ReviewNot all immune-checkpoint inhibitors are created equal: Meta-analysis and systematic review of immune-related adverse events in cancer trials
Introduction
The immune system plays an important role in maintaining checks and balance to protect the host from exogenous pathogens by distinguishing “self” from “non-self” (Postow et al., 2015a, Wolchok and Saenger, 2008). However, differentiating between malignant and benign cells is a challenge. The immune system and tumor cells exist in a dynamic state of equilibrium between two extremes (known as immune-editing): the elimination of the tumor by the immune system (T-cell activation) and the ability of the tumor to evade the immune response and proliferate unchecked (tolerance) (Kirkwood et al., 2008). This system involves both stimulatory and inhibitory signals to maintain immune tolerance. Without the latter, the body may eliminate the tumor but will likely develop autoimmune diseases that will destroy self tissues.
In recent years, the blockade of immune inhibitory signals using immune checkpoint inhibitors (ICI) has been approved as a strategy to treat a variety of malignancies such as melanoma (Hodi et al., 2010, Eggermont et al., 2015, Robert et al., 2015a, Weber et al., 2015, Postow et al., 2015b), lung (Borghaei et al., 2015, Garon et al., 2015), head and neck (Seiwert et al., 2016, Ferris et al., 2016), renal cell (Motzer et al., 2015, McDermott et al., 2016) and urothelial (Rosenberg et al., 2016) cancers, as well Hodgkin lymphoma (Ansell et al., 2015). This strategy consists of using one (Hodi et al., 2010, Eggermont et al., 2015, Robert et al., 2015a, Weber et al., 2015, Postow et al., 2015b, Borghaei et al., 2015, Garon et al., 2015, Motzer et al., 2015, Rosenberg et al., 2016, Ansell et al., 2015, McDermott et al., 2016, Ferris et al., 2016, Seiwert et al., 2016) or two (Postow et al., 2015b, Larkin et al., 2015, Antonia et al., 2016) monoclonal antibodies to target cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), or its ligand (PD-L1) to alleviate tumor-induced immunosuppression of T cells thereby enhancing antitumor effects (Pardoll, 2012). Promising trials are being developed for other cancers (e.g., breast cancer (Spellman and Tang, 2016)) for treatment with ICI.
Immune-related toxicities (irAEs) are a unique aspect of the ICI toxicity profile. These irAEs can affect dermatologic, gastrointestinal, hepatic, pancreatic, pulmonary, renal, endocrine, neurologic, hematologic, ophthalmologic, cardiac, and musculoskeletal organs as well cause infusion-related reactions. The overall and organ-specific irAEs profile differs among ICI classes and depends on the mechanism of action and target(s) inhibition (Fig. 1a and b). The intensity of irAEs can range from mild and manageable in the outpatient setting to severe and life threatening if diagnosed late or not treated aggressively and promptly with appropriate measures.
CTLA-4 is expressed exclusively on T-cells and regulates the amplitude of early T-cell activation. PD-1 is another well-characterized immune checkpoint receptor found on B-lymphocytes, NK cells, and also on T-cells after activation (Keir et al., 2008). CTLA-4, PD-1, and PDL-1 are all inhibitory molecules of the immune system. Whereas CTLA-4 is primarily involved in T-cell activation, PD-1 acts in peripheral tissues and the tumor microenvironment to limit effector T-cell function (Ribas, 2012). PD-L1 differs from PD-1 in its expression on the effector or target cells rather than the regulatory T cells that express CTLA-4 (Wolchok and Saenger, 2008, Ribas, 2012). We predict that inhibiting the function of CTLA-4, PD-1, or PD-L1 will result in a respective decrease in the degree of autoimmunity, since fewer activating T-regulatory cells and more non-T and target tumor cells are involved. Our hypothesis is to confirm that ICI targeting CTLA-4 induce more irAEs than ICI targeting PD-1 (Larkin et al., 2015) and that the latter induce more irAEs than ICI targeting PD-L1. Our objective was to compare, by immune checkpoint target(s) inhibition, the incidence of global irAEs, the incidence and nature of organ-specific irAEs, and the efficacy in terms of response rate through a meta-analysis and systematic review of the literature.
