Class Of Immune Checkpoint Inhibitors Research Articles

7699 Unanticipated Harmony: PD-L1 Inhibitor Treatment for Urothelial Cancer Resolving Graves' Disease in a Patient - A Case of Immune Modulation Surprises

Abstract Disclosure: K. Tiwari: None. C.A. Resta: None. Introduction: Programmed death ligand 1(PD-L1) inhibitors constitute a class of immune checkpoint inhibitors (ICI) employed in treating various cancers. Thyroid-related immune-related adverse events (irAEs), such as hypothyroidism, are found to be in 3.9% of patients with PD L1 treatments. This case explores a unique scenario where a patient with pre-existing Graves' disease, undergoing PD-L1 inhibitor therapy for cancer, experienced an unexpected sequence of events leading to the default treatment of Graves' disease and subsequent progression to hypothyroidism. Case Presentation: A 59-year-old male, who had been effectively managed on methimazole for Graves' disease over two years and had chosen not to pursue definitive therapy for the condition, presented with tremors and a bilaterally enlarged thyroid gland during treatment for urothelial carcinoma. Laboratory findings included a TSH of 0.03 mIU/L (nl 0.40-4.50 mIU/L), fT4 of 3.4 ng/dL (nl 0.8-1.8 ng/dl), and tT3 of 284ng/dl (nl 76-181 ng/dl). The patient had recently started treatment with Avelumab, a PD-L1 inhibitor, as maintenance therapy following 4 cycles of gemcitabine/cisplatin cycles. Concerned about worsening Graves' disease, the methimazole dose was increased, and follow-up labs were performed after three weeks. These results showed low-normal fT4 of 0.8 ng/dL, TSH of 1.01 mIU/L(N), and low T3 of 58 ng/dL. TSI was mildly elevated at 168%. Due to rapidly changing thyroid function tests and suspicion of thyroiditis, methimazole was stopped. A PET scan a week later indicated diffuse thyroid uptake consistent with thyroiditis. Repeat labs 10 days later revealed a TSH of 67.36 mIU/L(H) and fT4 of 0.4 ng/dL(L), indicative of overt primary hypothyroidism. The patient exhibited symptoms including fatigue, constipation, and cold intolerance. The patient was initiated on levothyroxine therapy to address overt primary hypothyroidism, likely secondary to destructive thyroiditis from ICI. Discussion: Thyroid irAEs are typically incidentally discovered during routine monitoring of ICI treatment. It includes thyrotoxicosis, subclinical hypothyroidism, and overt hypothyroidism. These events commonly occur in patients lacking pre-existing thyroid conditions. In contrast, our patient, with a history of Graves' disease, experienced resolution of Graves' disease following treatment with PD-L1 inhibitor use with subsequent progression to hypothyroidism. Conclusion: This case emphasizes the importance of recognizing atypical presentations of thyroid irAEs in individuals with pre-existing thyroid disorders undergoing ICI treatment. Presentation: 6/3/2024

Perioperative immunotherapy in nonsmall cell lung cancer.

To evaluate and summarize the current clinical efficacy, safety, treatment patterns, and potential biomarkers, to guide future treatment strategies for nonsmall cell lung cancer (NSCLC), improve patient prognosis, and provide a scientific basis for personalized therapy. In recent years, the class of immune checkpoint inhibitors (ICIs), with programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors at the helm, has catalyzed groundbreaking advancements within the perioperative treatment milieu for NSCLC. With the positive results of several phase III clinical trials, perioperative immunotherapy has been confirmed to significantly reduce the risk of postoperative recurrence in resectable NSCLC, becoming the new standard for perioperative treatment of stages II to III NSCLC. With the advent of the perioperative immunotherapy era, clinical issues such as the selection of the treatment population, the choice of regimen, the duration of treatment, whether patients with pCR need further adjuvant therapy, and the comprehensive management of patients throughout the perioperative period have attracted widespread attention. The perioperative treatment of NSCLC has fully entered the era of immunotherapy. Multiple clinical studies have confirmed that perioperative immunotherapy can significantly improve the survival benefit of resectable stages II to III NSCLC, establishing a new standard for the perioperative treatment of stages II to III NSCLC.

The abscopal effect: mechanism of occurrence and prospects of using it in therapy of metastatic cancer

The abscopal effect in oncology has been known for 70 years, but until recently its clinical significance was rather low. The development of immune response checkpoint inhibitors has led to an active study of this phenomenon. There is now evidence of improved survival among patients, in whom the abscopal effect has been documented, opening new perspectives for the treatment of cancers at different stages. This review presents data on the mechanisms of the abscopal effect, experimental and clinical data, current limitations and possible perspectives. The aim of the study was to investigate the current concept of the abscopal effect occurrence and to evaluate the prospects of using the abscopal effect in therapy of metastatic cancer. Material and Methods. We searched publications in Pubmed system from 2010 to 2023. Of 286 publications, 72 were used for writing the review. Results. In the era of widespread use of immune checkpoint inhibitors (ICIs) for cancer therapy, the abscopal effect appears to be an effective therapeutic approach with broad prospects of application in the treatment of patients with metastatic cancer. Conclusion. The incidence of the abscopal effect has increased with the advent of immune therapy, and the use of ICIs with radiation therapy (RT) has shown improved survival even in patients with advanced disease. More research is needed to establish standardized treatment protocols, including the optimal dose and timing of RT, as well as the efficacy and safety of combination therapy with different classes of ICIs. Further search for clinical and laboratory abscopal effect predictors, which could allow personalized treatment approaches, is required.

