Treatment Of irAEs Research Articles

Managing Select Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitors.

The increased use of immune checkpoint inhibitors (ICIs) across cancer programs has created the need for standardized monitoring and management of immune-related adverse events (irAEs). Delayed recognition without appropriate treatment can have serious and life-threatening consequences. The management of irAEs presents a unique set of challenges that must be addressed at a multidisciplinary level. Although various national and international guidelines and working groups provide high-level recommendations for the management of irAEs, practical guidance is lacking. Furthermore, timely collaboration between specialists requires institutional protocols that enable the early recognition, assessment, and treatment of irAEs. Such protocols should be developed by institution specialists and include algorithms for all healthcare providers involved in the care of patients treated with ICIs. At William Osler Health System in Brampton, Ontario, practical step-by-step multidisciplinary treatment approaches with recommendations for the management of irAEs were developed in collaboration with experts across Canada. Here, we provide an in-depth description of the approaches, outlining baseline investigations prior to the initiation of ICIs, as well as the monitoring and management of irAEs based on symptoms, severity, and involved organ systems. We encourage other centres to adapt and modify our approaches according to their specific needs and requirements.

Diagnostic and prognostic biomarkers in immune checkpoint inhibitor-related encephalitis: a retrospective cohort study

Immune checkpoint inhibitor-related encephalitis (ICI-encephalitis) is not well characterised and diagnostic and prognostic biomarkers are lacking. We aimed to comprehensively characterise ICI-encephalitis and identify diagnostic biomarkers and outcome predictors. This retrospective observational study included all patients with ICI-encephalitis studied in the French Reference Centre on Paraneoplastic Neurological Syndromes (PNS) and Autoimmune Encephalitis (2015-2023). ICI encephalitis was considered definite in case of inflammatory findings at paraclinical tests and/or well-characterised neural antibodies. Predictors of immune-related adverse event (irAE) treatment response, defined as a Common Terminology Criteria for Adverse Events v5.0 grade<3at any time after therapeutic intervention, were assessed by logistic regression analysis, and predictors of mortality by Cox regression analysis. Neurofilament light chain (NfL) was measured by enzyme-linked immunosorbent assay. Sixty-seven patients with definite encephalitis were identified (median age, 69 years; 66% male). A focal syndrome was observed in 43/67 patients (64%; limbic encephalitis, cerebellar ataxia, and/or brainstem encephalitis), while 24/67 (36%) had meningoencephalitis, a non-focal syndrome with altered mental status (22/24 patients, 92%) and pleocytosis (24/24 patients, 100%). Patients with focal encephalitis more frequently had abnormal brain MRI (26/42, 62% versus 8/24, 33%, p=0.025), PNS-related antibodies (36/43, 84% versus 1/24, 4%, p<0.001), and neuroendocrine cancers (22/43, 51% versus 1/24, 4%; p<0.001) than patients with meningoencephalitis. Focal encephalitis patients had a lower rate of irAE treatment response (7/39, 18%) and higher mortality (27/43, 63%) compared to meningoencephalitis patients (12/22, 77% and 5/24, 21%, respectively, p<0.001 each). PNS-related antibodies were associated with less irAE treatment response, independently of age, sex, and baseline severity (adjusted OR 0.05; 95%CI [0.01; 0.19]; p<0.001) as well as higher mortality, independently of age and cancer type (adjusted HR 5.07; 95% CI [2.12; 12.12]; p<0.001). Serum NfL discriminated patients with definite ICI-encephalitis (n=27) from cancer-matched controls (n=16; optimal cut-off >273.5pg/mL, sensitivity 81%, specificity 88%, AUC 0.87, 95% CI [0.76; 0.98]) and irAE treatment responders (n=10) from non-responders (n=17, optimal cut-off >645pg/mL, sensitivity 90%, specificity 65%; AUC 0.75, 95% CI [0.55; 0.94]). ICI-encephalitis corresponds to a set of clinically-recognisable syndromes. Patients with focal encephalitis, PNS-related antibodies, and/or higher serum NfL have low irAE treatment response rates. Research is needed on the underlying immunopathogenesis to foster therapeutic innovations. Agence Nationale de la Recherche.

