Toxicity Of Checkpoint Inhibitors Research Articles

Immune-related toxicities of checkpoint inhibitors: mechanisms and mitigation strategies.

The immune-related adverse events associated with treatment with immune checkpoint inhibitors result in significant morbidity for patients as well as considerable cost to the health-care system, and can limit the use of these beneficial drugs. Understanding the mechanisms of these side effects and how they can be separated from the antitumour effects of immune checkpoint inhibitors, as well as identifying biomarkers that predict the development of immune-related toxicities, will facilitate the conduct of trials to limit their onset and improve patient outcomes. In this Review, we discuss the different types of immune-related adverse events and how their treatment and identification of possible predictive biomarkers may shed light on their mechanisms, and describe possible strategies and targets for prophylactic and therapeutic intervention to mitigate them.

Immune checkpoint inhibitor-associated acute kidney injury and mortality: An observational study.

BackgroundImmune checkpoint inhibitors, approved for the treatment of various types of cancer, are known to cause a unique spectrum of side effects, including acute kidney injury (AKI). The aim of this study was to describe the incidence, risk factors, renal outcomes, and mortality of AKI in patients receiving checkpoint inhibitors.MethodsPatients receiving checkpoint inhibitors between January 2013 and May 2020 at the University Medical Center Utrecht, the Netherlands, were identified using the Utrecht Patient Oriented Database. AKI was defined as an increase in serum creatinine of ≥1.5 times the baseline value, based on the Kidney Disease: Improving Global Outcomes criteria. Cox proportional hazard regression analysis was used to assess risk factors for AKI and to evaluate the relationship between AKI and mortality. Persistent renal dysfunction was diagnosed in AKI patients with a final serum creatinine measurement of >1.3 times the baseline value.ResultsAmong 676 patients receiving checkpoint inhibitors, the overall incidence of AKI was 14.2%. Baseline variables independently associated with AKI were a gynecologic malignancy, monotherapy with ipilimumab, and the use of a diuretic, angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, or proton pump inhibitor at baseline. AKI was checkpoint inhibitor-associated in one third of all patients with AKI. Checkpoint inhibitor-associated AKI was mostly low-grade, occurred a median of 15 weeks after checkpoint inhibitor initiation, and resulted in persistent renal dysfunction in approximately 40% of the patients. Patients with all-cause AKI had a twofold increased mortality risk, but checkpoint inhibitor-associated AKI was not associated with increased mortality.ConclusionsIn this study, patients receiving checkpoint inhibitors frequently developed AKI due to various etiologies. AKI directly related to the effect of checkpoint inhibitor toxicity did not increase mortality. However, AKI not related to the effect of checkpoint inhibitor toxicity was associated with increased mortality.

Impact of COVID-19 on Patients with Cancer Receiving Immune Checkpoint Inhibitors.

To evaluate the impact of Sars-Cov-2 infection on mortality and immune checkpoint inhibitor (ICI) toxicity in patients with cancer receiving ICIs compared to those not receiving ICIs. We conducted a retrospective matched cohort study of 25 patients receiving ICIs within 1 year of coronavirus disease 2019 (COVID-19) diagnosis between March 20, 2020, and June 3, 2020, at the Dana-Farber Cancer Institute/Mass General Brigham. Cases were matched 1:1 with controls based on age, sex, and anticancer therapy within the prior 6 months. Seven of 25 (28%) patients receiving ICIs died from COVID-19 as compared with nine of 25 (36%) controls. Through multivariable analysis adjusting for age, sex, and anticancer therapy, ICI use was not associated with increased risk for COVID-19 death (OR [odds ratio] 0.36, 95% CI 0.07-1.87). Determinants of mortality included age (OR 1.14, 95% CI 1.03-1.27) and chronic obstructive pulmonary disease (OR 12.26, 95% CI 1.76-85.14). Statin use was protective against mortality (OR 0.08, 95% CI 0.01-0.63). Two patients experienced persistent immune-related adverse events (irAEs) (hypophysitis); one had new-onset irAE (hypothyroidism) during their COVID-19 course. Patients with ICIs had significantly higher platelet (p = 0.017) and D-dimer (p = 0.037) levels. Elevated troponin levels (p = 0.01) were associated with COVID-19 death in patients using ICI. There is insufficient evidence to conclude COVID-19-related outcomes are associated with ICIs, and we did not observe an increased risk of COVID-19-related death associated with ICIs. The potential protective effect of statin therapy and role of laboratory biomarkers warrant further investigation.