The Role of Anti-PD 1 (Programmed Cell Death-1) (Pembrolizumab) in Hepatocellular Carcinoma: A Narrative Literature Review

Hepatocellular carcinoma (HCC) is a malignant tumor originating from liver cells, HCC occurs in around 85% of patients diagnosed with cirrhosis. Treatment options for HCC consider liver function, extrahepatic spread, invasiveness, and the number and size of nodules. HCC therapy options include surgical resection, liver transplantation, tumor ablation, transarterial therapy and systemic chemotherapy. Pembrolizumab is a second-line systemic therapy option for the treatment of HCC after sorafenib therapy. Pembrolizumab is a class of immune checkpoint inhibitors (ICIs) and more specifically works as a programmed cell death-1 (PD-1) inhibitor.

Immune checkpoint monoclonal antibody-related adverse effects in neuro-ophthalmology.

Immunotherapy has renovated the field of oncology. Usually, cancer is treated by surgery, chemotherapy, and radiation. Immunotherapy is a promising treatment that harnesses the patient's own immune system to target cancer. Immune checkpoint inhibitors (ICIs) have proven to be a promising treatment avenue for managing cancer; however, their use had been associated with a unique spectrum of adverse side effects called immune-related adverse events (irAEs). As ICIs become increasingly relevant in cancer management, it is crucial to address these irAEs affecting various systems in the body, including the skin, liver, gastrointestinal tract, endocrine system, and the eye. Ocular toxicity and sight-threatening events are among the reported irAEs, impacting diverse ocular tissues. The most commonly reported ocular irAEs (OirAEs) are blurred vision, conjunctivitis, ocular surface disease uveitis, scleritis, and retinopathy. Nevertheless, the frequency and severity of these OirAEs can vary, even within the same class of ICIs. Thus, OirAEs can significantly impact the quality of life and patient compliance. Therefore, we aim to comprehensively analyze uncommon and severe ICI-related OirAEs associated with lung cancer by providing a comprehensive and updated review of immune checkpoint monoclonal antibody-related adverse effects in neuro-ophthalmology irAEs. Through a review of the relevant literature, we intend to illustrate the epidemiology, clinical characteristics, contributory factors, diagnosis, and management of ICI-associated ocular side effects. We will also discuss guidelines and best practice strategies for the prevention, monitoring, and management of these OirAEs.

Efficacy and safety of nurulimab+prolgolimab with continued prolgolimab therapy compared to prolgolimab alone as first-line therapy in patients with unresectable or metastatic melanoma: final results of the phase II OBERTON clinical study