Infliximab for Immune Checkpoint Inhibitor Therapy-Related Toxicities

What Is the Issue? Immune checkpoint inhibitor (ICI) therapy has become a treatment option for various types of advanced cancer, resulting in significant improvement in disease outcomes. However, ICIs can overstimulate the immune system leading to various side effects known as immune-related adverse events (irAEs) that can occur in any organ system. Administration of corticosteroids is the initial mainstay treatment of irAEs. However, there is little evidence of how to treat steroid-resistant irAEs. Treatment of steroid-resistant irAEs includes holding ICI and starting immunosuppressive therapy. Decision-makers are interested in understanding the use of infliximab, a selective immunosuppressive drug, for the treatment of steroid-resistant irAEs affecting various organs. What Did We Do? We identified and summarized the literature regarding the efficacy and safety of infliximab for the treatment of steroid-resistant irAEs. Due to the limitation of evidence, we included studies of any design, including case reports and case series. A research information specialist conducted a literature search of peer-reviewed and grey literature sources published between January 1, 2019 and April 8, 2024. One reviewer screened citations for inclusion based on predefined criteria, critically appraised the included studies, and narratively summarized the findings. What Did We Find? The evidence presented in this report was based on 2 systematic reviews of case reports and case series, 1 retrospective cohort study, and 40 additional publications consisting of 29 case reports and 11 case series. We identified 4 main irAEs, which were colitis, hepatitis, pneumonitis, and myocarditis. Very low-quality evidence, which was mainly derived from case reports and case series, suggests that infliximab may be effective for the treatment of steroid-resistant immune-induced colitis, while there are concerns regarding its use for the treatment of hepatitis due to potential hepatotoxicity and infectious complications. There is mixed evidence regarding the use of infliximab for the treatment of immune-induced pneumonitis and myocarditis. Recent consensus guidelines recommend the use of infliximab as first-line treatment for steroid-resistant immune-induced colitis, while its use for hepatitis is not recommended due to potential hepatotoxicity and infectious complications. The use of infliximab for the treatment of pneumonitis is an option, while its use for myocarditis remains to be determined. The usual dose of infliximab was 5 mg/kg, administered by IV. A higher dose of 10 mg/kg was seen in some cases. The number of infusions, the period between infusions and the length of treatment varied depending on the responsiveness of infliximab and the type and severity of irAEs. Treatment with infliximab as compared with vedolizumab resulted in comparable immune-induced colitis response rates, higher recurrent rate of colitis, and more hospitalizations despite a shorter time to clinical response. What Does This Mean? The very low-quality evidence identified suggests the potential benefits of infliximab in the management of immune-induced colitis due to its efficacy and fast response. When using the clinical evidence and recommendations summarized in this report to inform decisions, decision-makers should consider that the evidence is of very low quality, mainly derived from case reports and case series. Large prospective and comparative studies are needed to verify the findings and to determine the role of infliximab in the treatment of other irAEs.

Stringent monitoring can decrease mortality of immune checkpoint inhibitor induced cardiotoxicity.

Immune checkpoint inhibitor (ICI)-induced myocarditis is a rare immune-related adverse event (irAE) with a fatality rate of 40%-46%. However, irMyocarditis can be asymptomatic. Thus, improved monitoring, detection and therapy are needed. This study aims to generate knowledge on pathogenesis and assess outcomes in cancer centers with intensified patient management. Patients with cardiac irAEs from the SERIO registry (www.serio-registry.org) were analyzed for demographics, ICI-related information (type of ICI, therapy line, combination with other drugs, onset of irAE, and tumor response), examination results, irAE treatment and outcome, as well as oncological endpoints. Cardiac biopsies of irMyocarditis cases (n = 12) were analyzed by Nanostring and compared to healthy heart muscle (n = 5) and longitudinal blood sampling was performed for immunophenotyping of irMyocarditis-patients (n = 4 baseline and n = 8 during irAE) in comparison to patients without toxicity under ICI-therapy (n = 4 baseline and n = 7 during ICI-therapy) using flow cytometry. A total of 51 patients with 53 cardiac irAEs induced by 4 different ICIs (anti-PD1, anti-PD-L1, anti-CTLA4) were included from 12 centers in 3 countries. Altogether, 83.0% of cardiac irAEs were graded as severe or life-threatening, and 11.3% were fatal (6/53). Thus, in centers with established consequent troponin monitoring, work-up upon the rise in troponin and consequent treatment of irMyocarditis with corticosteroids and -if required-second-line therapy mortality rate is much lower than previously reported. The median time to irMyocarditis was 36 days (range 4-1,074 days) after ICI initiation, whereas other cardiotoxicities, e.g. asystolia or myocardiopathy, occurred much later. The cytokine-mediated signaling pathway was differentially regulated in myocardial biopsies as compared to healthy heart based on enrichment Gene Ontology analysis. Additionally, longitudinal peripheral blood mononuclear cell (PBMC) samples from irMyocarditis-patients indicated ICI-driven enhanced CD4+ Treg cells and reduced CD4+ T cells. Immunophenotypes, particularly effector memory T cells of irMyocarditis-patients differed from those of ICI-treated patients without side effects. LAG3 expression on T cells and PD-L1 expression on dendritic cells could serve as predictive indicators for the development of irMyocarditis. Interestingly, our cohort shows a very low mortality rate of irMyocarditis-patients. Our data indicate so far unknown local and systemic immunological patterns in cardiotoxicity.

Integrated analysis of single-cell data on role of NKG7high CD8+ Teff cells in driving immune-related adverse events.

