CTLA-4 Inhibitors Research Articles

Adverse Myocardial and vascular side effects of Immune Checkpoint Inhibitors: a prospective multimodal cardiovascular assessment (AMICI study)

Abstract Background Immune checkpoint inhibitors (ICIs) are transformative treatments in oncology, yet they are also associated with a range of cardiovascular (CV) events. Purpose To identify the incidence of CV events (including subclinical) in patients receiving ICIs for solid cancer, either alone or in association with other cancer therapies (e.g., chemotherapies, target therapies). Objectives and methods The Adverse Myocardial and vascular side effects of Immune Checkpoint Inhibitors(AMICI) study prospectively assessed the incidence of CV changes by means of a thorough multimodal assessment. This included repeated CV imaging (transthoracic echocardiograms (TTE), cardiac magnetic resonance imaging (CMR)), serum biomarkers (troponin, brain natriuretic peptides in a single laboratory), and ambulatory ECG monitoring, before and during (at 6 weeks and at 6 months) ICI therapy (Figure). Cardiovascular events included myocarditis, pericarditis, acute coronary syndrome, heart failure (HF), high degree conduction abnormalities (defined as new grade 2 or 3 atrioventricular block) or sustained ventricular arrhythmias (defined as 3 or more ventricular beats at a rate ≥ 120/min), CV death as a composite endpoint, validated by an independent expert panel Results Out of 130 solid cancer patients considered for ICI therapy, 49 patients (38 (77.6%) male; mean age 64.3 (­SD 11.0) years old) were included (June 2020 -December 2021). 22 (55.1%) suffered from kidney or bladder cancer; 7 (14.3%) had CV disease prior to cancer diagnosis; 4 (8.2%) received PD1 and CTLA4 inhibitors. Early CV events were observed in 9 (18.4%) patients at mean 40.1 (SD 5.9) days, with heart failure (HF) in 5 (10.2%), ventricular arrhythmias or new conduction disorders in 4 (8.2%) patients. History of AF (HR 4.49 (CI 1.11-18.14), P=0.035) predicted early CV events at 6 weeks (Table). At 6 months follow-up, 18 CV events were observed in 15/49 (31%) patients, with 6 (12.2%) HF events, 5 (10.2%) significant ventricular arrhythmias or conduction disorders and 4 (8.2%) AF. There was a significant decline in LVEF (P<0.001) in patients even in the absence of CV event (P=0.003) or HF (P=0.003). Higher creatinine at inclusion (HR 0.99 [0.98-1.00], P=0.006) predicted HF. Conclusions Cardiovascular complications arising during cancer treatment with ICIs are primarily due to the exacerbation of pre-existing HF or the onset of non-inflammatory heart rhythm disorders. The majority of these CV changes manifest shortly after starting ICIs and do not need hospital admission. Our results suggest that more close follow-up may be needed in patients with underlying CV conditions when starting ICI therapy, by means of CMR and ambulatory ECG holter monitoring.

Combined PD-1 and CTLA-4 Blockade in an International Cohort of Patients with Acral Lentiginous Melanoma.

Combination immune checkpoint blockade targeting PD-1 and CTLA-4 leads to high response rates and improved survival in advanced cutaneous melanoma (CM). Less is known about the efficacy of this combination in acral lentiginous melanoma (ALM). To determine the efficacy of combination immune checkpoint blockade targeting PD-1 and CTLA-4 in a real-world, diverse population of ALM. This multi-institutional retrospective study analyzed patients with histologically confirmed ALM treated with the combination of PD-1 and CTLA-4 inhibitors between 2010-2022. The primary objective of the study was objective response rate (ORR) per RECIST criteria. The secondary objectives were progression-free survival (PFS) and overall survival (OS). In total, 109 patients with advanced ALM treated with combined PD-1 and CTLA-4 blockade in any line of treatment were included. The majority of patients had stage IV disease (n=81, 74.2%). The ORR for the entire cohort was 18.3% (95% CI 11.6-26.9%), with 9 (8.3%) complete responses (CR) and 11 (10.1%) partial responses (PR). An additional 22 patients (20.2%) had stable disease (SD), and the disease control rate (DCR) was 38.5%. The median PFS was 4.2 months [95% CI 3.25-5.62], while the median OS was 17 months [95% CI 12.4%-23.1%]. A total of 95 patients (87.2%) had a treatment-related adverse event, with 40.4% (n=44/109) experiencing at least one grade 3 or 4 toxicity. Elevated LDH (p=.04), 2+ lines of prior therapy (p=.03), and Asian race/ethnicity (p=.04) were associated with worse OS, while Hispanic/Latino race/ethnicity was associated with better OS (p=.02). Combination of PD-1 and CTLA-4 blockade is less effective for ALM, as compared to CM, despite similar toxicity. Asian patients, in particular, appear to derive lower benefit from this regimen. Novel treatment approaches are needed for this rare melanoma subtype.