Efficacy and Safety of Checkpoint Inhibitor Treatment in Patients with Advanced Renal or Urothelial Cell Carcinoma and Concomitant Chronic Kidney Disease: A Retrospective Cohort Study.

Simple SummaryImmune checkpoint inhibition plays a pivotal role in the treatment of metastatic renal cell carcinoma and metastatic urothelial carcinoma. The association of chronic kidney disease with these tumors is well established. However, to what extent kidney failure modifies the efficacy or the toxicity profiles of checkpoint inhibitors has been poorly investigated. In this paper, we reviewed the files of 85 patients with renal cell carcinoma and 41 with urothelial cancer who had received checkpoint inhibitor treatment, and found that 37.6% and 41.5% had evidence of chronic kidney disease, respectively. We found that neither general treatment-related nor immune-related adverse events differed between patients with normal or impaired renal function. Using a multivariate analysis, we found that chronic kidney disease had no effect on progression-free survival. However, irrespective of the tumor entity, chronic kidney disease was found to positively influence overall survival. We conclude that treatment with checkpoint inhibitors in patients with chronic kidney disease is safe and efficient.Background: Checkpoint inhibitors are a standard of care in the treatment of advanced renal cell carcinoma (RCC) and urothelial carcinoma (UC). Patients with these tumors often suffer from concomitant chronic kidney disease (CKD). Limited data are available on the efficacy and toxicity of checkpoint inhibitors in patients with CKD. Methods: We retrospectively analyzed 126 patients who received checkpoint inhibitors for RCC (n = 85) or UC (n = 41) and analyzed the frequency of treatment- and immune-related adverse events (AEs). We performed a multivariate analysis to determine progression-free survival (PFS) and overall survival (OS). Results: A total of 38.9% of patients had CKD. Frequencies of general AEs (49.0% in CKD vs. 48.1%, p > 0.99999) and immune-related AEs (28.6 vs. 24.7%, p ≥ 0.9999) did not significantly differ between the groups. There was no difference in PFS for patients with RCC or UC and CKD or without CKD (RCC: 6.81 vs. 7.54 months, HR 1.000 (95%CI 0.548–01.822), p = 0.999; UC:2.33 vs. 3.67 months, HR 01.492 (95%CI 0.686–3.247), p = 0.431). CKD appeared to be a potential effect modifier for OS in both RCC and UC (RCC: NR vs. 23.9 months, HR 0.502 (95%CI 0.219–1.152), p = 0.104; UC:18.84 vs. 15.42 months, HR 0.656 (95%CI 0.296–1.454), p = 0.299). Conclusions: Checkpoint inhibitor treatment in our cohort of patients with CKD was as safe and efficient as in the cohort of patients without CKD.

Adverse Event Reporting with Immune Checkpoint Inhibitors in Older Patients: Age Subgroup Disproportionality Analysis in VigiBase.