Background. In an era of breakthroughs in cancer immunotherapy, CheckMate 067 studies declared the combination of PD-1 and CTLA-4 inhibitors a new standard of care for patients with metastatic melanoma (MM). A significant limitation of the widespread use of the combination of ipilimumab and nivolumab in routine clinical practice is the high risk of severe immune-mediated adverse events. Prolgolimab and nurulimab are a combination of fixed doses of original monoclonal antibodies (manufactured by JSC "BIOCAD," Russia) to the PD-1 receptor (prolgolimab) and the CTLA-4 receptor (nurulimab) (3:1 ratio). This paper presents the results of an international, multicenter, double-blind, placebo-controlled, comparative, randomized, phase II OBERTON clinical study to investigate the efficacy and safety of nurulimab + prolgolimab combination therapy with continued prolgolimab therapy compared to prolgolimab alone as first-line therapy in patients with unresectable melanoma (uRM) or MM (NCT03913923).
 Materials and methods. The study included patients with uRM or MM who were not previously treated for metastatic disease. The patients were randomized into two groups (1:1). Patients in group 1 were treated with a nurulimab (1 mg/kg) and prolgolimab (3 mg/kg) combination at a dose of 0.2 mL/kg (equivalent to 1 mg/kg of nurulimab and 3 mg/kg of prolgolimab) once every 3 weeks during the first 4 blinded infusions. Patients in group 2 received prolgolimab monotherapy at a dose of 3 mg/kg once every 3 weeks during the first 4 blinded infusions. Starting from infusion 5, patients in both groups received open prolgolimab 1 mg/kg once every 2 weeks. The primary endpoint of the study was progression-free survival (PFS). The study is registered on ClinicalTrials.gov under the number NCT05732805 and is currently ongoing, but recruitment of new patients has been completed.
 Results. One hundred seventeen patients were randomized and received at least one dose of the study therapy. At a median follow-up of 16.79 months, the median PFS was 12.2 (4.9; not achieved) months in the nurulimab + prolgolimab group and 2.8 (1.5; 4.7) months in the prolgolimab monotherapy group (95% confidence interval 0.36-0.90, hazard ratio 0.57). PFS at 24 months was 41% in the nurulimab + prolgolimab group and 25.4% in the prolgolimab monotherapy group. In both groups, the therapy was well tolerated. Grade 3-4 immune-mediated adverse events were reported in 15.5% of patients who received nurulimab + prolgolimab, compared with 1.7% of those who received prolgolimab alone. The most frequent grade 3-4 treatment-related adverse events in both treatment groups were increased alanine aminotransferase and aspartate aminotransferase and asthenia. Overall, the safety profile was favorable, as expected for the class of immune checkpoint inhibitors, anti-CTLA-4, and anti-PD-1 monoclonal antibodies.
 Discussion. The results demonstrate a favorable safety profile in both the nurulimab + prolgolimab combination and prolgolimab monotherapy groups as the first-line treatment for uRM or MM. The assessment of the primary endpoint, PFS, showed the benefit of combination immunotherapy followed by switching to prolgolimab compared to prolgolimab alone.
 Conclusion. Combination immunotherapy with the CTLA-4 inhibitor nurulimab and the PD-1 inhibitor prolgolimab, available as a combination of solutions of two drugs in a single vial, with a further switch to monotherapy with prolgolimab, can fill an important niche in the treatment of patients with uRM or MM. Confirmation of the obtained data on the efficacy and safety of the combined regimen of nurulimab + prolgolimab in comparison with PD-1 inhibitor monotherapy is expected from the ongoing phase III BCD-217-2 OCTAVA study (NCT05732805).

Lack of Efficacy of Immune Checkpoint Inhibitors in Cancer Patients Older Than 75?

This research was designed to compare the efficacy of immune checkpoint inhibitors (ICIs) in cancer patients among different age groups. Electronic databases were searched to identify relevant trials. Randomized-controlled trials (RCTs) with ICIs and RCTs that conducted subgroup analysis of overall survival (OS) and/or progression-free survival (PFS) based on age were included. Summary hazard ratio (HR) and 95% confidence interval (CI) were available. Totally, 35,777 individuals from 59 RCTs were recruited. ICIs can ameliorate OS and PFS of cancer patients in groups of below 65 year and 65-75 years. Conversely, patients in group of 75 years or above failed to acquire benefit from ICIs for both OS (HR=0.99, 95% CI: 0.91-1.09, P =0.8767) and PFS (HR=0.96, 95% CI: 0.82-1.11, P =0.5694). Subgroup analysis was performed based on class of ICIs, type of ICIs, type of cancer, line of treatment, blind method, and type of nonsmall-cell lung cancer. In all subgroups, OS and PFS were not significantly improved in patients 75 years or above. Cancer patients older than 75 years failed to acquire remarkable benefit from ICIs for both OS and PFS.

Immune Checkpoint Inhibitors and Venous Thromboembolism: An Analysis of the WHO Pharmacovigilance Database.

Data on venous thromboembolic events (VTEs) in patients receiving immune checkpoint inhibitors (ICIs) are scarce and conflicting. This study investigated the risk of reporting VTEs associated with ICIs in comparison with all other anticancer drugs. The World Health Organization pharmacovigilance database (VigiBase), comprising >30 million individual case safety reports, was queried. All reports on patients with cancer, involving at least one anticancer drug as a suspect or interacting drug and registered from January 1, 2008, to May 31, 2021, were included. The association between ICIs and the risk of reporting VTEs was estimated using the reporting odds ratio (ROR) as a measure of disproportionality with all other anticancer drugs as comparators. RORs were estimated as crude and adjusted RORs for age, sex, and other medications (excluding anticancer drugs) associated with risk of VTEs. Among 1,196 patients experiencing VTEs after ICI treatment, the median age was 65years and 57.6% were men. Anti-PD-1 agents (62.5%) were the most frequently reported. ICIs were not associated with higher reporting of VTEs when compared with other anticancer drugs (crude ROR 0.63, 95% confidence interval (CI) 0.60 to 0.67 and adjusted ROR 0.70, 95% CI 0.65-0.74). No signal of disproportionate reporting was found when considering each class of ICIs. In conclusion, ICIs were not associated with higher reporting of VTEs, in comparison with all other anticancer drugs in a large-scale pharmacovigilance database. Owing to the limitations inherent to pharmacovigilance studies, prospective studies, including an adequate comparison group, are needed to assess the risk of VTEs in ICI-treated patients.