Histopathological Characteristics and Distinction of Immune Checkpoint Inhibitor-Related Colitis

Abstract Introduction/Objective Immune checkpoint inhibitors (ICPIs) represent a groundbreaking class of cancer immunotherapy for patients with various advanced-stage solid cancers. ICPIs have been associated with immune- related adverse events, with ICPI-related colitis being a prominent concern due to its potential for life-threatening clinical complications. Recognizing the histopathologic characteristics specific to ICPI-related colitis is crucial for pathologists to provide an accurate diagnosis. Here we have collected and analyzed colon biopsies from patients with ICPI-related colitis following treatment of ICPIs to identify its distinctive histopathologic features and differentiate it from other colitis. Methods/Case Report Colon biopsies are collected from patients with ICPI-related colitis after receiving CTLA-4 and PD-L1 inhibitors as treatment for advanced melanoma. Histopathological features, including epithelial mucin depletion, enterocyte apoptosis, basal lymphoplasmacytosis, cryptitis, glandular architectural distortion, and granuloma, are compared with those in other colitis including ulcerative colitis, Crohn’s disease, microscopic colitis, ischemic and infectious colitis. Immunohistochemistry is employed to analyze inflammatory cell populations and specific enterocyte subtypes. Results (if a Case Study enter NA) ICPI-related colitis, following treatment with Ipilimumab and Nivolumab, commonly presents as active colitis, either with or without chronic colitis. Less frequently, it manifests as microscopic colitis, infectious or ischemic colitis. The acute active form of ICPI-related colitis resembles acute colitis in infectious or ischemic colitis; however, prominent enterocyte apoptosis and intraluminal apoptotic debris are relatively unique features to ICPI-related colitis. The chronic active form of ICPI-related colitis resembles inflammatory bowel diseases, particularly Crohn’s disease, but ICPI-related colitis exhibits an inflammatory injury more affecting surface mucosa and less basal lymphoplasmacytosis. Notably, the most distinctive feature of ICPI-related colitis is the depletion of specific mucinous epithelium observed in our cohort. Conclusion Recognizing specific histopathologic features of ICPI-related colitis, such as mucinous epithelial depletion, enterocyte apoptosis, and surface-dominant inflammation, are essential for pathologists in accurately diagnosing and distinguishing this disease to ensure proper clinical management for patients receiving ICPI treatment.

Signal detection of immune thrombocytopenia associated with immune checkpoint inhibitors

Immune checkpoint inhibitors (ICIs) have become an important treatment modality for various malignancies. Due to excessive inflammatory and immune responses, immune-related adverse events (irAEs), such as rash, pruritis, pneumonitis, hepatitis, hypothyroidism, hyperthyroidism and fatigue, can occur. Acquired immune thrombocytopenia is a rare irAE that can lead to severe low platelet counts and hemorrhage. A retrospective observational analysis was conducted on data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS). We searched for all reports recorded in the FAERS covering the period from 2011 Q1 to 2023 Q4 for target agents. Signal analysis was performed using the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN) and multi-item gamma Poisson shrinker (MGPS) algorithm. Nonparametric tests were used to compare the time to onset of thrombocytopenia-associated fractures between different regimens. There were 404 reports of immune thrombocytopenia in the FAERS database. Immune thrombocytopenia was associated with all ICIs except tremelimumab, and signals were detected by all 4 methods. The median time to the onset of immune thrombocytopenia caused by PD-1, PD-L1 and CTLA-4 inhibitors was 47 days (range: 21-139.2), 21 days (range: 13–131) and 9 days (range: 7–27), respectively. The Weibull shape parameter test revealed that pembrolizumab-, durvalumab-, and ipilimumab-induced thrombocytopenia had a random failure-type profile, and nivolumab- and atezolizumab-induced thrombocytopenia were characterized by an early failure-type profile. There was a significant reporting signal of ICI-induced thrombocytopenia associated with most ICIs. Immune thrombocytopenia has a greater incidence in males, elderly individuals and Asian populations, and PD-1 inhibitors were the most common cause. Clinicians should be aware of the signs of potential serious adverse events.

CTLA4 blockade abrogates KEAP1/STK11-related resistance to PD-(L)1 inhibitors.