e24114 Background: Immune-related adverse events (irAEs) frequently occur during immunotherapy and can impact various organ systems, which dampen the clinical outcomes of immune checkpoint inhibitors (ICIs). However, the precise immune hallmarks associated with irAEs remain further explored. Methods: We collected public (Bukhari et al., Zhu et al., Su et al., and Ma et al.) and our own scRNA-seq data across patients with different irAE types or without irAEs. By comparing T cell compositions between irAE and no-irAE patients, the subcluster correlated with the occurrence of irAE was identified. Subsequently, the integrated analyses were performed to explore its mechanisms in driving irAEs in both peripheral blood and local tissues. Results: Compared to no-irAE patients, a subcluster of effector T (Teff) cells was observed to increase notably in the peripheral blood of irAE patients during immunotherapy. This specific subcluster, named "NKG7high CD8+ Teff cells," was characterized by the significant expression of effector genes such as GZMH, CCL5, and especially NKG7. In contrast to other CD8+ T cells, the NKG7high CD8+ Teff cells exhibited stronger cytotoxicity functions, increased exosome secretion, and enhanced MIF-CD74 interaction with monocytes, which suggests the mechanistic link between its increased infiltration and the development of irAEs. Further investigation showed these characteristics were more remarkable in NKG7high CD8+ Teff from irAE patients than no-irAE patients. Subsequently, the increase of NKG7high CD8+ Teff during immunotherapy was validated in our own scRNA from immune thyroiditis patients, which was not observed in no-irAE patients. Across various irAE types, NKG7high CD8+ Teff subsets, along with their NKG7 expression, demonstrated heightened infiltration and expression in immune-related arthritis and myocarditis samples. After investigating the role of NKG7high CD8+ Teff in peripheral blood, we focused on its distribution and roles in local irAE tissue. NKG7high CD8+ Teff cells accumulated in immune-related thyroiditis tissues, and recruited macrophages through the IFNG and CSF1 signaling pathways, thereby inducing an immune overreaction. Meanwhile, in immune-related myocarditis mice heart tissues, NKG7high CD8+ Teff cells could interact with macrophages via the SPP1 signaling pathway and cause endothelial cell damage through the FASL-FAS pathway. Conclusions: This comprehensive study revealed the intricate mechanisms of NKG7high CD8+ Teff in inducing irAEs, providing valuable insights into their roles and potential implications in irAE treatment.

Immune-related adverse events in patients treated with immunotherapy according to corticosteroid exposure.

e14709 Background: Patients with cancer require treatment with corticosteroids for multiple reasons, including prevention of chemotherapy-related side effects. Although corticosteroid use has been associated with lower efficacy of immune checkpoint inhibitors (ICI) in some studies, whether corticosteroid exposure affects the presence and severity of immune-related adverse events (irAEs) remains unclear. Methods: Retrospective single-center study of patients diagnosed with solid tumors treated with ICI. Eligible patients were those who received at least one cycle of ICI and had at least 1 month of follow-up post-ICI initiation. Patient data were extracted from electronic medical records. Comparisons between groups were made based on steroid exposure (defined as the administration of &gt;10 mg of prednisone or its equivalent for &gt;10 days within a 30-day period or at any point during ICI treatment, excluding steroid treatment for irAEs). Associations between variables were assessed using independent samples T-test, Chi-square, and Fisher’s exact tests. Results: We included 135 patients (mean age 61 years, SD 13); 72 (54%) were male. Forty-two (31%) had been exposed to steroids (mean prednisone equivalent of 427 mg, SD 298). Most patients received ICI as palliative treatment for advanced disease (105/135; 78%), primarily as first-line therapy (79/105; 75%). Patients exposed to corticosteroids were more likely to have received ICI with chemotherapy (76% vs 1%, p&lt;0.001), were younger (56 vs. 63 years, p=0.009), more likely to be female (62% vs. 39, p=0.014), and had lower median Charlson Comorbidity Index scores (2 vs. 3, p=0.026). Steroid-exposed patients were more likely to have employed ICI in the neoadjuvant or adjuvant settings (36 vs. 16%, p=0.024) or as third or subsequent line therapy (26 vs. 8%, p=0.044). There were no statistically significant differences in the frequency of irAEs of any grade based on steroid exposure (31% vs 41%, p=0.252). However, patients who were exposed to steroids were significantly less likely to delay or suspend ICI (10% vs. 32%, p=0.005). No other parameters were associated with the rate or severity of irAEs. Conclusions: Our findings suggest that corticosteroid exposure does not increase the frequency of irAEs in patients treated with ICI, but it is associated with a reduced likelihood of discontinuing ICI due to irAEs. These observations suggest that corticosteroids may play a beneficial role in managing patients undergoing immunotherapy, particularly in sustaining treatment continuity despite irAEs. This study underscores the need for further investigation into optimal steroid use strategies to enhance patient outcomes with immunotherapy, especially in situations when they are commonly prescribed, such as premedication for chemotherapy.

Studying Outcomes after Steroid-Sparing Immunosuppressive Agent vs. Steroid-Only Treatment for Immune-Related Adverse Events in Non-Small-Cell Lung Cancer (NSCLC) and Melanoma: A Retrospective Case-Control Study.

The effects of steroid-sparing immunosuppressive agents (SSIAs), used for the treatment of immune-related adverse events (irAEs), on immune checkpoint inhibitor (ICI) antitumor activity is not well known. We compared tumor outcomes of patients who received corticosteroid monotherapy (CS) versus a corticosteroid plus SSIA (CS-SSIA) for irAE treatment, using statistical methods to address immortal time bias. We conducted a retrospective case-control study on patients ≥ 18 years with melanoma or non-small-cell lung cancer (NSCLC) treated with ≥1 ICI at a quaternary care center between 1 January 2016 and 11 January 2021. Patients were divided into two cohorts: CS or CS-SSIA. We used propensity score nearest-neighbor matching to match on tumor type, stage, and prior lines of therapy. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included the time from the start of the irAE treatment to the irAE resolution. Hazard ratios (HRs) for PFS and OS were calculated using the Cox proportional hazard regression method with both (1) the time to the steroid and SSIA as time-varying covariates and (2) a binary exposure classification not accounting for the time to the treatment. A total of 167 patients were included after matching (132 in the CS cohort and 35 in the CS-SSIA cohort). Sixty-six percent of all the patients had melanoma. The most common irAEs requiring treatment were gastroenterocolitis and hepatitis. In an adjusted analysis not accounting for immortal time bias, there were no significant differences in PFS (HR 0.75, 95% CI [0.46-1.23]) or OS (HR 0.82, 95% CI [0.46-1.47]). In analyses using a time-varying treatment indicator, there was a trend toward improved PFS in patients treated with SSIAs (HR 0.54, CI 0.26-1.10). There was no difference in OS (HR 1.11, CI 0.55-2.23). Patients with melanoma who specifically received infliximab had improved PFS compared to patients with CS only, after adjusting for immortal time bias (HR 0.32, CI 0.24-0.43). The use of SSIAs with CS did not have worse outcomes than CS monotherapy. In melanoma, our findings showed improved PFS for the use of infliximab versus steroid monotherapy for irAEs. Large, prospective, randomized controlled trials are needed to confirm these findings and guide the optimal treatment of irAEs.

