Over the past decade, the use of immune checkpoint inhibitors (ICI) has expanded across a wide spectrum of oncology indications. Immune-related adverse events (irAE) from ICIs represent a significant ...source of morbidity, and in rare instances, can lead to treatment-related mortality. There are significant opportunities to better identify patients at increased risk for immune-related toxicity, diagnose irAEs more accurately and earlier in their course, and develop more individualized therapeutic strategies once complications arise. Clinical characteristics, germline and somatic genetic features, microbiome composition, and circulating biomarkers have all been associated with higher risk of developing irAEs in retrospective series. Many of these data suggest that both antitumor and anti-host ICI-associated immune reactions may be driven by common features of either the tumor or the patient's preexisting immune milieu. While irAE diagnosis is currently based on clinical history, exclusion of alternative etiologies, and sometimes pathologic confirmation, novel blood-based and radiographic assays are in development to identify these complications more precisely. Anecdotal reports and small case series have highlighted the potential role of targeted immunomodulatory agents to treat irAEs, though further prospective investigation is needed to evaluate more rigorously their use in these settings. In this review, we highlight the current state of knowledge about predicting, diagnosing, and treating irAEs with a translational focus and discuss emerging strategies which aim to improve each of these domains.
The risk of immune checkpoint inhibitor therapy-related GI adverse events in patients with cancer and inflammatory bowel disease (IBD) has not been well described. We characterized GI adverse events ...in patients with underlying IBD who received immune checkpoint inhibitors.
We performed a multicenter, retrospective study of patients with documented IBD who received immune checkpoint inhibitor therapy between January 2010 and February 2019. Backward selection and multivariate logistic regression were conducted to assess risk of GI adverse events.
Of the 102 included patients, 17 received therapy targeting cytotoxic T-lymphocyte antigen-4, and 85 received monotherapy targeting programmed cell death 1 or its ligand. Half of the patients had Crohn's disease, and half had ulcerative colitis. The median time from last active IBD episode to immunotherapy initiation was 5 years (interquartile range, 3-12 years). Forty-three patients were not receiving treatment of IBD. GI adverse events occurred in 42 patients (41%) after a median of 62 days (interquartile range, 33-123 days), a rate higher than that among similar patients without underlying IBD who were treated at centers participating in the study (11%;
< .001). GI events among patients with IBD included grade 3 or 4 diarrhea in 21 patients (21%). Four patients experienced colonic perforation, 2 of whom required surgery. No GI adverse event-related deaths were recorded. Anti-cytotoxic T-lymphocyte antigen-4 therapy was associated with increased risk of GI adverse events on univariable but not multivariable analysis (odds ratio, 3.19; 95% CI, 1.8 to 9.48;
= .037; and odds ratio, 4.72; 95% CI, 0.95 to 23.53;
= .058, respectively).
Preexisting IBD increases the risk of severe GI adverse events in patients treated with immune checkpoint inhibitors.
Scant data describe exocrine pancreatic insufficiency (EPI) secondary to immune checkpoint inhibitor (ICI) use. The goal of this study is to describe the incidence, risk factors, and clinical ...characteristics of patients with ICI-related EPI.
A single center, retrospective case-control study was performed of all ICI-treated patients at Memorial Sloan Kettering Cancer Center between January 2011 and July 2020. ICI-related EPI patients had steatorrhea with or without abdominal discomfort or weight loss, started pancrelipase after initiation of ICI, and demonstrated symptomatic improvement with pancrelipase. Controls were matched 2:1 by age, race, sex, cancer type, and year of ICI start.
Of 12 905 ICI-treated patients, 23 patients developed ICI-related EPI and were matched to 46 controls. The incidence rate of EPI was 1.18 cases per 1000 person-years and the median onset of EPI was 390 days after the first dose of ICI. All 23 (100%) EPI cases had steatorrhea that improved with pancrelipase, 12 (52.2%) had weight loss, and 9 (39.1%) had abdominal discomfort; none had changes of chronic pancreatitis on imaging. Nine (39%) EPI patients had episodes of clinical acute pancreatitis preceding the onset of EPI, compared to 1 (2%) control (OR 18.0 (2.5-789.0), P < .001). Finally, the EPI group exhibited higher proportions of new or worsening hyperglycemia after ICI exposure compared with the control group (9 (39.1%) vs. 3 (6.5%), P < .01).
ICI-related EPI is a rare but clinically significant event that should be considered in patients with late onset diarrhea after ICI treatment and often is associated with development of hyperglycemia and diabetes.
Immune checkpoint inhibitor-related colitis is a common complication of immunotherapy use in patients with cancer. Current guidelines recommend treatment with standard dose infliximab (IFX) for ...corticosteroid-refractory colitis; however, this case series suggests IFX dose escalation may be a viable treatment option for refractory cases.
The optimal management for immune-related adverse events (irAEs) in patients who do not respond or become intolerant to steroids is unclear. Guidelines suggest additional immunosuppressants on the ...basis of case reports and expert opinion.
We evaluated patients with lung cancers at Memorial Sloan Kettering Cancer Center treated with immune checkpoint blockade from 2011 to 2020. Pharmacy records were queried to identify patients who received systemic steroids and an additional immunosuppressant (e.g., tumor necrosis factor-α inhibitor, mycophenolate mofetil). Patient records were manually reviewed to evaluate baseline characteristics, management, and outcomes.
Among 2750 patients with lung cancers treated with immune checkpoint blockade, 51 (2%) received both steroids and an additional immunosuppressant for a severe irAE (tumor necrosis factor-α inhibitor (73%), mycophenolate mofetil (20%)). The most common events were colitis (53%), pneumonitis (20%), hepatitis (12%), and neuromuscular (10%). At 90 days after the start of an additional immunosuppressant, 57% were improved from their irAE, 18% were unchanged, and 25% were deceased. Improvement was more common in hepatitis (five of six) and colitis (18 of 27) but less common in neuromuscular (one of five) and pneumonitis (3 of 10). Of the patients who died, 8 of 13 were attributable directly to the irAE and 4 of 13 were related to toxicity from immunosuppression (three infection-related deaths, one drug-induced liver injury leading to acute liver failure).
Steroid-refractory or resistant irAEs events are rare. Although existing treatments help patients with hepatitis and colitis, many patients with other irAEs remain refractory or experience toxicities from immunosuppression. A more precise understanding of the pathophysiology of specific irAEs is needed to guide biologically-informed treatments for severe irAEs.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event of treatment with immune checkpoint inhibitors (ICI). We hypothesize that genetic susceptibility to Crohn's disease (CD) ...and ulcerative colitis (UC) predisposes to IMC. In this study, we first develop a polygenic risk scores for CD (PRS
) and UC (PRS
) in cancer-free individuals and then test these PRSs on IMC in a cohort of 1316 patients with ICI-treated non-small cell lung cancer and perform a replication in 873 ICI-treated pan-cancer patients. In a meta-analysis, the PRS
predicts all-grade IMC (OR
=1.35 per standard deviation SD, 95% CI = 1.12-1.64, P = 2×10
) and severe IMC (OR
=1.49 per SD, 95% CI = 1.18-1.88, P = 9×10
). PRS
is not associated with IMC. Furthermore, PRS
predicts severe IMC among patients treated with combination ICIs (OR
=2.20 per SD, 95% CI = 1.07-4.53, P = 0.03). Overall, PRS
can identify patients receiving ICI at risk of developing IMC and may be useful to monitor patients and improve patient outcomes.
PDF