For patients with advanced non-small-cell lung cancer (NSCLC), dual immune checkpoint blockade (ICB) with CTLA4 inhibitors and PD-1 or PD-L1 inhibitors (hereafter, PD-(L)1 inhibitors) is associated with higher rates of anti-tumour activity and immune-related toxicities, when compared with treatment with PD-(L)1 inhibitors alone. However, there are currently no validated biomarkers to identify which patients willbenefit from dual ICB1,2. Here we show that patients with NSCLC who have mutations in the STK11 and/or KEAP1 tumour suppressor genes derived clinical benefit from dual ICB with the PD-L1 inhibitor durvalumab and the CTLA4 inhibitor tremelimumab, but not from durvalumab alone, when added to chemotherapy in the randomized phase III POSEIDON trial3. Unbiased genetic screens identified loss of both of these tumour suppressor genes as independent drivers of resistance to PD-(L)1 inhibition, and showed that loss of Keap1 was the strongest genomic predictor of dual ICB efficacy-a finding that was confirmed in several mouse models of Kras-driven NSCLC. In both mouse models and patients, KEAP1 and STK11 alterations were associated with an adverse tumour microenvironment, which was characterized by a preponderance of suppressive myeloid cells and the depletion of CD8+ cytotoxic T cells, but relative sparing of CD4+ effector subsets. Dual ICB potently engaged CD4+ effector cells and reprogrammed the tumour myeloid cell compartment towards inducible nitric oxide synthase (iNOS)-expressing tumoricidal phenotypes that-together with CD4+ and CD8+ T cells-contributed to anti-tumour efficacy. These data support the use of chemo-immunotherapy with dual ICB to mitigate resistance to PD-(L)1 inhibition in patients with NSCLC who have STK11 and/or KEAP1 alterations.

12616 Pembrolizumab-induced Autoimmune Adrenal Insufficiency: A Case Report And Literature Review

Abstract Disclosure: A. Calderon: None. E. Calderon-Martinez: None. J. Shakil, MD: None. A. Kansara: None. Immunechekpoint inhibitors (ICI)-related Primary Adrenal Insufficiency (PAI) is an uncommon entity. Compared to other endocrine-related adverse effects (irAES), antibody detection is less consistent. TPO and GAD65 antibodies are usually present in about 40-80% of the cases with hypothyroidism, hyperthyroidism, and diabetes. On the contrary, case reports and series for PAI seldom report the presence or absence of 21OH antibodies. We present a case and perform a literature review of PAI, in a patient who received pembrolizumab and developed PAI with 21 hydroxylase antibodies. A 62-year-old man with history HIV on ART (last CD4 count 590 cells/mm3) and locally advanced urothelial cancer on Pembrolizumab, presented with nausea, vomiting, abdominal pain, and decreased urine output. He was noted to be confused, and in hypoactive delirium. On admission, his chemistry panel he was noticed to have normal sodium and potassium levels. The CT scan of the abdomen revealed regional enteritis and was started on IV fluid therapy. His adrenal glands were described as normal on imaging. On the 16th day of hospitalization, the patient became unresponsive and hypotensive. He was transferred to the ICU. His sodium level was 132 mEq/L and potassium level was 6.1 mEq/L, bicarbonate level was 18 mEq/L, calcium of 10.3 mg/dl, and eosinophils of 15%. Random cortisol levels measured before administration of steroids were undetectable twice, 9 hours apart, with an ACTH level of 94. He underwent an ACTH stimulation test with cosyntropin 250 mcg IV with resulting undetectable cortisol levels after 30 and 60 minutes. CT and MRI of the brain showed no signs of hypophysitis. He was started on high-dose hydrocortisone with improvements in his mental status, hypotension, and gastrointestinal symptoms. He was discharged on hydrocortisone. His 21-Hydroxylase antibody was later found out to be positive. After combination immunotherapy regimens, CTLA-4 inhibitors are the most common to cause any irAE, however endocrine irAE particularly are mostly associated with PD-1 inhibitors. Among these, thyroid and pituitary disorders are the most common ones. Reports show that about 10% of patients receiving immunotherapy will develop endocrinopathy. ICI-induced PAI has been reported to occur in 7.6% of patients receiving combination therapy, and 2% of patients receiving Pembrolizumab. It has been reported that only 15% of patients will recover adrenal function. A meta-analysis that gathered 15 cases of ICI-induced PAI, found that only 2 cases had positive 21-hydroxylase antibodies. In our presented case, we have robust biochemical confirmation of PAI, with positive 21 hydroxylase antibody, after being on pembrolizumab for 9 months. Further information is needed to establish the pathophysiology, presentation, and prognosis of ICI-related PAI when anti adrenal antibodies are positive. Presentation: 6/1/2024