Simple SummaryDue to the changes that occur with aging in the immune system, older patients represent a subpopulation of concern for immune checkpoint inhibitor toxicity. This pharmacovigilance study aimed to assess whether older patient age (65 years and older) was a risk factor for increased reporting of adverse drug reactions with immune checkpoint inhibitors as compared to other antineoplastic drugs in VigiBase, the World Health Organization global database of spontaneous reporting. Disproportionality analysis by age subgroups (<18 years, 18–64 years, 65–74 years, 75–84 years and ≥85 years) did not highlight older patient age as risk factor for increased reporting of any specific toxicity with immune checkpoint inhibitors as compared to other antineoplastic drugs. A signal of disproportionate reporting emerged for eye disorders with immune checkpoint inhibitors in patients aged 18–64 years, which deserves further investigation aimed at elucidating risk factors and defining management strategies.Older patients represent a subpopulation of concern for immune checkpoint inhibitor (ICI) toxicity because of changes in the aging immune system and the potentially relevant clinical implications for their quality of life. Current evidence on ICI safety in older patients is conflicting. This study aimed to assess whether older patient age was a risk factor for increased reporting with ICIs as compared to other antineoplastic drugs in VigiBase, the World Health Organization database of suspected adverse drug reactions. Disproportionality analyses computing the reporting odds ratios (RORs) were performed by age subgroups (<18 years, 18–64 years, 65–74 years, 75–84 years and ≥85 years). There were not signals of disproportionate reporting with ICIs specifically detected in older patient age subgroups (≥65 years), which were not present in the disproportionality analysis over the entire dataset. A signal of disproportionate reporting with ICIs emerged for eye disorders only in the age subgroup 18–64 years (ROR 1.13, 95% confidence interval 1.05–1.23). These findings showed that adverse event reporting with ICIs in older patients was comparable to that in the overall patient cohort and prompt for the further investigation of eye disorders with ICIs to elucidating risk factors and defining management strategies.

A patient with gastroesophageal junction carcinoma and cough.

A 40-year-old, never smoker male with gastroesophageal junction carcinoma was evaluated for dyspnea and cough. Computed tomography scan was obtained which showed ground-glass opacities surrounded by rim of consolidation (Atoll sign). The patient underwent bronchoscopy with transbronchial lung biopsy and was diagnosed with organizing pneumonia secondary to checkpoint inhibitor toxicity.

Evaluation of an Interprofessional Training Program to Improve Cancer Drug Therapy Safety.

Drug therapy for cancer is a high-risk, high-volume clinical intervention that requires interprofessional teams. Given the complexity of anticancer drug therapy and safety concerns, an interdisciplinary team developed a novel training program for oncology registered nurses and pharmacists to improve cancer drug safety. Participants completed preworkshop learning assessments and received access to web-based modules on six topics: hazardous drug handling, drug extravasation, hypersensitivity reaction management, sepsis recognition, immune checkpoint inhibitor toxicities, and oral oncolytic adherence. In a 7-hour workshop, participants applied module content in interactive exercises and high-fidelity simulations. Preworkshop and postworkshop questionnaires assessed changes in knowledge and confidence in each topic. Program satisfaction and changes to clinical practice or policies were assessed 3 months after the workshop. Two hundred ninety-two nurses and 82 pharmacists applied to participate, and 103 (35%) and 44 (54%) have participated, respectively. Long-term follow-up data were available on 133 (90%) participants. Change scores in confidence to meet program objectives increased between pre- and postworkshop (range of increase 0.6-0.8, P < .01). Knowledge scores increased significantly between pre- and postworkshop (average improvement of 3.2 points, P < .01). Overall program satisfaction was high (mean 5.0, standard deviation [0.2] on a five-point scale). Seventy-seven (60%) reported that they had made at least one clinical practice or institutional policy change at 3 months. An interprofessional education program with online modules, in-person interactive sessions, and simulation activities is a promising strategy to deliver cancer drug safety content to practicing oncology clinicians.

Impact of age-related T cell dynamics on the identification of biomarkers predictive of immunotherapy discontinuation: a prospective cohort study.