Distinct autoantibody profiles across checkpoint inhibitor types and toxicities

ABSTRACT Immune checkpoint inhibitors (ICI) are increasingly used in combination. To understand the effects of different ICI categories, we characterized changes in circulating autoantibodies in patients enrolled in the E4412 trial (NCT01896999) of brentuximab vedotin (BV) plus ipilimumab, BV plus nivolumab, or BV plus ipilimumab-nivolumab for Hodgkin Lymphoma. Cycle 2 Day 1 (C2D1) autoantibody levels were compared to pre-treatment baseline. Across 112 autoantibodies tested, we generally observed increases in ipilimumab-containing regimens, with decreases noted in the nivolumab arm. Among 15 autoantibodies with significant changes at C2D1, all nivolumab cases exhibited decreases, with more than 90% of ipilimumab-exposed cases showing increases. Autoantibody profiles also showed differences according to immune-related adverse event (irAE) type, with rash generally featuring increases and liver toxicity demonstrating decreases. We conclude that dynamic autoantibody profiles may differ according to ICI category and irAE type. These findings may have relevance to clinical monitoring and irAE treatment.

A scoping review of vasculitis as an immune-related adverse event from checkpoint inhibitor therapy of cancer: Unraveling the complexities at the intersection of immunology and vascular pathology

Background/purposeVasculitis as an immune-related adverse event (irAE) from checkpoint inhibitor therapy (ICI) to treat cancer is a rare clinical event, and little is known regarding its nosology, clinical manifestations, or response to treatment and outcomes. MethodsTo address these gaps, we used the Preferred Reporting Items for Systemic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) framework to further define this complication. Two independent PUBMED searches in September and November of 2022 revealed 127 publications with 37 excluded from title by relevance, 43 excluded by article type, and 23 excluded due to lack of biopsy results, or biopsy negative for vasculitis. Twenty-nine documented cases from 24 publications were included for final analysis. Basic demographics, ICI details, timing of onset of vasculitis symptoms, irAE treatment and outcomes were collected. The vasculitides were classified using 2022 ACR/EULAR Vasculitis Classification Criteria as well as 2012 Revised Chapel-Hill Nomenclature. Adaptations from Naidoo et al. 2023 [1] consensus definitions for irAEs were used and efforts were made to classify steroid-responsive versus unresponsive irAEs. ResultsOf the 29 cases reviewed, the average age of patients was 62.1 ± 11.0, composed of 58.6 % (n = 17) male and 41.3 % (n = 12) female. Prominent cancer types were lung cancer (41.4 %; n = 12), melanoma (41.4 %; n = 12), and renal cancer (10.3 %; n = 3), with majority being stage 4 (75.9 %, n = 22) and stage 3 (10.3 %, n = 3). Only 8 cases met the ACR/EULAR criteria, and by Chapel-Hill Nomenclature, approximately a third were small-vessel vasculitis (31.0 %; n = 9) with n = 4 positive for ANCA. Most biopsies were taken from the skin (37.9 %, n = 11) and kidney (24.1 %, n = 7). Patients were either treated with single (65.5 %, n = 19), dual (17.2 %; n = 5), or sequential (17.2 %; n = 5) ICI regimen which included anti-PD-1 therapy in all but one case, with mean of 8.7 ± 10.5 cycles received. Mean time to onset of symptoms from start of ICI was 7.2 ± 7.8 months, with 55.2 % occurring >3 months since the initial immunotherapy. Vasculitis treatment included glucocorticoids in 96 % of cases and immunotherapy was often discontinued (44.8 %; n = 13). Clinical improvement of irAE was documented in 86.2 % (n = 25). Data were missing in terms of fate of ICI (34.5 %; n = 10) and tumor outcomes (41.4 %; n = 12). Cancer progressed in 20.7 % (n = 6), stable in 34.5 % (n = 10) cases, and 6 patients died of all-causes. ConclusionVasculitis as an irAE appears clinically heterogeneous and rare. Among reported cases with adequate documentation, vasculitis is of delayed onset following the initiation of immunotherapy. Outcomes of ICI-vasculitis were generally favorable, responding to glucocorticoids and immunotherapy withdrawal. There is an urgent need for more standardized reporting of rare irAEs such as vasculitis to clarify clinical risks, classification, relationship to immunotherapy and outcomes.

