Treatment Of Immune-related Adverse Events Research Articles

Association Between Immune-related Adverse Events and Efficacy of Immune Checkpoint Inhibitors in Non–small-cell Lung Cancer

BackgroundImmune checkpoint inhibitors (ICIs) are available for first- and further lines of treatment of patients with advanced non–small-cell lung cancer (NSCLC). These treatments are associated with adverse events called immune-related adverse events (IRAEs). The incidence, diagnosis, and treatment of IRAEs are quite acknowledged; however, the link between IRAEs and the efficacy of ICIs requires further clarification. The objectives of this study were to assess the association between IRAEs incidence and severity and ICIs efficacy in patients with advanced NSCLC. MethodsIn this retrospective study, clinical, biological, treatment, and outcome data were collected from patients with advanced NSCLC who received at least 1 cycle of ICIs from April 2013 to February 2017. The primary endpoint was to assess the association of IRAEs incidence with overall survival (OS). Secondary endpoints were the association of IRAEs with progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). ResultsOverall, 270 patients were studied. The median OS was 14 months, median PFS was 2.6 months, ORR was 13%, and DCR was 51%. OS, PFS, and ORR were significantly better for patients with IRAEs compared with patients with no IRAEs, translating to median OS not reached versus 8.21 months, respectively (hazard ratio, 0.29; 95% confidence interval [CI], 0.18-0.46; P < .001); PFS was 5.2 versus 1.97 months (hazard ratio, 0.42; 95% CI, 0.32-0.57; P < .001); and ORR was 212.9% versus 5.7% (odds ratio, 4.9; 95% CI, 2.18-11.05; P < .001). ConclusionsThis report presents the largest case series showing longer OS and PFS and better ORR when IRAEs occurred in a population of patients with advanced NSCLC treated with ICIs. The biological background for this phenomenon is being explored prospectively.

Use of traditional Chinese medicine in the treatment of immune-related adverse events of cancer immunotherapy

Abstract Immune checkpoint inhibitors (ICPI) have shown considerable promise in the treatment of tumors. However, immune-related adverse events (irAEs) caused by ICPI have been reported in nearly every organ system. Whilst this represents a new challenge in the field of cancer treatment, traditional Chinese medicine (TCM) provides benefits in the treatment of irAEs. This article reviews the studies of the treatment of immune-related gastrointestinal diseases and dermatosis with TCM and introduces the collaborative efforts between China and France in the implementation of TCM for the treatment of irAEs.

Impact of Baseline Steroids on Efficacy of Programmed Cell Death-1 and Programmed Death-Ligand 1 Blockade in Patients With Non-Small-Cell Lung Cancer.

Treatment with programmed cell death-1 or programmed death ligand 1 (PD-(L)1) inhibitors is now standard therapy for patients with lung cancer. The immunosuppressive effect of corticosteroids may reduce efficacy of PD-(L)1 blockade. On-treatment corticosteroids for treatment of immune-related adverse events do not seem to affect efficacy, but the potential impact of baseline corticosteroids at the time of treatment initiation is unknown. Clinical trials typically excluded patients who received baseline corticosteroids, which led us to use real-world data to examine the effect of corticosteroids at treatment initiation. We identified patients who were PD-(L)1-naïve with advanced non-small-cell lung cancer from two institutions-Memorial Sloan Kettering Cancer Center and Gustave Roussy Cancer Center-who were treated with single-agent PD-(L)1 blockade. Clinical and pharmacy records were reviewed to identify corticosteroid use at the time of beginning anti-PD-(L)1 therapy. We performed multivariable analyses using Cox proportional hazards regression model and logistic regression. Ninety (14%) of 640 patients treated with single-agent PD-(L)1 blockade received corticosteroids of ≥ 10 mg of prednisone equivalent daily at the start of the PD-(L)1 blockade. Common indications for corticosteroids were dyspnea (33%), fatigue (21%), and brain metastases (19%). In both independent cohorts, Memorial Sloan Kettering Cancer Center (n = 455) and Gustave Roussy Cancer Center (n = 185), baseline corticosteroids were associated with decreased overall response rate, progression-free survival, and overall survival with PD-(L)1 blockade. In a multivariable analysis of the pooled population, adjusting for smoking history, performance status, and history of brain metastases, baseline corticosteroids remained significantly associated with decreased progression-free survival (hazard ratio, 1.3; P = .03), and overall survival (hazard ratio, 1.7; P < .001). Baseline corticosteroid use of ≥ 10 mg of prednisone equivalent was associated with poorer outcome in patients with non-small-cell lung cancer who were treated with PD-(L)1 blockade. Prudent use of corticosteroids at the time of initiating PD-(L)1 blockade is recommended.