7437 Harnessing Diabetes Technology for Management of Immune Checkpoint Inhibitor Associated Diabetes

Abstract Disclosure: A. Knape: None. A. Kotwal: None. D. Rohlfsen: None. A. Patel: None. W. Goldner: None. Background: Immune checkpoint inhibitors (ICIs) are a key treatment modality for many cancers. One percent of patients who receive ICIs can develop insulin deficient ICI associated diabetes (ICI-DM). These patients often have complex oncologic therapy plans making treatment of newly diagnosed insulin deficient diabetes challenging which often results in additional healthcare-related burden for the patient. Methods: This is a retrospective case series of five adults who developed ICI-DM after receiving either PD-1, CTLA-4 or PDL-1 inhibitors or a combination. Data on demographics, medical history and labs were collected in addition to mode of glucose monitoring and treatment after diagnosis of ICI-DM. Results: Patients were age 44-72 at diagnosis of ICI-DM, three were female. Two were admitted to the hospital in DKA, one was diagnosed in the ER with severe hyperglycemia without DKA, two had outpatient hyperglycemia without DKA. Glucose at diagnosis ranged from 215-510 mg/dL. C-peptide was low for all patients. Fingerstick blood sugar (FSBS) monitoring and basal/bolus insulin was immediately initiated for all patients. All were transitioned from FSBS to continuous glucose monitor (CGM) and 2/5 ultimately transitioned to sensor-augmented insulin pump therapy (AID). Time in range on CGM improved in four patients with percent time in range improving between 10-48%. In two patients, hypoglycemia frequency declined by 6% and 3%. Hyperglycemia frequency declined by 13% and 48% in patients on AID therapy and by 14% and 25% in two of those on basal/bolus insulin therapy. All patients preferred CGM over FSBS and remained on CGM therapy. Those who chose AID preferred it over basal/bolus insulin therapy stating it was less complicated than basal/bolus insulin with CGM. Conclusions: We report successful treatment of five cases of ICI-DM with CGM + basal/bolus insulin or AID. 80% demonstrated improved time in range and decreased overall frequency of hyperglycemia. 40% had decreased frequency of hypoglycemia. CGM allows for dynamic adjustment of insulin therapy in a population with complex medical regimens resulting in fluctuating glucose levels. The integrated pump and sensor technology in AID was less burdensome than basal/bolus in those who chose it. Managing ICI-DM is complicated. The burden of this entity can be lessened by harnessing the power of diabetes technology. Presentation: 6/2/2024

Evaluation of the efficacy of combined immune checkpoint inhibitors in advanced melanoma treatment - Long term outcomes and emerging therapeutic perspectives: a narrative review

Combination therapy with immune checkpoint inhibitors, specifically CTLA-4 and PD-1 blockade, has shown promise in treating advanced melanoma. However, this approach often results in increased toxicity, necessitating a careful evaluation of both efficacy and safety. This review explores clinical outcomes, survival rates, and adverse events associated with these therapies. A systematic review of PubMed, Scopus, and clinical trial databases was conducted for studies published from 2014 to 2024. Studies assessing the combined use of CTLA-4 and PD-1 inhibitors in melanoma patients were included, focusing on overall survival (OS), progression-free survival (PFS), and treatment-related adverse events (AEs). The combination of CTLA-4 and PD-1 inhibitors significantly improved clinical outcomes in advanced melanoma. In trials like CheckMate 067, the five-year overall survival rate reached 52%, with a notable improvement in progression-free survival. However, these benefits came with substantial toxicity, as approximately 55% of patients experienced grade 3 or 4 treatment-related adverse events, including colitis, hepatitis, and pneumonitis. Despite these challenges, combination therapy led to durable responses in a subset of patients, underscoring its efficacy. The review emphasizes the need for balancing efficacy with toxicity management in clinical practice. While CTLA-4 and PD-1 inhibitor combinations improve survival in advanced melanoma, increased toxicity presents challenges. Further research is needed to optimize treatment strategies and enhance patient selection to balance efficacy and safety.

Real-world response assessment of immune checkpoint inhibition: comparing iRECIST and RECIST 1.1 in melanoma and non-small cell lung cancer patients.