Incidence of immune-related adverse events in U.S. veterans treated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) are associated with potentially severe immune-related adverse events (irAEs). Emerging clinical practice reports have suggested higher incidence of irAEs in real-world settings than initially observed in phase III clinical trials. Objectives were to determine the incidence of irAEs associated with ICIs in a clinical population, the Veterans Health Administration, characterize their time to onset, and explore potential risk factors. This retrospective observational study included patients from eight Midwest VA medical centers who initiated an ICI between January 1, 2014, and June 30, 2022. Courses of incident prednisone therapy lasting at least seven days at a dose ≥ 20 mg/day were used to identify irAEs, within two years following ICI initiation. A multivariate Cox proportional hazards regression model was used to explore potential irAE risk factors. Of 1314 patients, the incidence of irAEs was 19.8%, with most (86.5%) occurring within one year of ICI initiation. Monthly incidence rates peaked three months following ICI initiation at 3.0% and decreased thereafter. Female gender (hazard ratio [HR] = 2.01, 95% confidence interval [CI]: 1.01-4.00) and combination therapy with ipilimumab and nivolumab (HR = 2.46, 95% CI: 1.44-4.21) were significantly associated with irAE incidence. These findings are consistent with recent studies in clinical populations that demonstrate higher irAE incidence rates than originally reported in clinical trials. Our findings may enhance prompt recognition and treatment of irAEs for VA patients.

High Dose Cyclophosphamide for the Treatment of Severe Immune Checkpoint Inhibitor Related Adverse Events.

Immune-related adverse events (irAEs) are a group of autoimmune syndromes that arise following therapy with immune checkpoint inhibitors (ICIs) and are characterized by disinhibition of cell-mediated immunity and decreased self-tolerance. First line treatment of irAEs is typically steroids. Severe irAEs that are refractory to steroids can be life threatening and treatment protocols are an area of unmet need. Standardized clinical guidelines for management of severe corticosteroid refractory irAEs are currently not available and thus are an area of unmet need. We present two patients who were treated with nivolumab and subsequently developed steroid refractory irAEs in the forms of transverse myelitis, arthritis, and peri-engraftment respiratory distress syndrome. Treatment with a single high dose of cyclophosphamide resulted in rapid and sustained clinical improvements in two patients experiencing steroid refractory irAEs following ICI therapy. Cyclophosphamide may benefit patients with wide spectrum of irAEs while having a favorable toxicity profile.

Automating the identification of patients admitted to tertiary care hospital with immunotherapy related adverse events (irAEs).

566 Background: Immune checkpoint inhibitors (ICIs) have revolutionized oncology by offering prolonged survival in advanced cancers that were previously treatment-refractory. However, the effectiveness of these agents is accompanied by the potential for autoimmune toxic effects known as immune-related adverse events (irAEs). These adverse effects are difficult to predict, can be long-lasting, and occasionally fatal. Early identification and treatment of irAEs can reduce morbidity and enable prompt resumption of anti-cancer therapy, ultimately improving patient outcomes. Methods: We manually reviewed 658 patient charts of individuals who received ICIs and were admitted to a tertiary care hospital over a three-month period. This process identified 750 phrases indicative of irAEs. Subsequently, an in-house Epic reporting team developed a program to search for these specific phrases within the charts of patients admitted to the hospital who had received ICIs in the 24 months prior to their admission. During the program's development, its performance was compared to the previous manual chart review process. Results: A comparative analysis was conducted between the new program and the current manual chart review over a three-month period. Implementing the new program resulted in a 68% reduction in the average number of charts requiring manual review (69 vs. 219 per month). Furthermore, the program identified an additional 17% of cases (21 vs. 18 per month). The positive predictive value increased by 400% (32% vs. 8% per month), and the time required to complete the task decreased by 70% (4.6 vs. 15 hours per month). Conclusions: Utilizing an EMR-based program that automatically searches for patients admitted with irAEs can significantly shorten the time required for identification and subsequent management of these complex patients.

Incidence and treatment of checkpoint inhibitor induced immune related adverse events in the emergency department.

438 Background: Immune checkpoint inhibitors (ICPis) are currently indicated for the treatment of various types of cancers. Through inhibition of the cancer cell’s checkpoint mediated T-cell evasion, ICPis allow for sustained T-cell activation and proliferation, resulting in increased cancer cell death. However, due to increased activation and proliferation of cytotoxic T-cells, ICPis have been associated with a wide spectrum of adverse effects, known as immune related adverse effects (irAEs). Although recently updated, the 2018 NCCN and ASCO guidelines state that treatment is based on the location and severity of irAEs. In general, grade 3 toxicities warrant suspension of ICPis and initiation of high-dose corticosteroids. Corticosteroids should then be tapered over the course of at least 4-6 weeks. The diagnosis of an irAE is challenging, toxicities may be misdiagnosed as there is a diverse familiarity with ICPis and their associated irAEs. Subsequently, care may be delayed, and patients may not receive appropriate guideline directed care. Methods: This multi-center chart review included 7 hospitals within a large health system. Our electronic health record was utilized to compile a report of patients who had received ICPIs within 12 months of presentation to an ED within the health system between 9/1/2019 and 9/1/2022. Assessed outcomes included incidence and type of irAE, time between last ICPi dose and presentation to the ED, steroid used for treatment, time to steroid, treatment driver, and the action that deviated from the 2018 ASCO/NCCN guideline directed treatment if applicable. Results: Of the 241 patients receiving an ICPi, 26 (10.8%) experienced an irAE that prompted a visit to an ED within our health system. Guideline directed treatment of irAE(s) was followed 76.9% of the time, with the steroid dose being too low (15.4%) and the steroid taper occurring too quickly (7.7%) being the two reasons for discordant treatment. Treatment started a median of 1.1 after presentation to an ED, with colitis as the most prevalent irAE in 11 patients (42%) presenting. For all patients, there was an average of 20 days between the last ICPi dose and presentation to ED. The main steroid used was methylprednisolone (42%). Conclusions: The 10.8% of patients who experienced an irAE that prompted a visit to an ED within our health system is a lower rate than what has been described in the literature previously, where rates of presentation to an ED due to an irAE ranged from 25-37%. This could be due to previous data coming from before or shortly after the publication of ASCO and NCCN guidelines in 2018, or because our outpatient medical staff has become more aware of irAEs and their appropriate treatment. Limitations include this review was retrospective, no patients had an irAE that was refractory to steroids, and the study period being soon after national guidelines were published.