Interprofessional Collaboration with Immune Checkpoint Inhibitor Therapy: the Roles of Gastroenterology, Endocrinology and Neurology.

To discuss immune checkpoint inhibitor therapy and identify opportunities for interprofessional collaboration in the management of toxicities in the areas of gastroenterology, endocrinology, and neurology. Published research and education articles in oncology, nursing, and various specialties. The use of immune checkpoint inhibitors is expanding; timely management of toxicity is critical for positive patient outcomes. There are many opportunities for interprofessional collaboration in the diagnosis and treatment of immune-related adverse events. Nurses play key roles in recognizing immune-related adverse events, providing patient education, and helping to facilitate interprofessional collaboration.

Effect of high-dose corticosteroids on CD4+ or CD8+ lymphocyte proliferation or IL-2 production after stimulation with pembrolizumab.

e14587 Background: Immune checkpoint inhibitor (ICI) therapy has improved survival of patients with melanoma and other types of cancers. The effect of immunosuppresive corticosteroids on ICI efficacy is unknown, however treatment of immune-related adverse events with high-dose steroid therapy impairs neither efficacy nor time to failure of ICI. In certain clinical circumstances (for instance in the treatment of patients with symptomatic brain metastases) it may be advantageous to begin ICI therapy despite a requirement for steroid therapy. This study examined the effect of high-dose steroid therapy on lymphocyte proliferation/functionality after stimulation with anti-CD3 in the presence of pembrolizumab (PD-1 inhibitor) ex vivo. Methods: Peripheral blood mononuclear cells (PBMCs) were collected from patients with either chronic hepatitis C infection or active malignant melanoma. CD4+ and CD8+ T cells were isolated and subjected to flow cytometry stating for the expression of PD-1. Isolated PBMCs were then pre-treated with prednisone (1 nM - 1 mM) before anti-CD3 stimulation. Anti-CD3-stimulated cells were then incubated with pembrolizumab (5 µg/mL) and their proliferative capacity and IL-2 secretion ability were measured by carboxyfluorescein succinimidyl ester (CFSE) staining and ELISA, respectively. Results: A dose-dependent inhibition of both lymphocyte proliferation and IL-2 production was observed, but at physiologically relevant nanomolar prednisone concentration the steroid effect was negligible. Millimolar prednisone concentrations resulted in &gt; 50% relative reduction in lymphocyte proliferation, however even at this steroid concentration treatment with pembrolizumab was able to further stimulate proliferation and IL-2 secretion versus anti-CD3stimulation alone. Conclusions: Despite heavily immunosuppressive treatment, CD4+ and CD8+ lymphocytes demonstrate proliferative capacity and immunological activity following treatment with pembrolizumab. This suggests that treatment with pembrolizumab may be efficacious despite a requirement for steroid therapy, a scenario often encountered in patients with brain metastases.

Infliximab for IPILIMUMAB-Related Colitis—Letter

Ipilimumab, an anticytotoxic T-lymphocyte–associated protein (CTLA)-4 antibody, was approved in 2011 by the FDA for the treatment of advanced melanoma ([1, 2][1]). Our study aimed to evaluate the impact of immunosuppressants used for the treatment of immune-related adverse events (irAE) on outcome

A novel melanoma therapy stirs up a storm: ipilimumab-induced thyrotoxicosis.

