scholarly journals Case Report: Simultaneous Hyperprogression and Fulminant Myocarditis in a Patient With Advanced Melanoma Following Treatment With Immune Checkpoint Inhibitor Therapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Whitney Barham ◽  
Ruifeng Guo ◽  
Sean S. Park ◽  
Joerg Herrmann ◽  
Haidong Dong ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Cell Activity ◽  
Stage Iv ◽  
Cytolytic Activity ◽  
Fulminant Myocarditis ◽  
Functional Markers ◽  
Tumor Resistance

We report here a patient with stage IV mucosal melanoma treated with dual immune checkpoint inhibitor (ICI) therapy (Nivolumab/Ipilimumab) who experienced rapid disease progression and metastatic spread within three weeks of first infusion. Surprisingly, this patient also developed fulminant myocarditis within the same time frame. Immunohistochemical staining of the primary tumor and a metastatic omental lesion revealed robust CD8+ PD-1+ T cell infiltration after ICI treatment, as would be expected following immune activation. However, the CD8+ T cell infiltrate was largely negative for both Granzyme B and TIA-1, suggesting these T cells were not capable of effective tumor lysis. We discuss the possibility that heightened pro-inflammatory T cell activity (rather than tumor-directed cytolytic activity) was induced by anti-PD-1 and anti-CTLA-4, which could have provoked both rapid tumor resistance mechanisms and myocarditis. This case highlights the fact that the mere presence of tumor infiltrating lymphocytes (TILs) does not necessarily correlate to ICI response and that additional functional markers are necessary to differentiate between inflammatory and cytolytic CD8+ TILs.

Abstract 15365: Natural History of Immune Checkpoint Inhibitor Associated Myocarditis With Preserved Ejection Fraction

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Joseph Nowatzke ◽  
John R Power ◽  
Wouter C Meijers ◽  
Olusola Orimoloye ◽  
Charlotte Fenioux ◽  
...  
Keyword(s):  
Natural History ◽  
Ejection Fraction ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Fulminant Myocarditis ◽  
Circulatory Support ◽  
Preserved Ejection Fraction ◽  
History Of ◽  
Electrical Pacing

Introduction: Immune Checkpoint Inhibitor (ICI)-associated myocarditis can be fatal, and is often characterized by arrhythmogenicity, although > 50% present with preserved ejection fraction (pEF). The natural history of ICI-myocarditis with pEF is unknown. Methods: We utilized a multicenter network of ICI-myocarditis cases spanning 12 countries to identify 83 cases of definite or probable myocarditis presenting with an EF above 50% on initial echocardiography. We further stratified patients based on continued pEF or worsening EF (rEF) during hospitalization. We compared independent variables, vital signs on presentation, and laboratory values between the two groups. Mortality was defined as those who died or were discharged to hospice within 90 days from admission. Fulminant myocarditis was defined as need for circulatory support, atrioventricular block requiring electrical pacing, ventricular tachycardia or fibrillation, or cardiac arrest while in the hospital. Results: Of the 83 patients, 15 developed a rEF; 68 maintained pEF during hospitalization. Although no significant change in heart rate was noted on presentation, systolic blood pressure was lower in the rEF group (111 vs 129, p=0.010). The rEF cohort were more prone to have a peak troponin elevation (432 vs 41, p=0.021), and to develop fulminant myocarditis (73% vs 26%, p=<0.001). Both in-hospital mortality (46% vs 17%, p=0.015) and 90-day all-cause mortality were significantly increased in those who develop a rEF (72% vs 29%, p=0.007). Overall, there was a 36.8% 90-day mortality rate for all those presenting with an initially normal EF. Conclusions: Patients with ICI-myocarditis can still have a fulminant course despite initial echocardiogram revealing EF>50%. In our database, 18% go on to develop new rEF and 73% die in the following 90 days. Decreased BP and troponin on presentation may identify patients at risk of subsequent rEF and fulminant course.