Adverse Cardiovascular Complications following prescription of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors: a propensity-score matched Cohort Study with competing risk analysis

BackgroundProgrammed death-1 (PD-1) and programmed death- ligand 1 (PD-L1) inhibitors, such as pembrolizumab, nivolumab and atezolizumab, are major classes of immune checkpoint inhibitors that are increasingly used for cancer treatment. However, their use is associated with adverse cardiovascular events. We examined the incidence of new-onset cardiac complications in patients receiving PD-1 or PD-L1 inhibitors.MethodsPatients receiving PD-1 or PD-L1 inhibitors since their launch up to 31st December 2019 at publicly funded hospitals of Hong Kong, China, without pre-existing cardiac complications were included. The primary outcome was a composite of incident heart failure, acute myocardial infarction, atrial fibrillation, or atrial flutter with the last follow-up date of 31st December 2020. Propensity score matching between PD-L1 inhibitor use and PD-1 inhibitor use with a 1:2 ratio for patient demographics, past comorbidities and non-PD-1/PD-L1 medications was performed with nearest neighbour search strategy (0.1 caliper). Univariable and multivariable Cox regression analysis models were conducted. Competing risks models and multiple propensity matching approaches were considered for sensitivity analysis.ResultsA total of 1959 patients were included. Over a median follow-up of 247 days (interquartile range [IQR]: 72-506), 320 (incidence rate [IR]: 16.31%) patients met the primary outcome after PD-1/PD-L1 treatment: 244 (IR: 12.57%) with heart failure, 38 (IR: 1.93%) with acute myocardial infarction, 54 (IR: 2.75%) with atrial fibrillation, 6 (IR: 0.31%) with atrial flutter. Compared with PD-1 inhibitor treatment, PD-L1 inhibitor treatment was significantly associated with lower risks of the composite outcome both before (hazard ratio [HR]: 0.32, 95% CI: [0.18-0.59], P value=0.0002) and after matching (HR: 0.34, 95% CI: [0.18-0.65], P value=0.001), and lower all-cause mortality risks before matching (HR: 0.77, 95% CI: [0.64-0.93], P value=0.0078) and after matching (HR: 0.80, 95% CI: [0.65-1.00], P value=0.0463). Patients who developed cardiac complications had shorter average readmission intervals and a higher number of hospitalizations after treatment with PD-1/PD-L1 inhibitors in both the unmatched and matched cohorts (P value<0.0001). Multivariable Cox regression models, competing risk analysis with cause-specific and subdistribution hazard models, and multiple propensity approaches confirmed these observations.ConclusionsCompared with PD-1 treatment, PD-L1 treatment was significantly associated with lower risk of new onset cardiac complications and all-cause mortality both before and after propensity score matching.

Endocrinopathies Associated with Immune Checkpoint Inhibitors

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that increase the efficiency of the immune system in the destruction of neoplastic cells. In recent years, these drugs have been increasingly used in the treatment of many neoplasms in advanced stages. However, the change in the regulation of the immune system induced by these drugs has the potential adverse effect of inducing autoimmunity in practically all organ systems. Endocrinopathies are one of the most common autoimmune adverse eventsof these drugs. Non-systematic review of endocrinopathies reported in the context of treatment with ICIs. A search was carried out on PubMed until January 31st, 2020, and articles were selected based on their relevance and excluded in case of redundant content. The following search terms were used: "immune checkpoint inhibitor" and "endocrinopathy" / "endocrine system diseases" / "pituitary" / "thyroid" / "diabetes" / "adrenal" / "parathyroid". Endocrinopathies with all classes of ICIs (anti-CTLA-4, anti-PD-1, anti-PD-L1) have been reported. Thyroid dysfunction is the most frequently reported endocrinopathy, mainly with anti-PD-1 and anti-PD-L1. Hypophysitis is the most prevalent with anti-CTLA-4. The incidence of autoimmune diabetes in this context is increasing, mainly with anti-PD-1 and anti-PD-L1. Rare cases of primary adrenal insufficiency, Graves' disease and primary hypoparathyroidism have also been reported. Knowing the spectrum of endocrinopathies triggered by ICI, as well as their clinical features, diagnosis and treatment criteria is essential, given its high prevalence and the increasing number of cancer patients treated with these new drugs.

Programmed Cell Death 1 (PD-1) and Programmed Cell Death Ligand 1 (PD-L1) inhibitors and adverse cardiovascular events: a population-based study