Toxicity-specific peripheral blood T and B cell dynamics in anti-PD-1 and combined immune checkpoint inhibition

Immune checkpoint inhibitors (ICI) have revolutionized the treatment landscape of advanced malignancies, but come with a diverse spectrum of immune-related adverse events (irAEs). Mechanistic studies can aid the transition from expert-opinion to evidence-based irAE treatment strategies. We aimed to longitudinally characterize peripheral blood T and B cell dynamics in ICI-treated patients by multicolor flow cytometry and serum multiplex immunoassay at baseline, ± 3 weeks and ± 6 weeks or upon clinically relevant irAEs. We analyzed samples from 44 ICI-treated patients (24 anti-PD-1 monotherapy, 20 combined anti-PD-1/anti-CTLA-4; cICI), of whom 21 developed irAEs, and 10 healthy donors. IrAEs after cICI were characterized by significantly enhanced proliferation of Th1-associated, mainly (CD4+) CD27− effector memory T cells, as well as Th17-associated immune responses and germinal center activation (reflected by CXCL13 and IL-21 increases). We observed no changes in CD21lo, memory, class-switched or newly activated B cell subsets. Particularly double-positive PD-1+LAG-3+ CD8+ T cells showed enhanced cytotoxic capacity in patients with irAEs after cICI. Within anti-PD-1 monotherapy, irAEs were associated with modestly enhanced Th1-associated responses reflected by increased serum CXCL9 and CXCL10. In conclusion, ICI-induced toxicity is dominated by enhanced Th1-associated responses, but in cICI we also found evidence for Th17-associated responses and germinal center activation. Together, our data add to the growing body of evidence that irAEs may be driven by newly activated CD4+ helper T cells, specifically after cICI. This study also supports tailored irAE treatment, based on ICI regimen, and to deploy specific strategies such as Th17 inhibition especially in cICI-associated irAEs.Graphical abstract

Comparing the impact of steroid sparing immunosuppression vs. steroid monotherapy for immune-related adverse events in non–small cell lung cancer and melanoma.

2637 Background: The effect of steroid-sparing immunosuppressive agents (SSIAs) for immune-related adverse events (irAEs) on immune checkpoint inhibitor (ICI) antitumor activity is not well-known. We compared tumor outcomes of patients who received corticosteroid monotherapy versus those who received an addition of SSIA for irAE treatment. Methods: We conducted a retrospective case-control study of patients age ≥18 years with melanoma or non-small cell lung cancer (NSCLC) who were treated with ≥1 ICI at a quaternary care center between 1/1/2016-11/1/2021. Patients must have received systemic corticosteroids or an SSIA for irAE treatment at least 1 week prior to death. Patients were divided into two cohorts: only corticosteroids (CS cohort) or steroids+SSIA (SSIA cohort). We used propensity score nearest-neighbor matching to match on tumor type, stage, and prior lines of therapy. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included time from start of irAE treatment to irAE resolution. Hazard ratios (HR) for PFS and OS were calculated using the Cox proportional hazard regression method with time to steroid and SSIA as a time-varying covariate. Results: After matching, 48 patients were included, 24 in each cohort. Median age was 65. 41.7% of patients had NSCLC and 58.3% melanoma, 79.2% had stage 4 disease. 62.5% received ICIs as first line therapy, 33.3% as second-line, and 4.2% as third-line or higher. There was no significant demographic difference between the cohorts. Colitis was the most common irAE (39.6%). After adjusting for age, tumor type, tumor stage, and weeks from ICI start to steroid start, patients in the SSIA cohort had a shorter OS (HR 2.31, p = 0.037). We did not find a statistically significant difference for PFS (unadjusted HR 0.52, p = 0.20; adjusted HR 0.62, p = 0.34). Time from irAE treatment to resolution was longer in the SSIA cohort (8.1 weeks) compared to the CS cohort (4.9 weeks), but this did not reach statistical significance (p = 0.07). Conclusions: We found an association between decreased OS and use of SSIAs for irAE treatment compared to CS monotherapy, but no significant difference in PFS between the two cohorts. Large, prospective, randomized controlled trials are needed to separate the effects of SSIAs from high-dose CS in order to guide optimal treatment of irAEs.

Role of nivolumab maintenance therapy in advanced melanoma patients following severe immune-related adverse events from combination nivolumab and ipilimumab.