To compare immune response evaluation criteria in solid tumors (iRECIST) and response evaluation criteria in solid tumors (RECIST) 1.1 for response assessment of immune checkpoint inhibitor (ICI) therapy in a real-world setting in patients with melanoma and non-small cell lung cancer (NSCLC). Two-hundred fifty-two patients with melanoma and NSCLC who received CTLA-4 inhibitor ipilimumab or PD-1 inhibitors nivolumab or pembrolizumab and who underwent staging CT of the chest and abdomen were retrospectively included. Treatment response evaluation according to the RECIST 1.1 and iRECIST guidelines was performed for all patients. Response patterns, as well as overall response rate (ORR), disease control rate (DCR), and time to progression (TTP), were compared between RECIST 1.1 and iRECIST. Out of 143 patients with progressive disease (PD) according to RECIST 1.1, 48 (33.6%) did not attain confirmation of progression (iCPD) as per iRECIST and six patients who were treated beyond RECIST 1.1 progression reached PD at a later point in time in iRECIST, resulting in a significant difference in TTP between iRECIST and RECIST 1.1 (618.3 ± 626.9 days vs. 538.1 ± 617.9 days, respectively (p < 0.05)). The number of non-responders as per RECIST 1.1 was 79, whereas it was 60 when using iRECIST. ORR was 28.5% for RECIST 1.1 and 34.1% for iRECIST, and corresponding DCR of 67.4% for RECIST 1.1 and 74.6% for iRECIST. iRECIST was more suitable than RECIST 1.1 for capturing atypical response patterns to ICI therapy in patients with melanoma and NSCLC, resulting in differences in the assessment of treatment response. Compared to RECIST 1.1, iRECIST may improve patient care and treatment decisions for patients with NSCLC or melanoma who are treated with immune checkpoint inhibitors in clinical routine. RECIST 1.1 may incorrectly assess atypical treatment patterns to immune checkpoint inhibitors. iRECIST better captured atypical response patterns compared to RECIST 1.1. iRECIST was more suitable for assessing response to immune checkpoint inhibitors in non-small cell lung carcinoma and melanoma.

Ophthalmic Immune-Related Adverse Events and Association with Survival: Results From a Real-World Database

PurposeAssessing immune-related ocular toxicities from immune checkpoint inhibitors (ICIs) is crucial, though rare. This study, utilizing real-world data, examines the occurrence of ophthalmic immune-related adverse events (irAEs) after ICI treatment and their impact on overall survival. DesignA retrospective cohort study MethodsData were obtained from TriNetX, an aggregated electronic health records database. Patients who developed ophthalmic irAEs within 1 year after the first instance of ICI therapy were included. Participants with defined ocular toxicities 6 months before ICI treatment were excluded. Subjects were paired with controls using propensity scores derived from demographics and cancer type. A Cox proportional hazard model was used to determine hazard ratios. A Kaplan-Meier survival function was evaluated with the log-rank test based on the development of ophthalmic irAEs in a 12-month landmark analysis. ResultsA cohort of 41,020 patients comprising 57.4% males with a mean age of 65.2±11.9 years was included. The five most prevalent ophthalmic irAEs in this cohort were dry eye syndrome (2%), conjunctivitis (0.87%), blepharitis (0.51%), anterior uveitis (0.39%), and keratitis (0.38%). Dry eye syndrome was the most common irAE among all ICI classes. Subjects taking CTLA-4 inhibitor plus PD-1 inhibitor and CTLA-4 inhibitors had higher rates of anterior uveitis (1.39% and 1.29%, respectively) than PD-1 inhibitors (0.27%) and PD-L1 inhibitors (0.14%) within 1 year after taking ICI. After a 12-month landmark analysis, there was a significant decreased chance of survival for the following categories: any ophthalmic irAE (HR, 1.37; 95% CI, 1.20-1.56; P < 0.0001), neuro-ophthalmic irAE (HR, 1.53; 95% CI, 1.09-2.14; P = 0.0124), and cornea and ocular surface irAE (HR, 1.34; 95% CI, 1.15-1.56; P < 0.0001). ConclusionsOphthalmic irAEs involving the anterior segment are more frequent than the posterior segment, regardless of ICI class. Ophthalmic irAEs may also portend decreased survival. This insight could help guide clinicians aggressively manage irAEs and allow patients to continue ICI therapy despite having ocular issues.

1112P Immunotherapy after progression to double immunotherapy: Pembrolizumab and Lenvatinib versus conventional chemotherapy for patients with metastatic melanoma after failure of PD-1/CTLA-4 inhibition

1112P Immunotherapy after progression to double immunotherapy: Pembrolizumab and Lenvatinib versus conventional chemotherapy for patients with metastatic melanoma after failure of PD-1/CTLA-4 inhibition

Inhibition of CTLA-4 accelerates atherosclerosis in hyperlipidemic mice by modulating the Th1/Th2 balance via the NF-κB signaling pathway

