Occurrence Of Immune-related Adverse Events Research Articles

Toxicities of immune checkpoint inhibitors and their management

Immunotherapeutic strategies, notably immune checkpoint inhibitors, have become a standard of care for the treatment of advanced cancers, with a growing spectrum of activity. These monoclonal antibodies target the co-inhibitory signals between tumor cells or antigen-presenting cells and T cells, thereby enhancing antitumour T cell activity. However, the occurrence of immune-related adverse events, that can affect all organ-system, represents a major limiting factor to the clinical development of these antibodies. Management of such toxicity requires a close collaboration between oncologists and organ-specialists, by using glucocorticoids and/or other immunosuppressive therapies, with the common objective not alter anti-tumor response.

Decline of programmed death-1-positive circulating T regulatory cells predicts more favourable clinical outcome of patients with melanoma under immune checkpoint blockade.

The role of T regulatory lymphocytes (Tregs) and their immunosuppressive mechanisms in the context of programmed death (PD)-1 blockade is not completely understood. To assess the impact of PD-1-blocking antibody treatment on Treg subpopulations in the blood. We studied circulating Treg subpopulations in patients with melanoma under nivolumab or pembrolizumab treatment using flow cytometry and correlated these findings with clinical outcomes. These analyses revealed that the frequency of CD4+ CD25++ CD127- PD-1+ lymphocytes (PD-1+ Tregs) significantly decreased after the first cycle of immunotherapy (23% vs. 8·6%, P = 0·043). Compared with patients who did not show a significant decline of PD-1+ Tregs after the first treatment, those who did had better clinical outcomes with respect to progression-free survival (PFS, P = 0·022) and melanoma-specific death (MSD, P = 0·0038). Multivariate analysis confirmed that a significant decline of PD-1+ Tregs in peripheral blood after the first treatment cycle is a significant predictor of more favourable PFS and MSD (P = 0·04 and 0·017, respectively). Interestingly, the occurrence of immune-related adverse events was also an independent predictor for decreased risk of MSD (P = 0·047; odds ratio 0·064, 95% confidence interval 0·0042-0·97). We provide preliminary evidence that circulating PD-1+ Tregs rapidly decline after the initiation of treatment with PD-1-blocking antibodies, which is associated with reduced risk of melanoma progression and MSD. Patients showing no decrease of these PD-1+ Tregs in peripheral blood are characterized by an impaired response to immune checkpoint blockade and worse outcome. What's already known about this topic? Programmed death (PD)-1-blocking antibodies are highly effective in melanoma treatment. However, more than half of patients do not benefit from this therapy and to date it is difficult to predict which patients will respond to it. What does this study add? PD-1-blocking antibody therapy rapidly results in a decline of circulating PD-1+ T regulatory cells (Tregs). What is the translational message? Patients showing a decrease of PD-1+ Tregs appear to have better clinical outcome under PD-1 treatment.

P1.01-74 A Retrospective Study Evaluating Clinical Predictors of Duration of Response to Immune Checkpoint Inhibitors in Advanced NSCLC

Immune Checkpoint Inhibitors (ICI) with/without chemotherapy have become the standard of care for the treatment of advanced/metastatic non-small cell lung cancer (NSCLC). Similar to the response rate, durability of response to ICI is quite variable. While PDL1 expression and Tumor Mutational Burden (TMB) have been described to predict response to ICI, little is known about the clinical predictors of duration of response (DoR). A retrospective chart review of patients (pts) with advanced NSCLC treated with ICI based therapy at Karmanos Cancer Institute was conducted. Data were collected on demographics, clinical characteristics, and tumor characteristics. Univariable and multivariable cox regression analyses were performed for six pre-chosen covariates (histology, prior radiation therapy, brain metastasis, occurrence of immune-related adverse events (irAEs), statin use and smoking status) to see the associations with the DoR to ICI. One hundred thirty-one pts were included in the analysis (68% adenocarcinoma, 60% received prior radiation, 20% had brain metastasis, 26% developed irAEs, 33% were on a statin, 69% former smokers, 12% current smokers and 19% never smokers). Overall median DoR was 149 days (range, 14-1934). On multivariable analysis, longer DoR to ICI was observed in pts with non-adenocarcinoma histology (HR: 0.65; p = 0.050; CI: 0.42-1.00, median DoR 242.5 days) and current smokers (HR: 0.53; p = 0.031; CI: 0.30-0.95, median DoR 206.5 days). Other variables, including the presence of brain metastasis, prior radiation therapy, occurrence of irAEs and statin use had no significant relationship with the DoR. Tumor histology and smoking status were statistically and clinically significant predictors of durability of response to ICI in advanced NSCLC, presumably secondary to higher TMB. Presence of brain metastasis did not adversely impact DoR to ICI.