Late-Onset Fulminant Myocarditis With Immune Checkpoint Inhibitor Nivolumab

2018 ◽  
Vol 34 (6) ◽  
pp. 812.e1-812.e3 ◽  
Author(s):  
Shogo Yamaguchi ◽  
Ryota Morimoto ◽  
Takahiro Okumura ◽  
Yuta Yamashita ◽  
Tomoaki Haga ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Late Onset ◽  
Checkpoint Inhibitor ◽  
Fulminant Myocarditis

scholarly journals Modulating the wayward T cell: New horizons with immune checkpoint inhibitor treatments in autoimmunity, transplant, and cancer

2020 ◽  
Vol 115 ◽  
pp. 102546
Author(s):  
Leonard H. Calabrese ◽  
Roberto Caporali ◽  
Christian U. Blank ◽  
Allan D. Kirk
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
New Horizons

scholarly journals Immune-Checkpoint Inhibitor-Induced Fulminant Myocarditis and Cardiogenic Shock

2019 ◽  
Vol 1 (1) ◽  
pp. 141-144 ◽  
Author(s):  
Osnat Itzhaki Ben Zadok ◽  
Ben Ben-Avraham ◽  
Anju Nohria ◽  
Katia Orvin ◽  
Mithal Nassar ◽  
...  
Keyword(s):  
Cardiogenic Shock ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Fulminant Myocarditis

Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: Primary phase III results from RELATIVITY-047 (CA224-047).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9503-9503
Author(s):  
Evan J. Lipson ◽  
Hussein Abdul-Hassan Tawbi ◽  
Dirk Schadendorf ◽  
Paolo Antonio Ascierto ◽  
Luis Matamala ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Objective Response ◽  
Cell Activity ◽  
Advanced Melanoma ◽  
Phase Iii ◽  
Fixed Dose ◽  
First Line ◽  
Programmed Death

9503 Background: Immune checkpoint inhibitor therapy has revolutionized the treatment of patients with advanced melanoma. However, novel combinations are needed to optimize the benefit-risk profile. Lymphocyte-activation gene 3 (LAG-3) regulates an immune checkpoint pathway, which inhibits T-cell activity, and is upregulated in many tumor types including melanoma. Relatlimab (RELA), a human IgG4 LAG-3-blocking antibody, restores effector function of exhausted T cells. RELA in combination with nivolumab (NIVO; anti-programmed death [PD]-1) modulates potentially synergistic immune checkpoint pathways and can enhance antitumor immune responses. RELATIVITY-047 is a global, randomized, double-blind, phase II/III study evaluating a novel immune checkpoint inhibitor combination of RELA+NIVO as a fixed-dose combination (FDC) treatment in first-line advanced melanoma. Methods: Patients with previously untreated advanced melanoma were randomized 1:1 to receive RELA 160 mg + NIVO 480 mg FDC intravenously (IV) every 4 weeks (Q4W) or NIVO monotherapy 480 mg IV Q4W, stratified by LAG-3 expression, programmed death ligand 1 expression, BRAF mutation status, and AJCC (v8) M stage. The primary endpoint was progression-free survival (PFS) per RECIST v1.1 as assessed by blinded independent central review. Secondary endpoints were overall survival and objective response rate. PFS in prespecified subgroups and safety were additional objectives. Results: 714 patients were randomized to RELA+NIVO FDC (n = 355) or NIVO (n = 359). Patient characteristics were well balanced between treatment groups. Median follow-up was 13.2 months. Median PFS in the RELA+NIVO FDC group (10.1 months [95% CI, 6.4–15.7]) was significantly longer than in the NIVO group (4.6 months [95% CI, 3.4–5.6]; hazard ratio, 0.75 [95% CI, 0.6–0.9]; P = 0.0055). PFS rates at 12 months were 47.7% (95% CI, 41.8–53.2) and 36.0% (95% CI, 30.5–41.6) for RELA+NIVO FDC and NIVO, respectively. PFS favored RELA+NIVO FDC across key prespecified subgroups. The incidence of grade 3/4 treatment-related adverse events (TRAEs) was higher in the RELA+NIVO FDC group (18.9%) versus NIVO (9.7%). There were 3 treatment-related deaths with RELA+NIVO FDC and 2 with NIVO. TRAEs (any grade) led to treatment discontinuation in 14.6% and 6.7% of patients in the RELA+NIVO FDC and NIVO groups, respectively. Conclusions: First-line treatment with RELA+NIVO FDC demonstrated a statistically significant PFS benefit compared to NIVO monotherapy in patients with advanced melanoma. RELA+NIVO FDC was well tolerated with a manageable safety profile and without unexpected safety signals. This is the first phase III study of a novel FDC to demonstrate a clinically meaningful benefit by dual inhibition of the LAG-3 and PD-1 pathways. Clinical trial information: NCT03470922.