The impact of biologic aging on immune checkpoint inhibitor (ICI) toxicity and efficacy is underexplored in metastatic melanoma (MM). In peripheral blood T-lymphocytes (PBTLs), biologic aging is characterized by changes in T-cell composition and cellular senescence. Whether indicators of PBTL biologic aging vary in MM patients or can be used to predict premature ICI discontinuation (pID) is unknown. We prospectively collected PBTLs from 117 cancer-free controls and 46 MM patients scheduled to begin pembrolizumab or nivolumab monotherapy. 74 mRNAs indicative of T-cell subsets, activation, co-stimuation/inhibition and cellular senescence were measured by Nanostring. Relationships between each mRNA and chronologic age were assessed in patients and controls. Candidate biomarkers were identified by calculating the hazard ratio (HR) for pID in patients divided into low and high groups based on log-transformed mRNA levels or the magnitude by which each mRNA measurement deviated from the control trend (Δage). Area under the curve (AUC) analyses explored the ability of each biomarker to discriminate between patients with and without pID at 6 months and 1 year. Fifteen mRNAs correlated with chronologic age in controls, including markers of T-cell subsets, differentiation, cytokine production and co-stimulation/inhibition. None of these mRNAs remained correlated with age in patients. Median follow-up was 94.8 (1.6-195.7) weeks and 35 of 46 patients discontinued therapy (23 progression, 7 toxicity, 5 comorbidity/patient preference). Elevated pre-therapy CD8A (HR 2.2[1.1-4.9]), CD45RB (HR 2.9[1.4-5.8]) and TNFRSF14 (HR 2.2[1.1-4.5]) levels predicted pID independent of Δage-correction. CD3ε, CD27 and FOXO1 predicted pID only after Δage-correction (HR 2.5[1.3-5.1]; 3.7[1.8-7.8]; 2.1[1.1-4.3]). AUC analysis identified Δage-CD3ε and -CD27 as candidate predictors of pID (AUC=0.73; 0.75). Correlations between transcriptional markers of PBTL composition and chronologic age are disrupted in MM. Correcting for normal, age-related trends in biomarker expression unveils new biomarker candidates predictive of ICI outcomes.

A Multidisciplinary Approach for Patients with Preexisting Lung Diseases and Immune Checkpoint Inhibitor Toxicities.

This commentary outlines the strategy employed by a multidisciplinary immune‐related toxicity team to evaluate patients who may be at high risk for the development of immune‐related toxicity, in particular, those with preexisting lung conditions and subsequent immune‐related pneumonitis.

Immune checkpoint inhibitor toxicities: systems-based approaches to improve patient care and research.

Immune checkpoint inhibitors (ICIs) have now been approved in numerous and diverse cancer types and combination regimens. Effective recognition and treatment of ICI toxicities, which might occur acutely, affect any organ system, and produce many distinct clinical syndromes, have emerged as essential goals of ICI management. Thus, developing robust diagnostic and management approaches for ICI toxicity across the health-care system is an urgent and unmet clinical need. In this Personal View, we describe barriers to high-quality care that have constrained the most effective management of patients with cancer receiving ICI treatment. We review education initiatives to enhance patient and physician awareness, which is necessary given the broad spectrum of ICI toxicities often experienced by patients, and assess various systems-based approaches that maximise the chances of appropriate management. In addition, we describe research pipelines that broaden evidence-based approaches and the pathobiology of these novel events. Developing effective, systematic approaches for the recognition and treatment of ICI toxicities will continue to grow in importance as these agents proliferate in cancer care.

Impact of pharmacist-managed immune checkpoint inhibitor toxicities.

Immune checkpoint inhibitors are associated with unique autoimmune side effects that differ from traditional cytotoxic chemotherapy. Pharmacists may play an important role in providing key supportive care measures necessary to aid patients and oncologists through immune-related adverse events (irAEs). This study aims to evaluate the impact of a pharmacist-managed irAE protocol in an oncology clinic. This study is a retrospective chart review of the implementation of a pilot irAE pharmacy protocol. Patients treated with an immune checkpoint inhibitor and subsequently identified to have dermatologic, gastrointestinal, hepatic, or thyroid toxicities and managed under the pilot irAE pharmacy protocol from 1 October 2018 to 28 February 2019 were enrolled. Study endpoints included number of pharmacist interventions and physician satisfaction. Additional endpoints included pharmacotherapy initiated, dose adjustments, and patient follow-ups. From 1 October 2018, to 28 February 2019, 17 patients were referred and approved by their primary oncologists for pharmacy management under the pilot irAE protocol. During the pilot period, pharmacists initiated 21 new medications for the treatment of irAEs, including thyroid hormone replacement in 7 patients (41%) and oral corticosteroids in 6 patients (35%) with a total of 28 dose adjustments. In addition, the pilot protocol included an assessment of physician satisfaction, which showed a reduced number of physician hours per month managing irAEs, increased physician confidence in irAE management, and a desire for continued pharmacist-management of irAEs. Oncology pharmacists had an impact on management of toxicities in our oncology clinic as indicated by the pharmacist interventions and physician satisfaction.