9520 Background: The combination of ipilimumab (ipi), and nivolumab (nivo) has been shown to be a highly effective treatment for metastatic melanoma. However, immune-related adverse events (irAEs) are common with this treatment, leading to treatment interruption and the use of immunosuppressive agents. There are no data on the impact of resuming single agent nivo on survival outcomes following recovery from the irAE and completion of immunosuppressive treatment. Some physicians hold therapy permanently as done on clinical trials and other physicians resume nivo after steroid taper. Methods: In this retrospective analysis, we examined a cohort of patients treated with ipi/nivo who developed irAEs that required treatment interruption and immunosuppressive therapy. The differences in practice patterns among physicians at our institution allowed us to examine the effect of single agent nivo resumption on survival after treatment of irAEs. Multivariate analysis of clinical factors associated with improved survival was performed. Results: We identified 165 patients who were treated with ipi/nivo and developed irAEs requiring treatment interruption and immunosuppressive therapy. To remove any impact of immediate disease progression on the analysis patients who progressed on ipi/nivo prior to or during treatment hold were removed from analysis. Of the remaining 131 patients, 45 resumed single agent maintenance nivo following the resolution of toxicity and completion of steroid taper. When stratified by age and adjusted for sex, M-stage, LDH, duration of therapy, and type of irAE causing the treatment pause, the effect of resumption of nivo upon survival remained highly significant (p = 0.001). Patients who resumed nivo had an 82% reduction in the hazard of death compared with patients who had not yet or never resumed nivo (HR: 0.18, 95% CI: 0.06 to 0.52). Of the patients who resumed nivo, 12 (26%) patients had subsequent irAEs with 5 patients having grade 3 irAEs (only one of whom had a recurrence of the prior ipi/nivo associated toxicity) and no grade 4 or 5 irAEs were noted. Conclusions: The resumption of single agent maintenance nivolumab following a treatment hold for ipi/nivo associated irAE and completion of immunosuppressive therapy increased overall survival compared to discontinuing nivo permanently in patients with metastatic melanoma after stratification for many factors. Toxicity observed post resumption of single agent nivolumab was manageable with no severe irAEs observed. These results suggest that restarting maintenance nivo post irAEs should be studied prospectively.

A single-centre experience of immune checkpoint inhibitors in patients with cancer in the Top End of the Northern Territory, Australia from 2016 to 2021.

e18841 Background: Immune checkpoint inhibitors (ICI) have transformed the oncological landscape, but are associated with immune-related adverse events (irAE) of varying frequency and severity. This regional single-centre experiential study evaluates the real-world incidence of irAE in patients in the Top End of the Northern Territory of Australia. The Top End represents a diverse population with high proportions of Aboriginal and Torres Strait Islander (ATSI) patients and patients living in remote and very remote areas. This captured cohort is under-represented in clinical trials. Methods: We identified all patients with solid tumours who were prescribed ICI between January 2016 and December 2021. We manually reviewed electronic and paper hospital records to record patient characteristics, treatments received, irAE, irAE treatment and patient outcomes. Results: 226 patients across 11 solid tumour streams received ICI. Of these, 58% had lung cancer, 27% melanoma, 5% head &amp; neck cancer, 4% renal cell carcinoma, and the remainder other tumour streams. 70% were male and the median age at diagnosis was 63 years [28-84 years]. 16% identified as ATSI(compared to 2.8% ATSI nation-wide and 26.3% ATSI in the Northern Territory). Of the investigational cohort, 13% were treated in the adjuvant and 87% in the palliative setting. 11% received combination versus 89% single-agent ICI. 30% of patients had concurrent chemotherapy. 122 patients (54%) experienced any grade irAE as documented by the treating oncologist in the medical records. 59 patients (26%) had a severe (grade 3, 4, or 5) irAE. The fatality rate was 0.88% (2 patients); both were treated with a PD-L1 inhibitor for non-small cell lung cancer (NSCLC) and diagnosed with immune-related pneumonitis. The most common irAE were rash (18%), colitis (16%), arthralgia/myalgia (13%), pneumonitis (12%), thyroiditis/hypothyroidism (12%), hepatitis (9%), and adrenal insufficiency (7%). 24% of irAE required hospitalisation and 32% led to discontinuation of treatment. The median number of irAE per patient was 1. Among patients with the most common tumour types (melanoma and NSCLC), rates of irAE were, in both cases, 59% any grade irAE and 20% severe irAE. When compared to published literature, real-world rates of any grade adverse event were significantly lower than reported number in trials – likely due to exclusion of common non-immune-related adverse events in our data set. Rates of severe and fatal irAE were in line with published data. Conclusions: Immune-related adverse events are common among patients in the Top End and reflect rates in the published literature. We did not identify any safety concerns in our cohort of patients – including amongst ATSI patients and those living in remote and very remote areas. Further data analysis is needed to assess frequency and severity of irAE by specific tumour type and ICI.

Multisystem immune-related adverse events from dual agent immunotherapy use.