Abstract Funding Acknowledgements Type of funding sources: None. OnBehalf Cardiovascular Analytics Group Background Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors are major classes of immune checkpoint inhibitors that are increasingly used for cancer treatment. However, they are associated with adverse cardiovascular events. Purpose To evaluate the cardiotoxicity of PD-1 and PD-L1 inhibitors, the present study aims to examine the incidence of new-onset cardiac complications in patients receiving PD-1 or PD-L1 inhibitors. Methods Patients receiving PD-1 or PD-L1 inhibitors since their launch up to December 31st, 2019 without pre-existing cardiac complications were included. Patient data were obtained using a territory-wide electronic health record database. The primary outcome was a composite of incident heart failure (HF), acute myocardial infarction (AMI), atrial fibrillation (AF) or atrial flutter followed up to August 31st, 2020. Propensity score matching between PD-L1 and PD-1 inhibitor use with a 1:1 ratio for patient demographics and comorbidities was performed. Results A total of 1925 patients were included. Over a median follow-up of 136 days (interquartile range [IQR]: 42-279), 318 (16.51%) patients met the primary outcome after PD-1/PD-L1 treatment: 242 (incidence rate [IR]: 12.57%) with HF, 38 (IR: 1.97%) with AMI, 53 (IR: 2.75%) with AF, 6 (IR: 0.31%) with atrial flutter. Compared with PD-1 inhibitor treatment, PD-L1 inhibitor treatment was significantly associated with a lower risk of composite outcome after matching (HR: 0.78, 95% CI: [0.62-0.99], P value = 0.0417). Patients who developed cardiovascular complications had shorter average readmission intervals and more hospitalization episodes after treatment with PD-1/PD-L1 inhibitors both before and after matching (P value &amp;lt; 0.0001). Conclusions Compared with PD-1 inhibitor users, PD-L1 inhibitor users had a significantly lower risk of new-onset composite cardiovascular complications. Abstract Figure. Kaplan-Meier survival curve

Prospects for the use of small interfering RNAs as inhibitors of immune checkpoints for immunotherapy in oncology

Immune therapy is one of the most promising areas of cancer treatment. It is aimed at a cascade of processes responsible for the antitumor immune response. The involved regulatory mechanisms become targets for various therapeutic approaches aimed at restoring the impaired functions of immune cells that eliminate cancer cells. The ability of malignant cells to affect receptors of immune checkpoints is one of the most important mechanisms for suppressing antitumor immunity. The development of immune check-point inhibitors (ICIs) based on monoclonal antibodies, as well as the methods of adoptive cell therapy (ACT), are a breakthrough in the immunotherapy of malignant diseases, but it carries a number of limitations such as insufficient efficiency, safety and cost-effectiveness. The use of RNA interference technologies opens up prospects for the development of fundamentally new class of ICIs and, as a consequence, the development of more efficient ACT methods. This review presents the main problems and prospects of the use of small interfering RNA (siRNA) as the ICIs are highlighted in order to optimize modern AKT approaches

MO221ONLY A SIMPLE CASE OF AKI IN AN ONCOLOGIC PATIENT?

Abstract Background Nivolumab is a drug belonging to the class of Immune Checkpoint Inhibitors (ICPI), the use of which has improved the prognosis for patients with various advanced malignancies. These agents are associated with several "immune-mediated" adverse effects, although the literature on Nivolumab renal toxicity is poor and anecdotal. A rare immune-mediated renal adverse event is acute interstitial nephritis (AIN) that often imposes Nivolumab suspension. Case report We present the case of a 75-year-old woman with stage IV melanoma (inguinal and external iliac lymph node metastases without localization of the primitive lesion). At diagnosis, renal function was normal by age (Creatinine 0.89 mg/dl; CKD EPI eGFR 71 ml/min/1.73 m2). After lymphadenectomy, an adjuvant treatment with Nivolumab was initiated. At 4-month follow-up, the patient was hospitalized for AKI (creatinine 2.6 mg/dl; eGFR 17,3 ml/min/1.73 m2). Although, renal function decline was not accompanied by signs of systemic immunoactivation, Nivolumab was suspended. In the following weeks, only a partial renal function recovery was observed, still limiting immunotherapy reintroduction. Thus, the patient was referred to our Onconephrology Outpatient Unit for a multidisciplinary approach. We performed a urinalysis with microscopy study of the sediment and observed rare dysmorphic red blood cells and leukocytes. To exclude a glomerulopathy, a comprehensive screening for autoimmune diseases and 24 hours proteinuria were also measured and found not significant (Table 1). Renal ultrasound did not show any relevant alteration. Based on our original suspicion of AIN, although in absence of an history of fever, rush or eosinophilia, we introduced Prednisone 25 mg/day. In the following weeks, blood and urine tests showed a significant improvement in renal function (serum creatinine 1.06 mg/dL, eGFR CKD-EPI 51 mL/min/1.73m2) and the absence of red blood cells, leukocytes and proteinuria in the urinalysis. Based on nephrologist advice, the patient was then able to resume the cancer treatment with a maintenance dose of prednisone equal to 5 mg/day. Conclusion AIN is a rare adverse effect of ICPIs that mandates the close monitoring of renal function in patients under immunotherapy with these agents. AKI occurrence in patients treated with ICPIs should always lead to investigate a possible AIN, even in the absence of the classic symptom set of fever, rush and eosinophilia and with minimal changes in urinalysis. Based on our single observation, and after an accurate literature review, we suggest the initiation of a corticosteroid treatment in oncologic patients on an ICPI complicated with AKI and with suspicion of AIN at urinalysis. Moreover, this case report thickens the importance of a multidisciplinary approach to oncologic patients not only when a conventional nephrotoxic chemotherapy has to be started, but also in case of ICIPs use. The nephrologist advice, in fact, could be useful in both preventing and treating severe renal complications such as AIN, also allowing the oncologic therapy maintenance.