Retrospective study to assess the efficacy and safety of checkpoint inhibitors in advanced urothelial carcinoma in real-world setting.

e17043 Background: Checkpoint Inhibitors (CPI) have become a new standard of treatment in advanced urothelial carcinoma. However, little is known regarding the outcome of patients in daily practice.We aimed to assess tumor response and toxicity of CPIs in a cohort of patients treated in “real world” conditions. In parallel, a comprehensive molecular study in tumor samples from these patients, is ongoing. Methods: We designed an observational retrospective study within the “Grupo Centro” collaborative group. Adult patients diagnosed of metastasic urothelial carcinoma (mUC) and treated with CPIs between 2011-2019 in any of the 20 centers of the group, were eligible. Results: Up to date 100 patients have been included (82% males) with a median age of 74 years (48 -96). In 82% patients primary was bladder cancer. Most common metastasic sites were bone (26%) and liver (16%).With a median follow up of 10,6 months(mo) median progression free survival (mPFS) was 6,6mo (1,4-95,4 range) and median Overall Survival (mOS) was 21.3mo (3,8-121,8). 38% of patients received CPIs in first line(L): atezolizumab:27, pembrolizumab: 10, nivolumab:1. The median number of cycles was 8,2. Up to 51% received platinum-based combinations in first line. 69% (69/100) pts received 2L treatment: 68% with CPIs, 27,5% with chemotherapy and 4% with FGFR inhibitors (as part of a clinical trial). 2L mPFS was 3,5 mo (1,9-25.9). 23% (23/100) patients received 3L, of them 26% (6/23) were treated with CPIs. 3L mPFS:8,3mo(0,4-43,8). As a whole, patients treated with CPI accross different lines, achieved complete response in 8% of the cases, partial response in 18% and stable disease in 15%. Up to 44% of cases presented progressive disease as best response and evaluation was not available in 15%. Most common G1-2 AEs related to immunotherapy were: asthenia:31%,pruritus:16% and anorexia: 9%.10% pts experienced G3-4 toxicity: asthenia G3: 4, diarrhea G3: 1, erythrodysesthesia G3:1, arthromyalgia G3: 1, cardiac arrest G4:1,pneumonitis G4:1,anemia G3:1. Conclusions: This study confirms the efficacy and security of CPIs in real world. Response rates and toxicity profile were comparable to those reported in clinical trials.

Immune-mediated adverse events following concomitant radiotherapy and immunotherapy in patients with melanoma and Merkel cell carcinoma: A preliminary report from an evolving retrospective registry.