ObjectiveThough an increased risk of atherosclerosis is associated with anti-CTLA-4 antibody therapy, the underlying mechanisms remain unclear. MethodsC57BL/6 mice were treated with anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody twice a week for 4 weeks, after being injected with AAV8-PCSK9 and fed a Paigen diet (PD). The proportion of aortic plaque and lipid accumulation were assessed using Oil Red O staining, while the morphology of atherosclerotic lesions was analyzed with hematoxylin and eosin staining. Collagen content was evaluated through Picrosirius Red (PSR) staining, while inflammatory cell infiltration was examined with immunofluorescence staining. CD4+ T cells secreting IFN-γ and IL-4, which represent Th1 and Th2 cells respectively, were detected by flow cytometry and real-time PCR. Protein levels of p-IκBα, IκBα, p-p65, and p65 were determined by Western blot. ResultsInhibiting CTLA-4 exacerbated PD-induced plaque progression and promoted CD4+ T cell infiltration in the aortic root. The anti-CTLA-4 antibody promoted CD4+ T cell differentiation toward the Th1 type, as indicated by an increase in the Th1/Th2 ratio. Compared to the anti-IgG group, treatment with anti-CTLA-4 antibody significantly elevated the protein levels of p-IκBα and p-p65, as well as the mRNA levels of TNF-α, IL-6, ICAM-1, and VCAM-1. Inhibiting the NF-κB signaling pathway attenuated the overall pathological phenotype induced by the anti-CTLA-4 antibody treatment. ConclusionAnti-CTLA-4 treatment promotes the progression of atherosclerosis by activating NF-κB signaling and modulating the Th1/Th2 balance. Our results provide a rationale for preventing and/or treating atherosclerosis accelerated by anti-CTLA-4 antibody therapy in cancer patients.

Infusion-related reactions from immune checkpoint inhibitors: A proportional and network meta-analysis.

38 Background: Immune checkpoint inhibitors (ICIs) have become the standard of care for the treatment of patients with solid tumors. Infusion-related reactions (IRRs) to ICIs have been reported in up to 20%, but the incidence varies among ICIs. Therefore, we aimed to report and compare the incidence of IRRs to each ICI therapy. Methods: We searched PubMed/MEDLINE, Embase, and Web of Science to identify phase 3 randomized controlled trials (RCTs) evaluating ICIs (CTLA-4, PD-1, PD-L1, and LAG-3 inhibitors) in solid tumors. We performed a random-effects model network meta-analysis to compare the odds ratio (OR) of IRRs by using RCTs comparing dual ICIs, ICI monotherapy, and placebo/observation. For a proportional meta-analysis, treatment arms evaluating ICI monotherapy, or dual ICIs, were selected to pool the incidence of IRRs. Results: A total of 25,250 patients from 47 phase 3 RCTs were included in the analysis. A network meta-analysis of treatment-related IRRs included 10 RCTs and showed that avelumab (OR 70.2, 95% confidence interval [CI]: 4.32-1140) and atezolizumab (40.72, 2.47-671.4) had a significantly higher risk of treatment-related IRRs compared with placebo/observation. Network ranking revealed that avelumab, atezolizumab, and relatlimab plus nivolumab were the top three therapies with risk of treatment-related IRRs. Proportional meta-analyses revealed that the pooled incidence of treatment-related IRRs was 5.39% for PD-1 plus CTLA-4 inhibitors, 8.25% for PD-L1 (avelumab: 13.1%, non-avelumab: 1.93%), 1.97% for CTLA-4, and 1.95% for PD-1 inhibitors. Results of immune-related IRRs were relatively consistent with those of treatment-related IRRs (Table). Conclusions: Avelumab has the highest risk of IRRs followed by atezolizumab and dual ICIs. This comparative study provides insight into the incidence of IRRs with ICI regimens. These results are useful in assessing which systemic therapies are responsible for IRRs, particularly when ICIs are combined with other agents. [Table: see text]

Association of peripheral edema with immune checkpoint inhibitors: A systematic review.

187 Background: Immune checkpoint inhibitors (ICIs) are widely used to treat patients with cancer but immune-related adverse events occasionally disrupt treatments and affect their quality of life. Peripheral edema from ICI therapy appears rare but can occur due to increased peripheral vascular permeability. Thus, we aimed to report the incidence and outcomes of peripheral edema from ICIs. Methods: Medline, Embase, and Web of Science were searched to identify phase 3 randomized controlled trials (RCTs) reporting the incidence of peripheral edema in patients treated with ICIs. We calculated the incident rate of peripheral edema based on treatment patterns (monotherapy and combination therapy) and ICI subtypes (PD-1, PD-L1, and CTLA-4 inhibitors). We also performed a systematic review to identify articles reporting treatment outcomes of peripheral edema from ICIs. Results: Overall, 60 RCTs comprising 22,590 patients were identified for the incidence analysis. Treatment-related peripheral edema (Grade 1-5) occurred in 2.8% from ICI monotherapy (n = 195/6969; PD-1 inhibitors: 2.2% [n = 104/4694], PD-L1: 3.7% [n = 58/1557], CTLA-4: 4.6% [n = 33/718]), 5.0% (n = 112/2257) from ICI with chemotherapy, and 8.7% (n = 205/2349) from ICI with molecular-targeted therapy. Grade 3-5 treatment-related peripheral edema occurred in 0.3% of patients treated with ICI monotherapy (Table). For treatment outcomes of peripheral edema, a systematic review identified 19 studies (17 case reports/series,1 phase 1/2 clinical trial, 1 pharmacovigilance study) comprising 40 patients with immune-related peripheral edema. In total, 82.5% (n = 33/40) of cases received glucocorticoid treatment, and 55.0% (n = 22/40) required a high dose (≥ 1 mg/kg/day) of prednisone. ICI was discontinued in 77.5% (n = 31/40) due to peripheral edema (permanent discontinuation in 35% [n = 14/40]). Conclusions: Peripheral edema occasionally occurs in patients treated with ICIs but its occurrence often requires glucocorticoid administration, which may impact cancer treatment outcomes. [Table: see text]