Incidence and Phenotypes of Endocrinopathies in Association With Immune Checkpoint Inhibitors: The Experience of Integrated Health Network

Introduction: Since 2011 FDA has approved several immune checkpoint inhibitors (ICI) as antineoplastic agents with very promising results. The side effects profile of ICI is different from that of conventional cancer therapies and predominated by immune-related adverse effects (IRAEs). Autoimmune endocrinopathies (AEs), such as disorders of the thyroid, pituitary, and adrenal glands are increasingly recognized IRAEs of ICI. If not diagnosed and treated early, AEs may cause serious harm in an already compromised patient by advanced malignancy. Therefore, it is necessary to recognize the incidence, phenotypes, and time to onset of various AEs in association with ICI. This retrospective study of a large cancer population treated at an integrated health network aims to do so. Methods: We conducted a retrospective chart review of adult patients treated with ICI as cancer therapy at Allegheny Health Network—a major healthcare provider in Western Pennsylvania—between 1/1/2016 and 6/30/2019. Inclusion criteria were ages 18-90 years who received one or more ICI within the study period, laboratory data available for a minimum of 6 months from date of the first ICI dose, and no pre-existing outcome of interest at the time of, or prior to, receiving the first ICI dose. Exclusion criteria were pre-existing thyroid, pituitary, or adrenal diseases. Results: We screened the records of 1200 patients who were treated for 47 different cancers for AEs. Of this sample, 57% were males 92.5% were White. Follow up period ranged between 6-57 months, during which 56% of patient died at a mean age of 67.1 years. The most common cancer diagnoses were non-small cell lung cancer (45.4%), malignant melanoma (11.7%), renal cell carcinoma (6.3%), and small cell lung cancer (6.2%). These patients received one or more agents from the three classes of ICI, including PD-1 (75.86%), PDL-1 (12.57%), and CTLA-4 (11.57%). The overall incidence of AEs was 18%. The distribution of AEs was as follows: primary hypothyroidism 15.3%, secondary hypothyroidism 0.5%, primary hyperthyroidism 3.5%, primary adrenal insufficiency 0.2%, secondary adrenal insufficiency 2.7%, and type 1 diabetes mellitus 0.2%. Of the 42 patients diagnosed with hyperthyroidism, 28 (66.7%) later developed primary hypothyroidism within a mean time of 9 weeks. There was no statistically significant association between the incidence of AEs and gender (P=0.748) or age (P=0.998). Conclusion: AEs are common sequelae of ICI and primary hypothyroidism is the most prevalent AEs among our study sample. This study should help increase awareness about the importance of routine screening of the AEs in cancer patients receiving ICI.

Future of immune checkpoint inhibitors: focus on tumor immune microenvironment.

Immunotherapy has become a powerful clinical strategy in cancer treatment. Immune checkpoint inhibitors (ICIs) have opened a new era for cancer immunotherapy. Nowadays, the number of immunotherapy drug approvals has increased, with numerous treatment options in clinical and preclinical development. However, there remain some obstacles to improve the efficacy of ICIs further. The tumor immune microenvironment (TIME) consists of cancer cell, immune cells and cytokines, et cetera. The dynamics of TIME determine the efficacies of ICIs. Although the ICIs showed manageable toxicity, immune-related adverse effects (irAEs) are still unignorable for clinicians. Since some primary resistance mechanisms exist in TIME, ICIs can only show effects in individual cancer patients. Even for the patients who responded, acquired resistance will occur to neutralize the effect of ICIs. Understanding how to increase the response rates and overcome the resistance to various classes of ICIs is the key to improving clinical efficacy. Besides the novel ICIs in development, there are some approaches to establish combination therapies are underway to improve further the efficacies of ICIs in treating cancer patients. Here, we describe the complicated TIME and state quo of ICIs to prospect the future of ICIs in cancer treatment.