Safety of Immune Checkpoint Blockade in Patients with Cancer and Preexisting Autoimmune Diseases and/or Chronic Inflammatory Disorders

Abstract Background: Checkpoint blockade therapy, in the form of immune checkpoint inhibitors (ICIs), is increasingly being used to prolong survival in cancer patients, but its use is limited by the occurrence of immune-related adverse events (irAEs). These can be serious and occasionally fatal. However, the safety of ICIs is currently unknown in cancer patients with preexisting autoimmune diseases (PADs) and/or chronic inflammatory disorders (CIDs) such as eczema. Aim: The aim of this study is to evaluate the safety of ICIs in cancer patients with PAD and/or eczema at our institution. Patients and Methods: A retrospective study of cancer patients who presented to the Emergency Department between March 1, 2011, and February 29, 2016, after ICI therapy was previously conducted. Among these patients, those with PAD and/or eczema were further evaluated for safety by determining the occurrences of de novo irAEs or preexisting disease exacerbation. Results: Twenty-two cancer patients with PAD and/or eczema who received ICIs were reviewed, in which 15 were male (68%). Their median age was 63 years (range: 40–78 years). Most patients received anti-PD-1drugs (68%). Melanoma was the most common malignancy (45%). Autoimmune thyroiditis/primary hypothyroidism was the most common PAD. Four patients were receiving treatment for PAD at baseline using systemic corticosteroids, anti-inflammatory agents, and other immunosuppressants. Nineteen patients experienced de novo irAEs and/or PAD exacerbation. In three patients, the irAE was severe (grade ≥3). In six patients, the irAE or exacerbation was managed with systemic corticosteroids. Twelve patients experienced resolution of the de novo irAE or PAD exacerbation without the need to withhold or discontinue ICI therapy. The median time to last follow-up or death from the first dose of ICI was 16.8 months (range: 2–80 months). Death due to cancer progression was reported in 17 patients. Conclusion: Although de novo irAEs and PAD exacerbation were common, most patients with PAD and/or CIDs tolerated ICI therapy well.

Novel Delivery Systems for Checkpoint Inhibitors.

Checkpoint inhibition (CPI) therapies have been proven to be powerful clinical tools in treating cancers. FDA approvals and ongoing clinical development of checkpoint inhibitors for treatment of various cancers highlight the immense potential of checkpoint inhibitors as anti-cancer therapeutics. The occurrence of immune-related adverse events, however, is a major hindrance to the efficacy and use of checkpoint inhibitors as systemic therapies in a wide range of patients. Hence, methods of sustained and tumor-targeted delivery of checkpoint inhibitors are likely to improve efficacy while also decreasing toxic side effects. In this review, we summarize the findings of the studies that evaluated methods of tumor-targeted delivery of checkpoint inhibitors, review their strengths and weaknesses, and discuss the outlook for therapeutic use of these delivery methods.

Abstract 4992: The occurrence of immune-related adverse events indicates better efficacy of immune checkpoint blockade in solid tumors: A systematic review and meta-analysis