Section snippets
Search strategy and sources (identification)
A systematic literature search was performed up to December 2016 in the MEDLINE database to identify relevant clinical trials conducted in humans using immune checkpoint inhibitor (ICI) to treat cancer (Fig. 2). We identified appropriate anti-CTLA-4 ICI trials using the keywords ipilimumab or tremelimumab, and anti-PD-1 ICI trials using the keywords nivolumab, pembrolizumab, and pidizilumab (CT-011). We used keywords durvalumab, atezolizumab, and avelumab to search for appropriate anti-PD-L1
Literature search
We identified 253 articles reporting ICI clinical trials through MEDLINE searches (Fig. 2). Among these studies, 163 were excluded after reading the title, abstract, and, if necessary, reading the manuscript. Studies were excluded because authors did not report number or incidence of global irAEs (any grade and grade 3 and above), they were duplicate studies, biomarker studies or reviews, not a clinical trial or EAP, or were a non-cancer study. The screening process left us with 90 studies with
Discussion
To our knowledge, this is the first systematic review and meta-analysis comparing overall and organ-specific irAEs in patients with cancers treated with ICI monotherapies and combinations based on their mechanism of actions. In our study, we showed a pathophysiologic explanation as to why irAEs are more likely to occur with CTLA-4 compared to PD-1 blockade, confirming what is known in melanoma, and demonstrated that irAES are more likely to occur with CTLA-4 and PD-1 ICI than PD-L1 blockade.
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Disclosures
No disclosures.
Funding
Georgia Cancer Center at Augusta University - United States.
Authors contribution
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Conceptualization: Formulation of overarching research goals and aims: B El Osta, R Sadek, SC Tang.
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Methodology: Development or design of methodology; creation of models: B El Osta, F Hu, R Sadek.
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Software: Programming, software development; designing computer programs; implementation of the computer code and supporting algorithms; testing of existing code components: F Hu, R Sadek.
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Validation: Verification, whether as a part of the activity or separate, of the overall replication/reproducibility
Acknowledgement
Department of Hematology / Medical Oncology - Atlanta VA Medical Center, Decatur, GA (Contents do not represent the views of the DoVA or the US Government). The authors thank Dr. Anthea Hammond for editing the manuscript.
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2022, Immunology and Allergy Clinics of North AmericaCitation Excerpt :Infusion reactions occur in 1% to 6% of patients, although these events tend to be mild and less than 1% of events are grade 3 or above.46,136,137 Notably, avelumab, an anti-PD-L1 mAb, has a higher risk of infusion reaction (approximately 25%), although these are also uncommonly severe (0%–3% grade 3) and nearly always subside after the first infusion.46,136–138 These events tend to occur during the infusion and may include “typical” infusion reaction symptoms, including rash, cough, wheezing, angioedema, hypotension, and even anaphylaxis.
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2022, Allergology InternationalCitation Excerpt :However, the frequency of the irAEs in each organ are different based on type of ICI treatment. Previous systematic reviews showed that the incidence of any grade irAE was higher in patients who received ICI targeting CTLA-4 (53.8%) than ICIs targeting PD-1 (26.5%) or PD-L1 (17.1%),4 and grade 3/4 (severe to life-threatening) irAEs were also more common with ICIs targeting CTLA-4 (31%) compared with ICI targeting PD-1 (10%).5 In detail, all grades of colitis (odds ratio [OR] 8.7, 95% confidence interval [CI] 5.8–12.9), hypophysitis (OR 6.5, 95% CI 3.0–14.3) and rash (OR 2.0, 95% CI 1.8–2.3) were more frequent with CTLA-4 blockade therapies; whereas pneumonitis (OR 6.4, 95% CI 3.2–12.7), hypothyroidism (OR 4.3, 95% CI 2.9–6.3), arthralgia (OR 3.5, 95% CI 2.6–4.8), and vitiligo (OR 3.5, 95% CI 2.3–5.3) were more common with PD-1/PD-L1 blockade therapies.5