Incidence and Clinical Features of Immune-Related Acute Kidney Injury in Patients Receiving Programmed Cell Death Ligand-1 Inhibitors

BackgroundProgrammed cell death receptor ligand 1 (PD-L1) inhibitors are immune checkpoint inhibitors (ICIs) with a side effect profile that may differ from other classes of ICIs such as those directed against cytotoxic T-lymphocyte−associated protein 4 (CTLA-4) and programmed cell death 1 receptor (PD-1). Being the more recently approved class of checkpoint inhibitors, there are no studies investigating the frequency, etiology and predictors of acute kidney injury (AKI) in patients receiving PD-L1 inhibitors.MethodsThis was a retrospective cohort study of patients who received PD-L1 inhibitors during 2017 to 2018 in our healthcare system. AKI was defined by a ≥1.5-fold rise in serum creatinine from baseline. The etiology of all cases of sustained AKI (lasting >48 hours) and clinical course were determined by review of electronic health records.ResultsThe final analysis included 599 patients. Within 12 months of ICI initiation, 104 patients (17%) experienced AKI, and 36 (6%) experienced sustained AKI; however, only 5 (<1%) experienced suspected PD-L1–related AKI. The PD-L1–related AKI occurred a median of 99 days after starting therapy. All patients concurrently received another medication known to cause acute interstitial nephritis (proton pump inhibitors, nonsteroidal anti-inflammatory drugs, or antibiotics) at the time of the suspected PDL1-related AKI.ConclusionAlthough AKI is common in patients receiving PD-L1 therapy, the incidence of suspected PD-L1–related AKI is low (<1%) and may be less common when compared to other classes of ICIs. This cohort provides further validation that other drugs associated with acute interstitial nephritis may be involved in the pathogenesis of ICI-related AKI.

SUN-183 Adrenalitis Induced by Nivolumab

Introduction: Tumor cells often express a programmed death-ligand 1 (PD-L1), which binds to the programmed death receptor-1 (PD-1) on activated T-cells to induce immune tolerance. Among the class of immune checkpoint inhibitors (ICI), Nivolumab is an anti-PD-1 antibody which blocks these tumor cell interactions. Although some endocrinopathies have been reported for other PD-1 inhibitors, the adverse event of adrenalitis with nivolumab has not been reported before. Clinical Case: A 65-year-old female presented to the hospital with complaints of nausea, vomiting, fatigue, and headache for five days. She was recently diagnosed with metastatic lung adenocarcinoma, complicated by cerebellar metastases, and the left cerebellar mass was resected. She was also started on Nivolumab. Her blood pressure was 98/65 mmHg on the presentation. Serum sodium was 122mEq/L (normal 135–145) and potassium was 5mEq/L (3.5–5). TSH, LH, and prolactin were all normal. Aldosterone was low: 23pmol/L (27.7–582.5) and renin was high: 11 ng/ml/h (0.167- 1.38). Morning cortisol levels were low: 2.2 ug/dl (5- 25) and concomitant ACTH was high: 78 pg/ml (7.2- 63.3). Upon standard high dose cosyntropin stimulation test, basal cortisol was 2.0 ug/dl (5- 25). Cortisol level 30 minutes post cosyntropin was 7.1 ug/dl, while Cortisol 60 minutes post cosyntropin was 12.2 ug/dl (normal >18 -20 ug/dl). Considering the low cortisol levels with high ACTH, and an inadequate rise in cortisol after the ACTH stimulation test, adrenal insufficiency was suspected as a result of adrenalitis due to Nivolumab. Hyponatremia along with low aldosterone and high renin levels also reinforced this clinical diagnosis. A computerized tomographic scan of the chest abdomen and pelvis only showed calcified uterine fibroids. She was initially resuscitated with intravenous fluids. Hydrocortisone 100 mg every 8 hours was started and then gradually tapered down to 60mg every 12 hours. Fludrocortisone was also initiated at 0.2mg daily. Symptoms began to improve, and sodium levels normalized to136 mEq/dl. She was discharged on 30mg of hydrocortisone and 0.1 mg of fludrocortisone daily and is stable since then. Conclusion: This is a rare case of Nivolumab-induced adrenalitis. It highlights the importance of checking for adrenal insufficiency in a patient who presents with symptoms of hypotension and hyponatremia while being on ICI drugs, as unidentified adrenal insufficiency and adrenal crisis can be fatal.

Are immune-related adverse events associated with the efficacy of immune checkpoint inhibitors in patients with cancer? A systematic review and meta-analysis