2635 Background: Immune-related adverse events (irAEs) are commonly seen in cancer patients who undergo immunotherapy treatment. Increasingly, there has been recognition that multiple different irAEs can occur during or/and after a single course of immunotherapy treatment, known as multisystem irAEs, though much remains unknown. The primary objective of this study was to assess for rate of multisystem irAEs in patients who received dual agent ipilimumab and nivolumab for cancer treatment. Methods: A retrospective cohort review was completed that included all cancer patients seen at Juravinski Cancer Centre who received at least one dose of ipilimumab and nivolumab from January 1, 2018 to May 31, 2022. Patient characteristics, cancer types, and number and types of irAEs were recorded. Multivariate logistic regressions were also completed comparing those who developed multisystem irAEs, single irAE, and no irAE. Results: A total of 123 patients were included in this study. Median age was 59 years old, with 69% male. 72 out of 123 patients (59%) had melanoma, 50/123 (41%) had renal cell carcinoma (RCC), and 1/123 (1%) had breast cancer. At least one irAE was seen in 72% of patients who were treated with ipilimumab and nivolumab, and most irAEs occurred during the combination phase (89% of first irAE, 59% of second irAE, 75% of third irAE, and 50% of fourth irAE). Multisystem irAEs were seen in 40% of the overall cohort. The most common irAE type was dermatitis (22%), followed by colitis (19%), hepatitis (17%), and thyroiditis (15%). 30 out of 89 patients (34%) who experienced irAE(s) required hospital admission for inpatient treatment of irAE(s). Patients who experienced multisystem irAEs had significantly higher rates of response to immunotherapy irAE (p &lt; 0.001) and improved overall survival (OS) than those who experienced single or no irAE. Conclusions: From our single-centre cohort study, there appeared to be a higher than previously quoted number of patients who experienced irAEs after receiving ipilimumab and nivolumab, with majority of them developing multisystem irAEs. Many patients experienced debilitating associated symptoms and hospital admission relating to irAEs. It is important for both the counselling and consent of patients, and for patient education, to discuss the possibility of multiple irAEs prior to dual immunotherapy initiation.

Peripheral blood immune cell and cytokine profiling of patients receiving corticosteroids for immune checkpoint inhibitor-related adverse events: Steroid dose and duration.

e14694 Background: Immune checkpoint inhibitors (ICI) have dramatically extended survival in numerous malignancies, but many patients treated with ICIs experience severe immune-related adverse events (irAEs) that can affect virtually any organ. Corticosteroids (steroids) tapered over weeks to months are usually effective but may affect ICI anti-tumor activity. Tapers are often imprecise, resulting in over- or undertreatment of some patients. There are no known blood biomarkers to guide steroid taper management. We therefore profiled peripheral blood immune cells and cytokines at key timepoints to identify biomarkers of response to steroids for irAE treatment. Methods: We collected blood samples before ICI, during irAE, at three steroid dose levels (high, intermediate, and low), and post-steroids from patients treated with ICI therapy at Yale Cancer Center. We measured 48 serum cytokines with a multiplexed immunoassay and immunophenotyped 40 markers on peripheral blood mononuclear cells with mass cytometry (CyTOF). We correlated changes in serum cytokine concentration across timepoints with clinical features. We applied a cluster analysis to the CyTOF data to identify immune cell types and their change in frequency across timepoints. Results: We evaluated 12 patients treated with anti-PD-1 + anti-CTLA-4 therapy who experienced at least 1 severe irAE (11 patients with melanoma, 1 patient with renal cell carcinoma). Five patients had colitis, 6 had hepatitis, and 1 had hepatitis and enteritis. Concentrations of TNFα, IFNγ-mediated cytokines (IL-12p40, IL-18, IL-27), and T cell homing chemokines (CXCL9, CXCL10) increased during irAEs and decreased during steroid therapy without significant change across steroid dose levels (p &lt; 0.05). We observed the largest changes in patients who experienced another irAE within 3 months (n = 5). IL-6 was notably higher in patients who required steroid taper escalation for recurrent symptoms before or soon after completing steroid therapy (n = 8, p = 0.02). Compared to other T cell subtypes, the frequency of CD4 T effector memory (Tem) cells increased during irAE and decreased upon completing steroid therapy but did not return to baseline (p &lt; 0.01). Conclusions: In patients treated with anti-CTLA-4 + anti-PD-1 therapy, IL-6 and IFNγ-mediated cytokines were elevated during irAEs and suppressed at multiple steroid dose levels despite symptom recurrence during the steroid taper. Increased CD4 Tem cell frequency during irAEs may reflect circulating pathogenic T cells, and the delayed decrease and incomplete return to baseline could be due to the severity of irAEs represented in this study. Specific cytokines may predict the occurrence of multiple irAEs and the need for a longer steroid taper. Additional longitudinal analyses of steroid effects on irAEs are needed to validate these findings.

Physician Views on the Provision of Information on Immune Checkpoint Inhibitor Therapy to Patients with Cancer and Pre-Existing Autoimmune Disease: A Qualitative Study.

Immune checkpoint inhibitors (ICIs) have improved cancer outcomes but can cause severe immune-related adverse events (irAEs) and flares of autoimmune conditions in cancer patients with pre-existing autoimmune disease. The objective of this study was to identify the information physicians perceived as most useful for these patients when discussing treatment initiation with ICIs. Twenty physicians at a cancer institution with experience in the treatment of irAEs were interviewed. Qualitative thematic analysis was performed to organize and interpret data. The physicians were 11 medical oncologists and 9 non-oncology specialists. The following themes were identified: (1) current methods used by physicians to provide information to patients and delivery options; (2) factors to make decisions about whether or not to start ICIs in patients who have cancer and pre-existing autoimmune conditions; (3) learning points for patients to understand; (4) preferences for the delivery of ICI information; and (5) barriers to the implementation of ICI information in clinics. Regarding points to discuss with patients, physicians agreed that the benefits of ICIs, the probability of irAEs, and risks of underlying autoimmune condition flares with the use of ICIs were most important. Non-oncologists were additionally concerned about how ICIs affect the autoimmune disease (e.g., impact on disease activity, need for changes in medications for the autoimmune disease, and monitoring of autoimmune conditions).