Delayed immune-mediated hepatitis after three cycles of pembrolizumab for the treatment of sinonasal melanoma.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that induce the anti-tumor effects of T cells by targeting co-inhibitory immune checkpoints. The development of ICIs has revolutionized the clinical practice of oncology, leading to significant improvements in outcomes; therefore, ICIs are now standard care for various types of solid cancers. Immune-related adverse events, the unique toxicity profiles of ICIs, usually develop 4-12 weeks after initiation of ICI treatment; however, some cases can occur >3 months after cessation of ICI treatment. To date, there have been limited reports about delayed immune-mediated hepatitis (IMH) and histopathologic findings. Herein, we present a case of delayed IMH that occurred 3 months after the last dose of pembrolizumab, including histopathologic findings of the liver. This case suggests that ongoing surveillance for immune-related adverse events is required, even after cessation of ICI treatment.

Neuromuscular complications of immune checkpoint inhibitor therapy.

Immune checkpoint inhibitor (ICPI) therapy unleashes the body's natural immune system to fight cancer. ICPIs improve overall cancer survival, however, the unbridling of the immune system may induce a variety of immune-related adverse events. Neuromuscular immune complications are rare but they can be severe. Myasthenia gravis and inflammatory neuropathy are the most common neuromuscular adverse events but a variety of others including inflammatory myopathy are reported. The pathophysiologic mechanism of these autoimmune disorders may differ from that of non-ICPI-related immune diseases. Accordingly, while the optimal treatment for ICPI-related neuromuscular disorders generally follows a traditional paradigm, there are important novel considerations in selecting appropriate immunosuppressive therapy. This review presents 2 new cases, a summary of neuromuscular ICPI complications, and an approach to the diagnosis and treatment of these disorders. Muscle Nerve, 2018.

Spectrum of Immune Checkpoint Inhibitor Anemias: Results From a Single Center, Early-Phase Clinical Trials Case Series Experience.

Immune checkpoint inhibitor anemias (ICI-A) are a rare entity which can be potentially life-threatening without prompt identification. The goal of the study is to characterize the presentation, evaluation, and outcomes of ICI therapy in early phase clinical trial setting to guide future research and to develop standardized care guidelines. Retrospective chart review of 333 patients who participated in early phase clinical trials at the University of Texas MD Anderson Cancer Center revealed four cases with ICI-A between 2016 and 2020. We identified a spectrum of four cases which included ICI-related autoimmune hemolytic anemias, hemophagocytic lymphohistiocytosis and thrombotic microangiopathy as a result of combinatory investigational therapies involving ICI. Patient presentation, evaluation, bone marrow pathology, interventions, and clinical course were reviewed. The median time to onset of hematological immune-related adverse events (heme-irAEs) in this retrospective series was 3.5 weeks (2 - 6 weeks). One patient had pre-existing untreated chronic lymphocytic leukemia. Glucocorticoids are an effective first-line treatment in most patients although most patients were not rechallenged but successfully had complete recovery and pursued further non-immunotherapy-based therapies. Cognizance of ICI-A in clinical trial setting is paramount to early recognition of heme-irAEs. Further research is needed to identify and stratify risk factors during clinical trial enrollment and optimal management strategies for immune-mediated hematologic toxicities.

Immune- and Non-Immune-Mediated Adverse Effects of Monoclonal Antibody Therapy: A Survey of 110 Approved Antibodies.

Identification of new disease-associated biomarkers; specific targeting of such markers by monoclonal antibodies (mAbs); and application of advances in recombinant technology, including the production of humanized and fully human antibodies, has enabled many improved treatment outcomes and successful new biological treatments of some diseases previously neglected or with poor prognoses. Of the 110 mAbs preparations currently approved by the FDA and/or EMA, 46 (including 13 antibody-drug conjugates) recognizing 29 different targets are indicated for the treatment of cancers, and 66, recognizing 48 different targets, are indicated for non-cancer disorders. Despite their specific targeting with the expected accompanying reduced collateral damage for normal healthy non-involved cells, mAbs, may cause types I (anaphylaxis, urticaria), II (e.g., hemolytic anemia, possibly early-onset neutropenia), III (serum sickness, pneumonitis), and IV (Stevens-Johnson syndrome, toxic epidermal necrolysis) hypersensitivities as well as other cutaneous, pulmonary, cardiac, and liver adverse events. MAbs can provoke severe infusion reactions that resemble anaphylaxis and induce a number of systemic, potentially life-threatening syndromes with low frequency. A common feature of most of these syndromes is the release of a cascade of cytokines associated with inflammatory and immunological processes. Epidermal growth factor receptor-targeted antibodies may provoke papulopustular and mucocutaneous eruptions that are not immune-mediated.