SummaryIpilimumab, a novel therapy for metastatic melanoma, inhibits cytotoxic T-lymphocyte apoptosis, causing both antitumor activity and significant autoimmunity, including autoimmune thyroiditis. Steroids are frequently used in treatment of immune-related adverse events; however, a concern regarding the property of steroids to reduce therapeutic antitumor response exists. This study describes the first reported case of ipilimumab-associated thyroid storm and implicates iopanoic acid as an alternative therapy for immune-mediated adverse effects. An 88-year-old woman with metastatic melanoma presented with fatigue, anorexia, decreased functional status, and intermittent diarrhea for several months, shortly after initiation of ipilimumab – a recombinant human monoclonal antibody to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4). On arrival, she was febrile, tachycardic, and hypertensive with a wide pulse pressure, yet non-toxic appearing. She had diffuse, non-tender thyromegaly. An electrocardiogram (EKG) revealed supraventricular tachycardia. Blood, urine, and stool cultures were collected, and empiric antibiotics were started. A computed tomography (CT) angiogram of the chest was negative for pulmonary embolism or pneumonia, but confirmed a diffusely enlarged thyroid gland, which prompted thyroid function testing. TSH was decreased at 0.16 μIU/ml (normal 0.3–4.7); free tri-iodothyronine (T3) was markedly elevated at 1031 pg/dl (normal 249–405), as was free thyroxine (T4) at 5.6 ng/dl (normal 0.8–1.6). With iopanoic acid and methimazole therapy, she markedly improved within 48 h, which could be attributed to lowering of serum T3 with iopanoic acid rather than to any effect of the methimazole. Ipilimumab is a cause of overt thyrotoxicosis and its immune-mediated adverse effects can be treated with iopanoic acid, a potent inhibitor of T4-to-T3 conversion.Learning points While ipilimumab more commonly causes autoimmune thyroiditis, it can also cause thyroid storm and clinicians should include thyroid storm in their differential diagnosis for patients who present with systemic inflammatory response syndrome.Immune-related adverse reactions usually occur after 1–3 months of ipilimumab and baseline thyroid function testing should be completed before initiation with ipilimumab.Conflicting data exist on the use of prednisone for treatment of CTLA4 adverse effects and its attenuation of ipilimumab's antitumor effect. Iopanoic acid may be considered as an alternative therapy in this setting.

Evaluation of the effect of systemic corticosteroids for the treatment of immune-related adverse events (irAEs) on the development or maintenance of ipilimumab clinical activity

9037 Background: Ipilimumab, a fully human monoclonal antibody that inhibits cytotoxic T-lymphocyte antigen-4, has clinical activity at 10 mg/kg in patients (pts) with advanced melanoma. Most grade 3/4 immune-related adverse events (irAEs) associated with ipilimumab can be managed with systemic corticosteroids following established treatment guidelines. However, little has been reported about the effects of corticosteroids used to treat irAEs on ipilimumab antitumor responses. Methods: Across 3 phase II studies with 10 mg/kg ipilimumab monotherapy in advanced melanoma (CA184008, 022, and 007; N=283), 83 pts (29.3%) achieved disease control [complete/partial responses (CR/PR), or stable disease (SD) ≥12 weeks] and 43/83 (52%) received steroids for treatment of irAEs. The pts' ability to develop and maintain disease control in the presence and absence of steroids was analyzed. Disease control was assessed by modified World Health Organization (mWHO) criteria and novel immune-related response criteria (irRC) (Hodi FS, et al. J Clin Oncol 26: 2008 [May 20 suppl; abstr 3008]). The range of follow-up was 5.7–6.3 months. Results: Of 117 pts who received steroids prior to response assessment, 26 pts achieved CR or PR, or maintained SD without disease progression by mWHO, and the remaining 91 pts had PD. Of 166 pts who either never received steroids or received them after response assessment, 31 achieved a CR, PR, or SD (by mWHO). Further, of 26 pts with CR/PR by mWHO, 14 received subsequent steroids and 11 maintained a response, while of 12 pts who received no subsequent steroids, 9 maintained a response. Similar results were obtained if irRC were used (see table ). Conclusions: Systemic corticosteroids for treatment of irAEs do not appear to impact the development or maintenance of ipilimumab clinical activity in advanced melanoma. [Table: see text] [Table: see text]