Abstract Introduction: Immune-related adverse events (irAEs) were mostly induced by immune checkpoint blockade (ICB) and were associated with the immune response. Whether irAEs are associated with clinical benefits during ICB treatment in cancer patients remains unclear. This systematic review and meta-analysis aimed to investigate the relationship between irAEs and clinical efficacy. Methods: We systemically searched and selected irAEs and clinical outcome data from cancer patients treated with ICB in the PubMed, Embase, and Cochrane Central Trial databases up to July 26, 2018. Keywords used for the search included PD-1, PD-L1, CTLA-4, immune checkpoint and immune-related adverse events. The relationships between the occurrence of irAEs and the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were assessed using relative risk (RR) or hazard ratio (HR) values and 95% confidence intervals (CIs) in random-effect models. Results: Nineteen eligible observational articles were included in this systematic review and fourteen studies including 3022 participants (1264 with irAEs and 1758 with non-irAE) were included in our meta-analysis. The occurrence of irAEs was significantly associated with higher ORR (RR = 2.36, 95% CI: 1.85-3.02; P < 0.001), better PFS (HR = 0.48, 95% CI: 0.26-0.70; P < 0.001), and longer OS (HR = 0.42; 95% CI = 0.18-0.67; P = 0.001) than those in the non-irAE group. Subgroup analysis showed that the effect size of ORR in anti-PD-1 therapy (RR = 2.68, 95% CI, 2.21-3.26) was inferior to that of the anti-CTLA-4 therapy (RR = 1.91, 95% CI, 0.44-8.32). The meta-regression models also found that ICB type (anti-CTLA-4 or anti-PD-1) were associated with significant heterogeneity (P = 0.005). Conclusion: In conclusion, irAEs indicate greater ORR, PFS and OS than non-irAEs in ICB treatment, and the relationship in anti-PD-1 therapy was stronger than in anti-CTLA-4 therapy. With appropriate management of irAEs, the clinical predictor, continued treatment may be possible to maximize its potential ICB benefits. Note: This abstract was not presented at the meeting. Citation Format: Xu Yang, Dongxu Wang, Jianzhen Lin, Jianping Xiong, Junyu Long, Yi Bai, Jin Bian, Hanchun Huang, Xiaobo Yang, Yilei Mao, Xinting Sang, Haitao Zhao. The occurrence of immune-related adverse events indicates better efficacy of immune checkpoint blockade in solid tumors: A systematic review and meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4992.

A retrospective study evaluating clinical predictors of duration of response to immune checkpoint inhibitors in patients with advanced non-small cell lung cancer.

e20665 Background: Immune Checkpoint Inhibitors (ICI) with/without chemotherapy has become the standard of care for the treatment of advanced/metastatic non-small cell lung cancer (NSCLC). Similar to the response rate, durability of response to ICI is quite variable. While programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB) have been described to predict response to ICI, little is known about the clinical predictors of duration of response (DoR). Methods: A retrospective chart review of patients (pts) with advanced NSCLC treated with ICI based therapy at Karmanos Cancer Institute was conducted. Data were collected on demographics, clinical characteristics, and tumor characteristics. Univariable and multivariable cox regression analyses were performed for six pre-chosen covariates (histology, prior radiation therapy, brain metastasis, occurrence of immune-related adverse events (irAEs), statin use and smoking status) to see the associations with the DoR to ICI. Results: One hundred thirty-one pts were included in the analysis (68% adenocarcinoma, 60% received prior radiation, 20% had brain metastasis, 26% developed irAEs, 33% were on a statin, 69% former smokers, 12% current smokers and 19% never smokers). Overall median DoR was 149 days (range, 14-1934 days). On multivariable analysis, longer DoR to ICI was observed in pts with non-adenocarcinoma histology (HR: 0.65; p = 0.050; CI: 0.42-1.00, median DoR 242.5 days) and current smokers (HR: 0.53; p = 0.031; CI: 0.30-0.95, median DoR 206.5 days). Other variables, including the presence of brain metastasis, prior radiation therapy, occurrence of irAEs and statin use had no significant relationship with the DoR. Conclusions: Tumor histology and smoking status were statistically and clinically significant predictors of durability of response to ICI in advanced NSCLC, presumably secondary to higher tumor mutational burden. Presence of brain metastasis did not adversely impact DoR to ICI.

Biomarkers, measured during therapy, for response of melanoma patients to immune checkpoint inhibitors: a systematic review.

Immune checkpoint inhibitors (ICIs), which target CTLA-4 or PD-(L)1 molecules, have shown impressive therapeutic results. Durable responses, however, are only observed in a segment of the patient population and must be offset against severe off-target immune toxicity and high costs. This calls for biomarkers that predict response during ICI treatment. Although many candidate biomarkers exist, as yet, there has been no systematic overview of biomarkers predictive during. Here, we provide a systematic review of the current literature of ICI treatment to establish an overview of candidate predictive biomarkers during ICI treatment in melanoma patients. We performed a systematic Medline search (2000-2018, 1 January) on biomarkers for survival or response to ICI treatment in melanoma patients. We retrieved 735 publications, of which 79 were finally included in this systematic review. Blood markers were largely studied for CTLA-4 ICI, whereas tumor tissue markers were analyzed for PD-(L)1 ICI. Blood cytology and soluble factors were more frequently correlated to overall survival (OS) than response, indicating their prognostic rather than predictive nature. An increase in tumor-infiltrating CD8 + T-cells and a decrease in regulatory T-cells were correlated to response, in addition to mutational load, neoantigen load, and immune-related gene expression. Immune-related adverse events were also associated frequently with a favorable response and OS. This review shows the great variety of potential biomarkers published to date, in an attempt to better understand response to ICI therapy; it also highlights the candidate markers for future research. The most promising biomarkers for response to ICI treatment are the occurrence of immune-related adverse events (especially vitiligo), lowering of lactate dehydrogenase, and increase in activated CD8 + and decrease in regulatory T-cells.

