ReviewImmune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors
Graphical abstract
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.
Section snippets
The CTLA-4 immune checkpoint
The first negative regulator of T cell activation to be identified was CTLA-4, a co-inhibitory receptor that is upregulated early during the course of T cell activation [17]. Bound by the same ligands (CD80/CD86) that provide co-stimulatory signals through CD28 on T lymphocytes, CTLA-4 conversely impedes acquisition of T cell effector function by 1) mediating trans-endocytosis and degradation of the ligands needed for co-stimulation [18] and 2) delivering inhibitory signals that block T cell
The PD-1 immune checkpoint
Though first discovered prior to CTLA-4 in 1992 as a molecule associated with programmed T cell death, PD-1 was not appreciated as a co-inhibitory receptor that negatively regulates T cell effector function until several years later, when autoimmune disease was observed in transgenic mice harboring PD-1−/− T cells [30]. At the same time, PD-L1 and PD-L2 were discovered as dual ligands for PD-1, and both were shown to inhibit T cell effector activity following PD-1 engagement [31, 32]. Although
Combinatorial blockade of the CTLA-4 and PD-1 immune checkpoint pathways
The clinical benefits of checkpoint blockade therapies targeting either the CTLA-4 or PD-1 pathways in cancer patients, along with the realization that these checkpoint pathways each regulate T cell function by distinct mechanisms that act on particular T cell subsets and at different stages of T cell differentiation, have prompted the investigation of combinatorial ICB regimens in the treatment of cancer. Combinatorial therapy with ipilimumab and nivolumab has led to unprecedented responses in
Toxicities associated with immune checkpoint blockade therapy for cancer
In addition to the clinical benefits that have been achieved thus far with ICB therapy, another striking observation that has emerged from the early trials with immune checkpoint inhibitors is the undesirable (and previously unforeseen) side effects that can result from their use. Indeed, the fact that immune checkpoint inhibitors are not directed solely to tumor-specific T cells means that the ability of these drugs to unleash desirable anti-tumor immune reactivity may be accompanied by the
Current challenges to immune checkpoint blockade therapy for cancer
In order to maximize both the efficacy and reach of ICB therapy for cancer patients, many challenges in this field must be addressed. In particular, it is necessary to gain insight into factors that influence response outcomes to ICB therapy and better understand why some patients exhibit complete and durable responses that prolong survival while others experience disease relapse within the first few months of treatment or fail to respond to ICB therapy at all. While efficacy varies by cancer
The future of immune checkpoint blockade therapy for cancer
Despite the challenges still being faced in the field of ICB therapy, the success of this approach in the treatment of a broad spectrum of cancers over the last decade has highlighted just how significant a role the immune system plays in the control of tumors, and historic outcomes in several clinical trials evaluating the efficacy of ICB regimens have reinvigorated the field of cancer immunotherapy. Marked by FDA approval of 6 immune checkpoint inhibitors in the last 7 years, the current
Funding
Research in the Hargadon laboratory is funded by a Jeffress Trust Awards Program in Interdisciplinary Research Grant from the Thomas F. and Kate Miller Jeffress Memorial Trust, Bank of America, N.A., Trustee, a Hampden-Sydney College Research Grant from the Arthur Vining Davis endowment, and generous donations from Mr. Michael Hargadon and Mrs. Patricia Hargadon to support the involvement of undergraduate students in research at Hampden-Sydney College. These funding sources were not involved in
Declarations of interest
None.
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