Immune Checkpoint Inhibitor Therapy in Oncology: Current Uses and Future Directions: JACC: CardioOncology State-of-the-Art Review

Abstract

Immune checkpoint inhibitors (ICIs) are a major class of immuno-oncology therapeutics that have significantly improved the prognosis of various cancers, both in (neo)adjuvant and metastatic settings. Unlike other conventional therapies, ICIs elicit antitumor effects by enhancing host immune systems to eliminate cancer cells. There are 3 approved ICI classes by the U.S. Food and Drug Administration: inhibitors targeting cytotoxic T lymphocyte associated antigen 4, programmed death 1/programmed death-ligand 1, and lymphocyte-activation gene 3, with many more in development. ICIs are commonly associated with distinct toxicities, known as immune-related adverse events, which can arise during treatment or less frequently be of late onset, usually relating to excessive activation of the immune system. Acute cardiovascular immune-related adverse events such as myocarditis are rare; however, data suggesting chronic cardiovascular sequelae are emerging. This review presents the current landscape of ICIs in oncology, with a focus on important aspects relevant to cardiology.

Keywords: CTLA-4, cytotoxic T lymphocyte associated antigen 4; ICI, immune checkpoint inhibitors; LAG-3, lymphocyte-activation gene 3; MSI, microsatellite instability; PD-L1, programmed death-ligand 1; TMB, tumor mutational burden; TME, tumor microenvironment; biomarkers; cardio-oncology; cardiotoxicity; immune checkpoint inhibitors; immune related adverse events; immunotherapy; irAE, immune-related adverse event; medical oncology.

Graphical abstract

Central Illustration

Current Landscape and Contemporary Issues of Immune Checkpoint Inhibitors The use of immune checkpoint inhibitors in oncology has grown significantly in the past decade, with significant focus on expanding indications, determining predictors for response, treating immune-related adverse events (irAEs), and developing methods to assess tumor response. Further efforts are required to address emerging contemporary issues surrounding potential chronic cardiotoxicities, optimal length of therapy, and health equity. CTLA-4 = cytotoxic T lymphocyte associated antigen 4; LAG-3 = lymphocyte-activation gene 3; PD-1 = programmed death 1; PD-L1 = programmed death ligand 1.

Figure 1

Tumor Microenvironment The tumor microenvironment consists of immune cells (CD8 T cells, CD4 T cells, regulatory T cells [T_regs], natural killer [NK] cells, dendritic cells, macrophages, myeloid-derived suppressor cells [MDSCs]) within the extracellular matrix, stromal cells, surrounding vascular supply, and numerous cytokines.^, Through expression of various cytokines (inhibitory cytokines shown by red lines, stimulatory cytokines shown by black arrows), the tumor microenvironment can promote tumor growth and immune evasion. Created with BioRender. Arg1 = arginase 1; IDO = indoleamine 2,3-dioxygenase; IL = interleukin; iNOS = inducible nitric oxide synthase; PGE₂ = prostaglandin E2; R-NOS = reactive nitric oxide species; TGF = transforming growth factor; VEGF = vascular endothelial growth factor.

Figure 2

Mechanisms of T Cell Activation, Response, and Immune Checkpoint Inhibitors T cell activation is a multiple signal process that begins with tumor antigen presentation by antigen-presenting cells (APCs) from the innate immune system to T cells via the major histocompatibility complex (MHC). A second co-stimulatory signal from the binding of CD80 and CD86 on APCs to CD28 on T cells is also required.^, The intracellular cascade from these signals results in the differentiation of resting CD8 T cells into activated cytotoxic CD8 T cells, which have the ability to recognize tumor cells and promote tumor cell apoptosis through secretion of various cytotoxins. This process is further assisted by additional co-stimulatory signals (black 2-way arrows) or inhibited by co-inhibitory signals (red lines) that are both present in T cell activation and response. Cytotoxic T lymphocyte associated antigen 4 (CTLA-4), programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1), and lymphocyte-activation gene 3 (LAG-3) are co-inhibitory signal targets for immune checkpoint inhibition, allowing increased T cell activation and response toward tumor cells. Additional nonimmune mechanisms of immune checkpoint inhibitors (not depicted) may be involved in the treatment of lymphoma. Created with BioRender. TCR = T cell receptor; TIGIT = T cell Immunoreceptor with Ig and ITIM domains.

Figure 3

U.S. Food and Drug Administration–Approved Immune Checkpoint Inhibitors as of April 2022 There are ≥20 approved indications for immune checkpoint inhibitors at time of writing, although this is expected to expand significantly in the future. Created with BioRender. ∗Also approved for use in adjuvant or neoadjuvant settings. dMMR = deficient mismatch repair; HCC = hepatocellular carcinoma; MSI-H = microsatellite instability-high; NSCLC = non-small cell lung cancer; SCLC = small cell lung cancer; TMB-H = tumor mutational burden-high; other abbreviations as in Figure 2.

Figure 4

Main Organs Affected by Immune-Related Adverse Events Any organ system can be affected. Most common are skin, endocrine, gastrointestinal tract, kidney and lung. Cardiovascular immune-related adverse events are rare but carry significant mortality and morbidity. Created with BioRender.

Figure 5

General Management Principles of irAEs The management of immune-related adverse events (irAEs) depends on severity and involves consideration for suspension of therapy, corticosteroids, and/or immunosuppression., , Management of some organ-specific irAEs may differ from the provided flow chart. CTCAE = Common Terminology Criteria for Adverse Events; ICI = immune checkpoint inhibitor.

Figure 6

Predictive Biomarkers for Response to ICI Therapy Biomarkers evaluating tumor and host immunogenicity have the potential to predict response to ICIs. Created with BioRender. Abbreviations as in Figures 2, 3, and 5.