Immune Checkpoint Blockade: A New Paradigm in Treating Advanced Cancer

Abstract

The approval of the immune checkpoint inhibitor ipilimumab for the treatment of advanced melanoma in 2011 spearheaded the development of other anticancer therapies with immune mechanisms of action, including other immune checkpoint inhibitors. Instead of acting directly on the tumor, these therapies work to "remove the brakes" on the immune system to restore antitumor immune responses. In addition to ipilimumab, which targets the cytotoxic T lymphocyte-associated antigen 4 pathway, several new drugs that target the programmed death-1 pathway are in phase III trials across tumor types, including melanoma, lung cancer, and renal cell carcinoma. In keeping with their unique mechanism of action, these immune checkpoint inhibitors have shown both conventional and unconventional response patterns, including initial apparent tumor progression followed by regression, and adverse events (AEs) that are likely immune-related. Advanced practitioners (APs) treating patients receiving immuno-oncology agents are in a key position to educate patients about expectations with these therapies and to screen patients for AEs and initiate appropriate and timely interventions. This review summarizes current immune checkpoint inhibitor data and provides patient management strategies for APs to optimize patient outcomes with these novel therapies.

Figure 1

Ipilimumab is a fully human anti–CTLA-4 antibody designed to block CTLA-4:B7 binding, thereby allowing costimulatory signaling and generation of antitumor T-cell responses (A). Anti–PD-1 and anti–PD-L1 monoclonal antibodies work by inhibiting PD-1:PD-L1 binding and restoring antitumor immune responses (B). Adapted with permission from Langer (2014), Lippincott Williams & Wilkins/ Wolters Kluwer Health.

Table 1

Immune Checkpoint Inhibitors With Active Phase II and/or III Cancer Trials

Figure 2

Select immune-related adverse events

Figure 3

Management strategy guidelines for immune-related adverse events associated with ipilimumab. ALT = alanine transaminase; AST = aspartate transaminase; LFT = liver function tests; ULN = upper limit of normal (Fecher et al., 2013; Weber et al., 2012).

Figure 4

Relative time course for the appearance of different immune-related adverse events reported for ipilimumab, with rash and diarrhea occurring first after treatment initiation, followed by liver or endocrine toxicities, usually of a lower grade. Reprinted with permission. © 2012 American Society of Clinical Oncology. All rights reserved. Weber JS et al. J Clin Oncol. 2012; 30(21):2691–2697.