• arthritis
• immune checkpoint inhibitors
• irAEs
• secondary prophylaxis
• tocilizumab

• anti-CTLA 4-antibody
• anti-PD-1 antibody
• autoimmune hemolytic anemia
• case report
• immune-related adverse events
• immunotherapy
• melanoma
• myocarditis

• Humans
• Male
• Female
• Melanoma/drug therapy
• Melanoma/etiology
• Anemia, Hemolytic, Autoimmune/chemically induced
• Anemia, Hemolytic, Autoimmune/therapy
• Immune Checkpoint Inhibitors/adverse effects
• Immunotherapy/adverse effects
• Immunotherapy/methods
• Neoplasms, Second Primary/etiology
• Dyspnea/etiology
• Adrenal Cortex Hormones/therapeutic use

• autoimmunity
• cancer
• immune checkpoint inhibitor
• immune related adverse events

• K08 DK129829 NIDDK NIH HHS

• Gynecologic malignancy
• immune checkpoint inhibitor
• rechallenge
• recurrence

• Humans
• Female
• Adult
• Middle Aged
• Aged
• Genital Neoplasms, Female
• Immune Checkpoint Inhibitors/adverse effects
• Nivolumab/therapeutic use
• Retrospective Studies
• Chronic Disease
• Recurrence

• adverse events
• gastrointestinal
• immunotherapy
• meta-analysis
• tumor

• Humans
• Nivolumab/adverse effects
• Ipilimumab/adverse effects
• Neoplasms/drug therapy
• Diarrhea/drug therapy
• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Colitis/chemically induced
• Colitis/drug therapy

• Hepatocellular carcinoma
• Immunotherapy
• Interventional radiology
• Nanomedicine

• R01 CA218659 NCI NIH HHS
• R01 EB026207 NIBIB NIH HHS

Malignant pleural mesothelioma has limited therapeutic options and a poor outcome. Antiangiogenic agents might increase the efficacy of immunotherapy as second-line treatment of advanced-stage malignancies.

A patient with stage IIIB pleural mesothelioma received second-line treatment with a combination of pembrolizumab, bevacizumab and chemotherapy following standard chemotherapy under the guidance of second-generation sequencing. He achieved a partial response after four cycles of treatment with progression-free survival of 5 mo. Pembrolizumab was suspended due to grade 2 immunerelated pneumonia, which was resolved by oral glucocorticoids. However, disease progression was observed after immunotherapy rechallenge and anlotinib therapy. The patient had disease progression, multiorgan dysfuntion and died suddenly in October 2019.

The combination of immune checkpoint inhibitor, anti-angiogenic agents and chemotherapy showed effective response for advanced pleural mesothelioma, but with adverse reactions.

• Pleural mesothelioma
• Immune checkpoint inhibitor
• Next-generation Sequencing
• Immunerelated pneumonia
• Immunotherapy rechallenge
• Case report

Combining two immune checkpoint inhibitors (ICIs) instead of using one can effectively improve the prognosis of advanced malignant tumors. At present, ipilimumab alongside nivolumab is the most widely used combinatorial regimen of ICIs. However, the risk of treatment-related adverse events is higher in combinatorial regimens than in single-drug regimens. Thus, this study aimed to evaluate the risks of common adverse events associated with the combinatorial regimen of ipilimumab and nivolumab by using meta-analysis.

We searched Pubmed, Medline, EMBASE, and Cochrane Library for reports published by 30 September 2021. A randomized controlled study was developed and analyzed using the statistical software R to determine the efficacy of the combinatorial treatment. Risk estimates (hazard ratios, RR) and 95% confidence intervals for various common serious adverse events were used.

A total of 23 randomized control trials (n = 3970 patients) were included. Our meta-analysis indicated the risks of adverse events of any grade and grade ≥ 3 as 90.42% (95%CI: 85.91% ~ 94.18%) and 46.46% (95%CI: 39.37% ~ 53.69%), respectively; the risks of treatment-related death and adverse events leading to discontinuation were estimated at 0.42% (95% CI, 0.18% ~ 0.72%) and 19.11% (95% CI, 14.99% ~ 24.38%), respectively. Classification of 19 common adverse events. The top 5 grade 1-2 adverse events were found to be fatigue (30.92%, 95% CI: 24.59% ~ 37.62%), pruritus (26.05%, 95%CI: 22.29%~29.99%), diarrhea (23.58%, 95% CI: 20.62% ~ 26.96%), rash (19.90%, 95%CI: 15.75% ~ 25.15%), and nausea (17.19%, 95% CI:13.7% ~ 21.57%). The top 5 grade ≥ 3 adverse events were identified as increased alanine aminotransferase(8.12%, 95% CI: 5.90%~10.65%), increased lipase(7.62%, 95% CI: 4.88% ~ 10.89%), and colitis (6.39%, 95%CI: 3.98% ~ 10.25%), increased aspartate aminotransferase (6.30%, 95% CI: 4.61% ~ 8.22%), and diarrhea(5.72%, 95%CI: 3.50% ~ 8.44%). Subgroup analysis revealed some differences in the adverse events between the N1-I3 and N3-I1 subgroups and between subgroups of different cancer types.