Gene Expression Profiling in Kidney Transplants with Immune Checkpoint Inhibitor-Associated Adverse Events

2021 ◽  
pp. CJN.00920121
Author(s):  
Benjamin Adam ◽  
Naoka Murakami ◽  
Graeme Reid ◽  
Katie Du ◽  
Ruqaya Jasim ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Interstitial Nephritis ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Validation Cohort ◽  
Checkpoint Inhibitor ◽  
Expression Patterns ◽  
Acute Interstitial Nephritis ◽  
Potential Biomarker

Background and objectives: Immune checkpoint inhibitors are increasingly used to treat various malignancies but their application in kidney transplant patients is complicated by high allograft rejection rates. Immune checkpoint inhibitor-associated rejection is a novel, poorly understood entity demonstrating overlapping histopathological features with immune checkpoint inhibitor-associated acute interstitial nephritis, which poses a challenge for diagnosis and clinical management. We sought to improve the understanding of these entities through biopsy-based gene expression analysis. Design, setting, participants, and measurements: NanoString was used to measure and compare the expression of 725 immune-related genes in 75 archival kidney biopsies, including a 25-sample discovery cohort comprising pure T-cell mediated rejection (TCMR) and immune checkpoint inhibitor-associated acute interstitial nephritis (ICI-AIN), and an independent 50-sample validation cohort comprising ICI-AIN, immune checkpoint inhibitor-associated T-cell mediated rejection (ICI-TCMR), immune checkpoint inhibitor-associated crescentic glomerulonephritis, drug-induced acute interstitial nephritis (Drug-AIN), BK virus nephropathy, and normal biopsies. Results: Significant molecular overlap was observed between ICI-AIN and TCMR. Nevertheless, IFI27, an interferon-alpha induced transcript, was identified and validated as a novel biomarker for differentiating ICI-TCMR from ICI-AIN (validation cohort: P<0.001, AUC=100%, accuracy=86%). Principal component analysis revealed heterogeneity in inflammatory gene expression patterns within sample groups; however, ICI-TCMR and ICI-AIN both demonstrated relatively more molecular overlap with Drug-AIN than TCMR, suggesting potential dominance of hypersensitivity mechanisms in these entities. Conclusions: These results indicate that, although there is significant molecular similarity between immune checkpoint inhibitor-associated rejection and AIN, biopsy-based measurement of IFI27 gene expression represents a potential biomarker for differentiating these entities.

scholarly journals Refractory Immune Checkpoint Inhibitor-Induced Colitis Improved by Tacrolimus: A Case Report

Healthcare ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 418
Author(s):  
Yasuhito Kunogi ◽  
Keiichi Tominaga ◽  
Keiichiro Abe ◽  
Mimari Kanazawa ◽  
Takanao Tanaka ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Cell Activity ◽  
Postoperative Recurrence ◽  
Gi Tract ◽  
Severe Diarrhea ◽  
Sodium Hydrate

Immune checkpoint inhibitors (ICIs) increase T-cell activity and antitumor immune response. However, they also have immune-related adverse effects that can affect the gastrointestinal (GI) tract. A 62-year-old male patient who had undergone right lung upper lobectomy for adenocarcinoma of the lung received chemotherapy with pemetrexed sodium hydrate, carboplatin, and pembrolizumab to prevent postoperative recurrence of liver metastasis. However, the patient experienced severe diarrhea four months after the start of chemotherapy. Although a corticosteroid and two biological preparations were administered to alleviate the diarrhea, no improvement was observed. Eventually, remission was achieved when tacrolimus was administered. Treatment with corticosteroids is recommended for patients with GI adverse effects of ICIs. Rapid introduction of infliximab is necessary for refractory patients. Nevertheless, for refractory cases such as that of our patient, for whom even this regimen is inefficacious, tacrolimus might be recommended to induce remission as with cases of ulcerative colitis.

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