The predictive potential of autoimmune-inflammatory syndrome induced by adjuvants (ASIA) criteria to assess the risk of adverse events and efficacy of immune checkpoint inhibitor therapy.

At the moment, there are no approved predictive markers of immune adverse events (irAES) induced by immune checkpoint inhibitors (ICIs) and the treatment efficacy. The early stages of irAES have some similarities with adjuvant-induced autoimmune/pro-inflammatory syndrome (ASIA). This study aims to assess the predictive possibility of using the "ASIA questionnaire" in patients on immune checkpoint inhibitor therapy in comparison with determination of PD-L1 expression to predict the risk of irAES development and therapy efficacy. We examined patients (n = 91) being treated for solid tumors. The signs of ASIA were found in 74% (66/91), while ASIA syndrome was diagnosed in 54% of cases (49/91). No statistically significant difference in the frequency of ICI-dependent complication development regarding the presence of previous ASIA clinical manifestations, hereditary factors, sex, different trigger factors was found. Index based on combination of PD-L1 determination and ASIA index was created. With reference > 2.5 units, the disease control rate (DCR) could be predicted with sensitivity 100.0% and specificity 70.00%, p = 0.007. The study did not reveal the diagnostic value of ASIA questionnaire to assess the risk of adverse events; however, in early stages, the development of ASIA symptoms diagnosed with the questionnaire in complex with PD-L1 expression allowed to predict a treatment efficacy.

The immuno-oncological implications of insulin.

Emerging evidence has implicated insulin in regulating the phenotypes of various immune cells through canonical downstream signalling effectors of insulin, namely, the PI3K/Akt/mTOR pathway. Notably, these signalling components also exhibit crosstalk with other immune signalling pathways, such as the JAK/STAT pathway (activated by cytokines and growth factors), and, importantly, are also negatively regulated by the immune checkpoint blockers (ICBs), PD-1 and CTLA-4. Here, we point out recent findings, suggesting that insulin may promote a pro-inflammatory phenotype with potential implications on ICB therapy. As an example, the contemporary paradigm holds that, while T cell receptor recognition of distinct MHC-expressed epitopes ensures specificity, co-activation of CD28 along with signal inputs form various cytokines and insulin operates to 'fine-tune' the immune response via PI3K and other downstream signalling molecules. These considerations highlight the urgent need for focused investigations into the role of insulin in regulating immune cell function in the context of ICB therapies.

Vitiligo Adverse Event Observed in a Patient With Durable Complete Response After Nivolumab for Metastatic Renal Cell Carcinoma.

Background: Renal cell carcinoma is the third most prevalent urological cancer worldwide and about 30% of patients present with metastatic disease at the time of diagnosis. Systemic treatments for metastatic renal cell carcinoma have improved recently. Vascular endothelial growth factor targeting therapies were the previous standard of care. However, immune checkpoint inhibitors used in second line therapy have now been shown to improve patient survival. We report a case of metastatic renal cell carcinoma with nivolumab as a second-line therapy after progression with tyrosine kinase inhibitor therapy. Unusual adverse events in metastatic renal cell carcinoma, such as vitiligo, were observed in this patient who developed a remarkable documented pathological complete response to his renal tumor. Case presentation: A 60-year-old caucasian male was diagnosed with a pulmonary metastatic clear cell renal cell carcinoma. Sunitinib was used as first line treatment without success. He received nivolumab in second-line treatment. He developed several immune-related adverse events, most notably vitiligo. The patient had a radiological complete response on metastatic sites, with a significant decrease of renal tumor volume and underwent cytoreductive nephrectomy after 2 years of treatment, confirming the pathological complete response. The patient remains disease-free for 10 months without further systemic therapy after nivolumab discontinuation. Conclusions: Pathological complete response with nivolumab in metastatic renal cell carcinoma is rare. This case further highlights the potentially predictive role of immune-related adverse events during nivolumab therapy for metastatic renal cell carcinoma and raises questions concerning the role of nephrectomy after immune checkpoint inhibitor therapy. Further studies are needed to better identify predictive factors for treatment response to immunotherapy in metastatic renal cell carcinoma, and to better understand the role of nephrectomy after nivolumab treatment.