This study summarized the risks of common adverse events in the co-treatment of malignant-tumor patients with ipilimumab and nivolumab and identified the impacts of various initial administration schemes on the risks of such events, thereby providing an important reference for the toxicity of co-treatment with ipilimumab and nivolumab.

https://www.crd.york.ac.uk/prospero/, identifier: CRD42020181350.

• cytokine
• cytotoxic T lymphocyte antigen-4
• genitourinary cancer
• immune checkpoint inhibitor
• immunosuppression
• immunotherapy
• immunotherapy rechallenge
• immunotherapy-related toxicity

• drug-induced liver injury (DILI)
• gene therapy
• immune checkpoint inhibitors
• immune-mediated hepatitis
• immunotherapy

Nivolumab combined with ipilimumab has improved the prognosis of patients with advanced melanoma. However, this therapy is frequently associated with immune-related adverse events. Published data suggested that objective responses rates appear to be superior in patients who developed immune-related adverse events. The primary aim of this study was to evaluate the association between immune-related adverse events and disease control rate, progressive-free survival, and overall survival in patients with stage IV melanoma treated with first-line PD-1-based immunotherapy. In this manuscript, we show that the presence of immune related side effects is related to better overall response and longer survival in patients with advance stage melanoma treated immuno-therapy, suggesting that immune-related adverse events might be a predictive factor of response in those patients.

(1) Background: Immune checkpoint inhibitors have improved the prognosis of patients with advanced melanoma. Published data suggested that the objective response rates appear to be superior in patients who developed immune-related adverse events (irAEs). (2) The primary aim of this cohort study was to evaluate the association between irAEs and disease control rate in patients with stage IV melanoma treated with first-line PD-1-based immunotherapy. (3) Among 319 patients, 53% experienced at least one irAE. A higher percentage of patients with irAEs had disease control compared to those without irAEs (69.8% vs. 49.3%). In multivariate analysis, development of grade 3 and 4 irAEs was significantly associated with a protective effect for the outcome primary resistance (OR: 0.40 95% CI 0.23–0.70, p = 0.001). The presence of any grade irAEs was significantly associated with longer OS (irAEs grade 1–2 HRadj: 0.61 95% CI: 0.4–0.93, p = 0.02, irAEs grade 3–4 HRadj: 0.55 95% CI 0.31–0.99, p = 0.04), but not with PFS (irAEs grade 1–2 HRadj: 1.21 95% CI: 0.91–1.79, p = 0.16, irAEs grade 3–4 HRadj: 1.14 95% CI 0.83–2.02, p = 0.24). (4) The presence of irAEs with laboratorial expression is positively associated with response and OS, suggesting that irAEs might be a predictive factor in this setting.

• anti-CTLA-4
• anti-PD-1
• immune-related adverse events
• immunotherapy
• melanoma
• response
• survival

• immune checkpoint inhibitors
• immune-related adverse events

• Aged
• Female
• Humans
• Immune Checkpoint Inhibitors/adverse effects
• Immune Checkpoint Inhibitors/therapeutic use
• Immune System/drug effects
• Kaplan-Meier Estimate
• Male
• Neoplasms/drug therapy
• Neoplasms/immunology
• Recurrence
• Retrospective Studies

• TL1 TR002546 NCATS NIH HHS
• National Institue of Health TL1 training grant
• Moore/Moreau Pilot Research grant

• cancer immunotherapy
• image guided medicine
• immune checkpoint inhibitor
• interventional oncology
• nanocarrier

• R01 CA218659 NCI NIH HHS
• R01 EB026207 NIBIB NIH HHS

• Immune checkpoint inhibitors
• Meta-analysis
• Outcome
• Rechallenge
• Solid tumors

• Humans
• Immune Checkpoint Inhibitors
• Neoplasms/drug therapy
• Progression-Free Survival
• Prospective Studies

This study examined the real-world experience and occurrence of immune-related adverse events (irAEs) under cancer checkpoint immunotherapy, and the relationship between its treatment rechallenge status and their impact on clinical outcomes. The current study demonstrates that immune checkpoint inhibitors (ICI) reinitiation after an irAE-related interruption in the setting of cancer immunotherapy was not associated with significantly improved survival outcome when compared with those without ICI treatment reinitiation after irAE-related therapy interruption.