3144 Background: Radiotherapy (RT) potentiates immune-mediated responses against tumor antigens, an effect that is enhanced by checkpoint inhibitors (CPIs) and may hold therapeutic promise. However, the mechanisms underlying this abscopal effect can theoretically increase the rate of immune-mediated adverse events (irAEs). We estimated the incidence of irAEs in a single-institution cohort treated with concomitant RT and immunotherapy. Methods: We retrospectively screened 731 patients that received RT and CPIs at our institution. Patients diagnosed with melanoma or Merkel cell carcinoma (MCC) who underwent RT concurrently or within 30 days of CPI administration were eligible. A radiation period (RP) comprised the interval between the first and last treatment days (≤90 days); a patient could contribute multiple RPs. Data on new irAEs diagnosed within 3 months after RT and relevant demographic and clinicopathologic variables were collected; univariate analysis was performed with the chi-squared test. Results: 35 patients (23 male, 12 female) contributed 43 RPs; mean age was 65.5 years (range: 39-90). Five had MCC, and 30 had melanoma (24 cutaneous, 1 uveal and 5 urogenital melanomas). PD-1 inhibitors were most commonly employed (22 RPs), followed by ipilimumab-nivolumab (14 RPs), ipilimumab (4 RPs), and avelumab (3 RPs). CPIs were administered concurrently with RT in 32 RPs and sequentially in 11 RPs. Fourteen RPs comprised intracranial radiation. Importantly, 45.7% of patients (16/35) experienced irAEs, which manifested within a month of RT in 25.7% (9/35). Four patients experienced grade ≥3 irAEs leading to hospitalization; one died of respiratory failure after developing pneumonitis. On univariate analysis, no significant association between tumor type, CPI regimen, concurrent RT, intracranial vs. extracranial RT, and irAE incidence was noted. A trend for increased irAEs within the ipilimumab-nivolumab group was observed (p = 0.27). Conclusions: Almost half of patients developed new irAEs following RT, with 25% (4/16) of cases warranting hospitalization; these incidence rates appear to exceed rates from historical data and raise concerns about the additive toxicity of CPIs and RT. Comparison to non-RT cohorts and survival analyses are ongoing.

Immune checkpoint inhibitor toxicity and associated outcomes in a geriatric population.

e24014 Background: Increased use of immune checkpoint inhibitor (ICI) therapy over various cancer types has resulted in a parallel rise in immune-related adverse events (irAEs). There is limited data with regards to understanding irAEs in the elderly population despite its widespread use. We aimed to investigate irAEs in elderly patients receiving checkpoint inhibitor immunotherapy in a community oncology practice setting. Methods: Our retrospective study included patients ≥65 years old treated at a community oncology practice setting from January 1, 2011 through September 30, 2019 who received at least one treatment of a PD-1 or PDL-1 inhibitor (PDI) and/or CTLA-4 checkpoint inhibitor. We evaluated the prevalence of irAEs, determined if age, class of ICI, or oncologic response (clinical and radiographic) was associated with higher grades of irAE. The impact of irAEs on progression-free survival (PFS) and overall survival (OS) was also analyzed. Results: A total of 210 patients were identified, of which 76 developed irAEs. The overall mean age was 75.0 ± 7.2 years. Males accounted for 58% and the overall majority were Caucasian. The most common cancers were lung (56.7%), melanoma (20.0%) and genitourinary (14.8%). The prevalence of irAEs was 36.2% with a distribution of grades 1-2-3-4-5 being 31.6% - 43.4% - 17.1% - 6.6% and 1.3%, respectively. Hazard ratio adjusted for number of cycles for OS was 1.47 (95% CI, 0.98 to 2.19; p = 0.058) and PFS was 1.11 (95% CI, 0.72 to 1.71). Conclusions: To our knowledge, this is one of the few studies that has explored irAEs in the geriatric population. There was no association between ICI-associated higher-grade toxicities and oncologic response in our elderly population. Although there was a trend in OS, we found no statistical differences between elderly patients with irAEs and those without for OS and PFS. Further study is needed to explore the occurrence irAEs in the elderly to improve management of these patients.

A review of cancer immunotherapy toxicity.

Cancer immunotherapies, including checkpoint inhibitors and adoptive cell therapy, manipulate the immune system to recognize and attack cancer cells. These therapies have the potential to induce durable responses in multiple solid and hematologic malignancies and thus have transformed treatment algorithms for numerous tumor types. Cancer immunotherapies lead to unique toxicity profiles distinct from the toxicities of other cancer therapies, depending on their mechanism of action. These toxicities often require specific management, which can include steroids and immune-modulating therapy and for which consensus guidelines have been published. This review will focus on the toxicities of checkpoint inhibitors and chimeric antigen receptor T cells, including pathophysiology, diagnosis, and management.