BackgroundA number of studies have reported an association between the occurrence of immune-related adverse events (irAEs) and clinical efficacy in patients undergoing treatment with immune checkpoint inhibitors (ICIs), but the results remain controversial.MethodsUnder the guidance of a predefined protocol and Preferred Reporting Items for Systematic Reviews and Meta-analyses statement, this meta-analysis included cohort studies investigating the association of irAEs and efficacy of ICIs in patients with cancer. The primary outcome was overall survival (OS), and the secondary outcome was progression-free survival (PFS). Subgroup analyses involving the cancer type, class of ICIs, combination therapy, sample size, model, landmark analysis, and approach used to extract the data were performed. Specific analyses of the type and grade of irAEs were also performed.ResultsThis meta-analysis included 30 studies including 4971 individuals. Patients with cancer who developed irAEs experienced both an OS benefit and a PFS benefit from ICI therapy compared to patients who did not develop irAEs (OS: hazard ratio (HR), 0.54, 95% confidence interval (CI), 0.45–0.65; p < 0.001; PFS: HR, 0.52, 95% CI, 0.44–0.61, p < 0.001). Subgroup analyses of the study quality characteristics and cancer types recapitulated these findings. Specific analyses of endocrine irAEs (OS: HR, 0.52, 95% CI, 0.44–0.62, p < 0.001), dermatological irAEs (OS: HR, 0.45, 95% CI, 0.35–0.59, p < 0.001), and low-grade irAEs (OS: HR, 0.57, 95% CI, 0.43–0.75; p < 0.001) yielded similar results. The association between irAE development and a favorable benefit on survival was significant in patients with cancer who were undergoing treatment with programmed cell death-1 inhibitors (OS: HR, 0.51, 95% CI, 0.42–0.62; p < 0.001), but not cytotoxic T-lymphocyte antigen-4 inhibitors (OS: HR, 0.89, 95% CI, 0.49–1.61; p = 0.706). Additionally, the association was significant in patients with cancer who were treated with ICIs as a monotherapy (OS: HR, 0.53, 95% CI, 0.43–0.65; p < 0.001), but not as a combination therapy (OS: HR, 0.62, 95% CI, 0.36–1.05; p = 0.073).ConclusionsThe occurrence of irAEs was significantly associated with a better ICI efficacy in patients with cancer, particularly endocrine, dermatological, and low-grade irAEs. Further large-scale prospective studies are warranted to validate our findings.Systematic review registrationPROSPERO CRD42019129310.

Immune Response Checkpoint Inhibitors: New Risks of a New Class of Antitumor Agents

The introduction into clinical practice of immune checkpoint inhibitors that block cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed cell death ligand-1 (PD-L1), has improved the prognosis of patients with malignant neoplasms of diff erent localisation. The antitumour eff ect of immune checkpoint inhibitors is based on blocking CTLA-4 and PD-1/PD-L1 signaling pathways and enhancing lymphocyte antitumour activity. However, inhibition of immune checkpoints may lead to dysregulation of immune responses and appearance of a new type of adverse reactions resulting from changes in the activity of immunocompetent cells. The aim of the study was to analyse adverse reactions associated with the use of immune checkpoint inhibitors. It was demonstrated that the structure of immune-mediated adverse reactions varied depending on the class of immune checkpoint inhibitors. The incidence of immune-mediated adverse reactions was higher with CTLA-4 inhibitors as compared with PD-1/PD-L1 inhibitors, and increased signifi cantly in the case of combination therapy. The treatment with CTLA-4 inhibitors most often resulted in skin reactions (rash, itching), gastrointestinal tract reactions (diarrhea, colitis), and endocrine gland problems (hypophysitis). The treatment with PD-1 inhibitors most often led to respiratory disorders (pneumonitis), and in some cases to gastrointestinal disorders (diarrhea, colitis), skin reactions (rash, itching), and endocrine gland problems (hypothyroidism), but they were less common. The treatment with PD-L1 inhibitors was associated with the development of pneumonitis. The development of immune-mediated adverse reactions may require discontinuation of treatment and administration of immunosuppressants, therefore early diagnosis and timely treatment of complications are important prerequisites for successful antitumour therapy. Further study of the mechanisms of immune-mediated adverse reaction development will optimise antitumour therapy with immune checkpoint inhibitors.

Incidence and characteristics of neurotoxicity in immune checkpoint inhibitors with focus on neuromuscular events: Experience beyond the clinical trials.

Immune checkpoint inhibitors (ICIs) are associated with various neurological adverse events (NAEs). We herein explored the incidence and clinical phenotype of immune-related NAEs in cancer patients. Medical records of ICI-treated cancer patients were reviewed between the years 2010 and 2018, with an aim to characterize immuno-related NAEs. A total of 1185 ICIs-treated patients were identified, 63.7% of which were males and 36.3% were females, with a mean age of 63.4 ± 7.3 years. Twenty-four from the overall ICIs-treated patients (2%) developed NAEs. No differences were identified in terms of age, sex, tumor type and class of ICIs between the patients who developed NAEs and those who did not. The median number of cycles of ICI treatment before NAEs onset were 4.5 (1-10), and the median time was 102 days. Peripheral nervous system (PNS) involvement was present in 14 patients (58.4%) and central nervous system (CNS) involvement in 10 (33.3%), including 2 patients with aseptic meningitis and polyradicular involvement. Amongst PNS complications, there were five (20.8%) with axonal sensory neuropathies, four (16.7%) with Guillain-Barre-like syndromes, and four (16.7%) with myositis and/or myasthenic syndromes. The majority of patients with PNS-related NAEs (n = 11; 78.6%) improved after ICIs discontinuation and treatment with immune-modulating therapies. The time to neuromuscular toxicities onset was significantly shorter, compared to CNS NAEs (median 70 vs 119 days, P = .037). Immune-related NAEs mostly present with neuromuscular complications. Discontinuation of ICIs and appropriate treatment should be commenced early throughout the process, in order to maximize a favorable outcome.