Introduction: There is growing recognition of immune related adverse events (irAEs) from immune checkpoint therapies being correlated with treatment outcomes in certain malignancies. There are currently limited data or consensus to guide management of irAEs with regards to treatment rechallenge. Methods: We conducted a retrospective analysis with an IRB-approved protocol of adult patients seen at the WVU Cancer Institute between 2011–2019 with a histopathologic diagnosis of active cancers and were treated with immune checkpoint inhibitors (ICI) therapy. Results: Demographics were similar between the ICI interrupted irAE groups within cancer types. Overall, out of 548 patients who received ICI reviewed, there were 133 cases of ≥1 irAE found of any grade. Being treated with anti-CTLA-4 inhibitor ICI was associated with lower risk of death compared to anti-PD-1 ICI. The overall survival difference observed for irAE positive patients, between rechallenged (37.8 months, reinitiated with/without interruption; 38.6 months, reinitiated after interruption) and interrupted/non-reinitiated (i.e., discontinued) groups (24.9 months) was not statistically significant, with a numerical trend favoring the former. Conclusions: Our exploratory study did not identify significantly different survival outcomes among the Appalachian West Virginia adult cancer patients treated with ICI who developed irAE and had treatment reinitiated after interruption, when compared with those not reinitiated.

• checkpoint inhibitor
• immune related adverse event
• rechallenge of immunotherapy

Safety of rechallenge of immune checkpoint inhibitor (ICI) after grade ≥2 immune-related adverse events (irAEs) leading to ICI discontinuation remains unclear.

All adverse drug reactions involving at least one ICI reported up to December 31, 2019 were extracted from the French pharmacovigilance database. Patients were included if they experienced at least one grade ≥2 irAE resulting in ICI discontinuation, with subsequent ICI rechallenge. The primary outcome was the recurrence of at least one grade ≥2 irAE in these patients after ICI rechallenge.

We included 180 patients: 61.1% were men (median age of 66 years), 43.9% had melanoma and 78.9% were receiving anti-programmed cell death 1. First ICI discontinuation was related to 191 irAEs. After ICI rechallenge, 38.9% of the patients experienced at least one grade ≥2 irAE. Among them, 70.0% experienced the same irAE, 25.7% a distinct irAE, and 4.3% both the same and a distinct irAE. Lower recurrence rates of irAEs were associated with rechallenge with the same ICI treatment (p=0.02) or first endocrine irAEs (p=0.003). Gastrointestinal irAEs were more likely to recur (p=0.007). The median duration from ICI discontinuation to rechallenge and the severity of the initial irAE did not predict recurrent irAEs after ICI rechallenge (p=0.53 and p=0.40, respectively).

In this study, 61.1% of the patients who discontinued ICI treatment for grade ≥2 irAEs experienced no recurrent grade ≥2 irAEs after ICI rechallenge. Although ICI rechallenge appears to be safe under close monitoring, it should always be discussed balancing usefulness of rechallenge, patient comorbidities and risk of recurrence of first irAE(s). Due to inherent bias associated with pharmacovigilance studies, further prospective studies are needed to assess risk factors that may influence patient outcomes after ICI rechallenge.

• autoimmunity
• immunotherapy

Cases of exacerbation of pre-existing neuromuscular diseases induced by immune checkpoint inhibitors (ICIs) have rarely been reported because patients with autoimmune diseases have generally been excluded from ICI therapy due to the increased risk of exacerbation. We describe the first case of an elderly patient who experienced exacerbation of a previously undiagnosed sporadic inclusion body myositis (sIBM), the most common myopathy in the geriatric population, which was triggered by anti-programmed cell death-1 therapy.

A 75-year-old man who was receiving pembrolizumab presented with limb weakness. Three years prior, he had noticed slowly progressive limb weakness, but he received no diagnosis. After the first infusion of pembrolizumab, his creatine kinase (CK) levels had increased. The neurological examination and muscle biopsy findings confirmed the diagnosis of sIBM and suggested exacerbation of sIBM induced by pembrolizumab. After the patient’s CK levels decreased, pembrolizumab was restarted. The tumor progressed after its treatment with pembrolizumab. The patient died after 15 months of follow-up.

In patients with slowly progressive limb weakness, sIBM should be explored before ICI therapy. In addition, if patients show high CK levels after ICI introduction, it is necessary to confirm whether they have sIBM in order to avoid unnecessary immunosuppressive therapies and assess whether they can tolerate ICI reintroduction.

• Immune checkpoint
• Immune-related adverse events
• Inclusion body myositis
• Pembrolizumab