Lower risk of severe checkpoint inhibitor toxicity in more advanced disease

BackgroundImmune checkpoint inhibitor (ICI) can cause severe and sometimes fatal immune-related adverse events (irAEs). Since these irAEs mimick immunological disease, a female predominance has been speculated on. Nevertheless, no demographic or tumour-related factors associated with an increased risk of irAEs have been identified until now.MethodsRisk ratios of severe (grade ≥3) irAEs for age, sex, WHO performance status, number of comorbidities, stage of disease, number of metastases and serum lactate dehydrogenases (LDH) were estimated using data from anti-PD1-treated patients with advanced melanoma in the prospective nationwide Dutch Melanoma Treatment Registry.Results111 (11%) out of 819 anti-programmed cell death 1 treated patients experienced severe irAEs. Patients with non-lung visceral metastases (stage IV M1c or higher) less often experienced severe irAEs (11%) compared with patients with only lung and/or lymph node/soft tissue involvement (stage IV M1b or lower; 19%; adjusted risk ratio (RRadj) 0.63; 95% CI 0.41 to 0.94). Patients with LDH of more than two times upper limit of normal had a non-significantly lower risk of developing severe irAEs than those with normal LDH (RRadj 0.65; 95% CI 0.20 to 2.13). None of the other variables were associated with severe irAEs.ConclusionIn patients with melanoma, more advanced disease is associated with a lower rate of severe irAEs. No association with sex was found.

Gastrointestinal adverse events associated with immune checkpoint inhibitor therapy.

Immunotherapy with checkpoint inhibitors has revolutionized cancer therapy and is now the standard treatment for several different types of cancer, supported by favorable outcomes and good tolerance. However, it is linked to multiple immune manifestations, referred to as immune-related adverse events (irAEs). These adverse events frequently affect the skin, colon, endocrine glands, lungs, and liver. The gastrointestinal system is one of the most commonly affected organ systems and is responsible for the most frequent emergency visits resulting from irAEs. However, because immune checkpoint inhibitors are a recent addition to our arsenal of cancer drugs, many health-care providers remain unfamiliar with the management of irAEs. Gastroenterologists involved in the treatment of oncology patients who have received checkpoint inhibitors are currently encountering cases of abdominal pain, diarrhea, and other nonspecific symptoms that may be challenging to manage. This article reviews the gastrointestinal, hepatic, and pancreatic toxicities of checkpoint inhibitors and provides an approach to their diagnosis and recommended workup. It also highlights the management of irAEs according to their toxicity grading and specifically discusses the instances in which corticosteroids should be administered and/or the immune checkpoint inhibitors should be withheld.

Mechanistic classification of immune checkpoint inhibitor toxicity as a pointer to minimal treatment strategies to further improve survival

Improved anti-tumour responses under immune checkpoint inhibition (ICI) are associated with concomitant autoimmune disease development termed immune related adverse events (irAEs), of which approximately 5% are rheumatic in nature. Generally, oncologists and other specialists vigorously treat irAEs in spite of the generally accepted beneficial effect of irAEs on tumour survival. Herein, we highlight mechanistic insights on how tumour responses and certain types of autoimmunity appear to be inextricably linked around CD8+ T-cell mediated responses and that strategies that interfere with such shared immunopathgenesis could impact of survival. We discuss the possible circumstances in which intensive immunosuppressive therapy for irAEs that occur with ICIs might blunt anti-tumour immunity. We also discuss potential therapeutic strategies for emergent ICI related autoimmunity and propose some treatment considerations and research questions to minimize the impact of overzealous immunosuppression strategies on tumour responses. Thus, refraining from using powerful therapeutic armamentarium to treat irAEs, especially when these are not considered as life-threating might improve the prognosis of ICI therapy.

Immune Checkpoint Inhibitor Toxicity in Head and Neck Cancer: From Identification to Management.

