming tumor immune subversion (Fig. 1). In this review, we highlight the current landscape of FDA-approved immune checkpoint inhibitors for cancer (Table 1), with emphasis on: 1) the ways in which ICB regimens have already revolutionized cancer immunotherapy and 2) the factors that must be considered going forward in order to maximize the potential of immune checkpoint inhibitors as anti-cancer therapeutic agents.