Comparison of platinum combination chemotherapy plus pembrolizumab versus platinum combination chemotherapy plus nivolumab-ipilimumab for treatment-naive advanced non-small-cell lung cancer in Japan (JCOG2007): an open-label, multicentre, randomised, phase 3 trial.

The combination of platinum-based chemotherapy and an antibody to PD-1 or to its ligand PD-L1, with or without an antibody to CTLA-4, has improved the survival of individuals with metastatic non-small-cell lung cancer (NSCLC). However, no randomised controlled trial has evaluated the survival benefit of adding a CTLA-4 inhibitor to platinum-based chemotherapy plus a PD-1 or PD-L1 inhibitor. This open-label, randomised, phase 3 trial was conducted at 48 hospitals in Japan. Eligible patients were aged 20 years or older with previously untreated advanced NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with known driver oncogenes were excluded. Participants were randomly assigned (1:1) to receive platinum-based chemotherapy (four cycles) plus pembrolizumab (pembrolizumab group) or platinum-based chemotherapy (two cycles) plus nivolumab-ipilimumab (nivolumab-ipilimumab group). The primary endpoint was overall survival and assessed in all randomly assigned patients on an intention-to-treat basis. The trial is registered in the Japan Registry for Clinical Trials, jRCTs031210013, and is now closed to new enrolment and is ongoing. Between patient accrual initiation on April 6, 2021, and discontinuation of the trial on March 30, 2023, 11 (7%) of 148 patients in the nivolumab-ipilimumab group had a treatment-related death. Because of the high number of treatment-related deaths, patient accrual was terminated early, resulting in 295 patients (236 [80%] male and 59 [20%] female) enrolled; the primary analysis was done on the basis of 117 deaths (fewer than the required 329 deaths). By May 25, 2023 (data cutoff), overall survival did not differ significantly between the nivolumab-ipilimumab group and the pembrolizumab group (median 23·7 months [95% CI 17·6-not estimable] vs 20·5 months [17·6-not estimable], respectively; hazard ratio 0·98 [90% CI 0·72-1·34]; p=0·46). Non-haematological adverse events of grade 3 or worse occurred in 87 (60%) of 146 patients in the nivolumab-ipilimumab group and 59 (41%) of 144 patients in the pembrolizumab group. The pembrolizumab group tended to have a better quality of life compared with the nivolumab-ipilimumab group. The safety and efficacy data suggest an unfavourable benefit-risk profile for nivolumab-ipilimumab combined with platinum-based chemotherapy relative to pembrolizumab combined with platinum-based chemotherapy as a first-line treatment for patients with advanced NSCLC, although a definitive conclusion awaits an updated analysis of overall survival. The National Cancer Center Research and Development Fund and Japan Agency for Medical Research and Development.

Advances in immunotherapy for mucosal melanoma: harnessing immune checkpoint inhibitors for improved treatment outcomes.

Mucosal melanoma (MM) poses a significant clinical challenge due to its aggressive nature and limited treatment options. In recent years, immunotherapy has emerged as a promising strategy for MM, with a particular focus on immune checkpoint inhibitors such as PD-1 and CTLA-4 inhibitors. These inhibitors have demonstrated substantial efficacy by harnessing the body's immune response against tumors. Moreover, adoptive cell transfer (ACT), anti-angiogenic therapy, and combination therapies have garnered attention for their potential in MM treatment. ACT involves modifying T cells to target melanoma cells, showing promising antitumor activity. Anti-angiogenic therapy aims to impede tumor growth by inhibiting angiogenesis, while combination therapies, including immune checkpoint inhibitors and targeted therapies, offer a multifaceted approach to overcome treatment resistance. This comprehensive review explores the advancements in immunotherapy for MM, highlighting the role of diverse therapeutic modalities in enhancing treatment outcomes and addressing the challenges posed by this aggressive malignancy.