Prevalence of immune-related systemic adverse events in patients treated with anti-Programmed cell Death 1/anti-Programmed cell Death-Ligand 1 agents: A single-centre pharmacovigilance database analysis

AimThe growing use of immune checkpoint inhibitors (ICIs) is associated with the occurrence of immune-related adverse events (irAEs). Few data are published on systemic, immunohaematological and rheumatic irAEs. In a pharmacovigilance database analysis, we screened for these irAEs and calculated their prevalence. Patients and methodsParticipants were recruited via Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC)11Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie, managed by the Gustave Roussy cancer centre (Villejuif, France). a French registry of grade ≥2 irAEs occurring in ICI-treated patients. The pathologies of interest were systemic autoimmune and inflammatory diseases, rheumatic diseases and immune cytopenia. ResultsOut of 908 patients treated with anti-Programmed cell Death 1 (PD1)/anti-Programmed cell Death-Ligand 1 (PD-L1) agents (together with an anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) agent in 40 cases) between December 2012 and December 2016 at a single centre, 21 patients experienced systemic irAEs. The types and the prevalence of irAEs were as follows: immune thrombocytopenia (0.2%), Sjögren syndrome (0.3%), rheumatoid arthritis (0.2%), polymyalgia rheumatica (0.2%), psoriatic arthritis (0.2%), seronegative polyarthritis (0.7%) and sarcoidosis (0.2%). Patients with Sjögren syndrome or seronegative polyarthritis were more likely to have received combination therapy with ipilimumab (2.5% for both).We described these 21 cases, together with nine additional cases from five other centres. Most irAE were moderately severe (grade 2, 63%). The median time to onset was 57°days (interquartile range (IQR) 24–117). The ICI was withdrawn in 12 cases, 25 patients (83%) received corticosteroids, and five patients (17%) received immunosuppressant/immunomodulatory agents. The irAEs resolved fully or partially in 28 cases (93%). ConclusionAlthough systemic, immunohaematological and rheumatic diseases are rarely associated with ICI use, the prevalence is higher when two ICIs are combined. Corticosteroids are often effective and may enable the continued administration of ICIs. Studies designed to identify at-risk patients are warranted.

Predictive biomarkers and effectiveness of MUC1-targeted dendritic-cell-based vaccine in patients with refractory non-small cell lung cancer.

The dendritic cell (DC)-based vaccine targeting the highly immunogenic tumor antigen, MUC1, has been promising for a cancer immunotherapy; however, predictive biomarkers for beneficial clinical responses of the vaccine remain to be determined. DCs loaded with MUC1-derived peptide were subcutaneously administered to patients with MUC1-positive non-small cell lung cancer (NSCLC) that was refractory to standard anticancer therapies, every 2 weeks. The effectiveness and tolerability of the vaccine were evaluated, and predictive biomarkers of clinical responses were explored. Between August 2005 and May 2015, 40 patients received the vaccines. The median survival time (MST) after the initial vaccination was 7.4 months, and the 1-year survival rate was 25.0%. The MST for patients who received more than six vaccinations was 9.5 months, and the 1-year survival rate was 39.3%. In this cohort, patients who experienced immune-related adverse events, including skin reactions at the vaccination site and fever, had significantly longer survival times compared with patients without those immune-related adverse events (12.6 versus 6.7 months, p = 0.042). Longer survival times were also observed in patients whose peripheral white blood cells contained >20.0% lymphocytes (12.6 versus 4.5 months; p = 0.014). MUC1-specific cytotoxic immune responses were achieved in all of seven patients analyzed who received six vaccinations. The MUC1-targeted DC-based vaccine induced an antitumor immune response that promoted prolonged survival of patients with refractory NSCLC. The occurrence of immune-related adverse events and having a higher percentage of peripheral lymphocytes were predictive biomarkers of a beneficial clinical response during cancer immunotherapy for NSCLC.