Benefiting from the continuously clarifying underlying biology of immune checkpoints and ligand–receptor interactions, the emergence of new anticancer treatment strategy, immunotherapy has shown substantial benefits on several liquid and solid tumors. Immune checkpoint inhibitors (ICIs) can block the negative regulatory components and enhance the T cell function, thus leading to prominent anticancer activity. On account of their promising effect on various malignancies shown in clinical trials, ICIs have been considered to be the most potent anticancer agents in the near future. Head and neck cancer is the seventh most common neoplasm worldwide, and the gross 5-year survival rate was only 60%. Managing locoregionally advanced, recurrent, or metastatic head and neck tumors is still a challenging problem for both oncologists and surgeons. Recent clinical trials employing the immune-modulating antibodies that target cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death 1 (PD-1) herald a new era of anticancer therapy. However, like all other anticancer drugs, ICIs also have side effects while upregulating the immune system to enhance antitumor response, which were known as immune-related adverse events (irAEs). Generally, most irAEs were transient, but sometimes they can cause serious organ dysfunction, even fatal. In addition, due to the distinct anatomical feature, advanced head and neck tumors often affect the upper aerodigestive tract and cause serious dyspnea or dysphagia. Toxicities of ICIs may be more lethal for such patients. Thus, with the increasing application of anti-checkpoint agents in head and neck cancer, there is urgent need to ascertain the safety of this novel treatment strategy. Here, we compile this review of existing clinical trials on the toxicity of ICIs during cancer treatment. The particular clinical manifestation, characteristics of complication development in fatal cases, and the management strategies were discussed. This may provide vital information for future oncology trials and clinical practice.

Abstract 806: PD-1 in Cardiac Immune Responses After Ischemic Injury or Transverse Aortic Constriction

Background: Heart failure is associated with inflammation, but the precise immune mechanisms that contribute to cardiomyopathy remain elusive. Myocarditis is a rare toxicity of checkpoint inhibitors, which are oncologic therapies that block signaling through the immunoinhibitory molecule PD-1. We investigated whether PD-1 attenuates cardiac immune responses. Methods: Expression of PD-1 and its ligand PD-L1 on cardiac cell populations were assessed by flow cytometry. The functional implications of PD-1 signaling were determined using PD-1 blocking antibodies (Abs) in two surgical models of cardiac injury: ischemia/reperfusion and transverse aortic constriction (TAC). Ischemic injury was measured by troponin release and histology. Systolic function was assayed by echocardiography, diastolic function by invasive pressure-volume loops, and fibrosis by histology. Results: PD-L1 is expressed on most cardiac endothelial cells and a small fraction of cardiomyocytes. While intracardiac T cells do not express PD-1 under baseline conditions, 15% of both CD4 and CD8 T cells express PD-1 after TAC. Blocking PD-1 signaling after ischemic injury did not affect troponin levels (5.8 ng/ml in mice receiving isotype control (IC) Ab vs 7.8 ng/ml in mice receiving anti-PD-1 Ab, p=0.26), size of infarct (1.6% of ventricular cross-sectional area for IC Ab vs 2.0% for anti-PD-1 Ab, p=0.27), or systolic function (fractional shortening 52.6% for IC Ab vs 53.2% for anti-PD-1 Ab, p=0.92). Similarly, abrogation of PD-1 signaling after TAC did not worsen systolic dysfunction (fractional shortening 36.8% for IC Ab vs 32.4% for anti-PD-1 Ab, p=0.38), diastolic function (dP/dT minimum -9445 mmHg/s vs -10950 mmHg/s, p=0.44; Tau 6.8 ms for IC Ab vs 6.0 ms for anti-PD-1 Ab, p=0.45), or the extent of cardiac fibrosis (1.4% of ventricular cross-sectional area for IC vs 1.7% for anti-PD-1 Ab, p=0.41). Conclusion: Collectively, these data do not implicate PD-1 as an important regulator of intracardiac immune responses in the injury models tested. This suggests that additional pathways may contribute to myocarditis occurring in cancer patients treated with anti-PD-1 Ab, the identification of which could provide insight into immune mechanisms active in heart failure.