Histone acetylation risk model predicts prognosis and guides therapy selection in glioblastoma: implications for chemotherapy and anti-CTLA-4 immunotherapy

BackgroundGlioblastoma is characterized by high aggressiveness, frequent recurrence, and poor prognosis. Histone acetylation-associated genes have been implicated in its occurrence and development, yet their predictive ability in glioblastoma prognosis remains unclear.ResultsThis study constructs a histone acetylation risk model using Cox and LASSO regression analyses to evaluate glioblastoma prognosis. We assessed the model’s prognostic ability with univariate and multivariate Cox regression analyses. Additionally, immune infiltration was evaluated using ESTIMATE and TIMER algorithms, and the SubMAP algorithm was utilized to predict responses to CTLA4 inhibitor. Multiple drug databases were applied to assess drug sensitivity in high- and low-risk groups. Our results indicate that the histone acetylation risk model is independent and reliable in predicting prognosis.ConclusionsLow-risk patients showed higher immune activity and longer overall survival, suggesting anti-CTLA4 immunotherapy suitability, while high-risk patients might benefit more from chemotherapy. This model could guide personalized therapy selection for glioblastoma patients.

Case Report: Multiple Endocrine Insufficiency Secondary to the use of CTLA-4 Inhibitors for the Treatment of Subungual Melanoma

Case Report: Multiple Endocrine Insufficiency Secondary to the use of CTLA-4 Inhibitors for the Treatment of Subungual Melanoma

Adverse Events of PD-1, PD-L1, CTLA-4, and LAG-3 Immune Checkpoint Inhibitors: An Analysis of the FDA Adverse Events Database.

This study aimed to identify the 25 most prevalent adverse events (AEs) associated with FDA-approved immune checkpoint inhibitors (ICIs)-specifically, PD-1, PD-L1, CTLA-4, and LAG-3 inhibitors-using data from the FDA Adverse Events Reporting System (FAERS), a publicly available repository of reported drug adverse events, and AERSMine, an open-access pharmacovigilance tool, to investigate these adverse events. For PD-1 inhibitors, the most common AEs were diarrhea, fatigue, and pyrexia, with notable instances of neutropenia and hypothyroidism, particularly with toripalimab and dostarlimab. PD-L1 inhibitors also frequently caused pyrexia, diarrhea, and fatigue, with interstitial lung disease and hypothyroidism showing a class effect, and drug-specific AEs such as hepatotoxicity and chills. CTLA-4 inhibitors predominantly resulted in diarrhea and colitis, with ipilimumab frequently causing pyrexia and rash, while tremelimumab exhibited unique AEs such as biliary tract infection. The LAG-3 inhibitor relatlimab reported fewer AEs, including pyrexia and pneumonia. Rare but significant AEs across all inhibitors included myocarditis and myasthenia gravis. This study provides a detailed overview of the 25 most common AEs associated with ICIs, offering valuable insights for clinical decision-making and AE management. Further research is necessary to elucidate the mechanisms underlying these AEs and to develop targeted interventions to enhance the safety and efficacy of ICI therapy in patients with cancer.

The expression of ERAP1 is favorable for the prognosis and immunotherapy in colorectal cancer: a study based on the bioinformatic and immunohistochemical analysis.

Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an emerging pharmacological target in cancer immunotherapy. This study was set out to examine the expression profiles and implications for prognosis and immunotherapy of ERAP1 in CRC. Based on bioinformatics and immunohistochemical analysis, we analyzed ERAP1 for potential diagnostic and prognostic significance in CRC. Functional enrichment analysis was conducted to detect the pathways associated with ERAP1, thus determining possible mechanisms. ESTIMATE, TIMER, and CIBESORT probed the links between ERAP1 and tumor-infiltrating immune cells. Lastly, we examined how ERAP1 expression correlated with the sensitivity to immunotherapy. Tumor tissues had decreased levels of ERAP1 expression relative to normal tissues. Patients whose ERAP1 expression was low suffered a worse chance of survival. Besides, it was shown that ERAP1 expression was associated with the advanced M stage and pathologic stage. Survival analysis revealed that low ERAP1 expression, age, pathologic stage, T stage, and M stage were independent indicators for unfavorable CRC patients' prognoses. The 1-, 3-, and 5-year OS calibration curves all fit well with the ideal model, suggesting that the age-ERAP1-T-stage-M-stage nomogram is a reliable predictor of OS. Additionally, we discovered that ERAP1 expression was associated with immune response and infiltration of various immune cells, such as down-regulated inhibitory immune cells and up-regulated stimulating immune cells. Sensitivity to PD-1 and CTLA4 inhibitors was associated with high ERAP1 levels. In summary, ERAP1 has potential as a diagnostic and prognostic biological marker, highlighting new insights into the study of CRC and the design of effective therapies.