Immune Checkpoint Inhibitors and Immune-Related Adverse Events in Patients With Advanced Melanoma

Chang, Ching‐Yuan; Park, Haesuk; Malone, Daniel C.; Wang, Ching Yu; Wilson, Debbie L.; Yeh, Yu Min; Boemmel-Wegmann, Sascha van; Lo-Ciganic, Wei Hsuan

doi:10.1001/jamanetworkopen.2020.1611

Cited by 80 publications

(48 citation statements)

References 36 publications

(129 reference statements)

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“…This suggests that reduction of tumor size is a clinical marker for the development of irAEs. To further support that, early reports from lung cancer and melanoma patients demonstrated a similar correlation between the anti-tumor effect of ICI and the severity of the irAEs [16][17][18]. A proposed mechanism of irAEs is that ICI reduce the self-tolerance of central memory or tissue resident T cells leading to the infiltration of tissues [19].…”

Section: Discussionmentioning

confidence: 79%

A novel mouse model for checkpoint inhibitor-induced adverse events

et al. 2021

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Immune checkpoint inhibitors have demonstrated significant efficacy in the treatment of a variety of cancers, however their therapeutic potential is limited by abstruse immune related adverse events. Currently, no robust animal model exists of checkpoint inhibitor-induced adverse events. Establishing such a model will improve our mechanistic understanding of this process, which in turn will inform design of improved therapies. We developed a mouse model to determine inflammatory toxicities in response to dual checkpoint blockade in the presence of syngeneic tumors. Mice from susceptible genetic backgrounds received intraperitoneal injections of anti-mouse PD-1 and CTLA-4 antibodies. The mice were monitored for weight loss and histologic evidence of inflammation. Blood was collected for basic metabolic panels and titers of anti-nuclear antibodies. In parallel, mice were also treated with prednisolone, which is commonly used to treat immune related adverse events among cancer patients. Among all the genetic backgrounds, B6/lpr mice treated with anti-CTLA-4 and anti-PD-1 antibodies developed more substantial hepatitis, pancreatitis, colitis, and pneumonitis characterized by organ infiltration of immune cells. Mice that developed tissue infiltration demonstrated high serum levels of glucose and high titers of anti-nuclear antibodies. Finally, while administration of prednisolone prevented the development of the inflammatory adverse events, it also abrogated the protective anti-tumor effect of the checkout inhibitors. Genetic background and treatment modalities jointly modified the inflammatory adverse events in tumor bearing mice, suggesting a complex mechanism for checkpoint inhibitor-related inflammation. Future studies will assess additional genetic susceptibility factors and will examine possible contributions from the administration of other anti-inflammatory drugs.

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Section: Discussionmentioning

confidence: 79%

A novel mouse model for checkpoint inhibitor-induced adverse events

et al. 2021

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“…Although immunotherapy is a targeted therapy and therefore it is better tolerated compared to common chemotherapy, it has been associated with the emergence of a new panel of dysimmune toxicities called irAEs [ 9 , 118 – 120 ].…”

Section: Immune-related Adverse Events To Immunotherapymentioning

confidence: 99%

Immunotherapy in the Treatment of Metastatic Melanoma: Current Knowledge and Future Directions

Ralli

Botticelli

Visconti

et al. 2020

Journal of Immunology Research

164

138

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Melanoma is one of the most immunologic malignancies based on its higher prevalence in immune-compromised patients, the evidence of brisk lymphocytic infiltrates in both primary tumors and metastases, the documented recognition of melanoma antigens by tumor-infiltrating T lymphocytes and, most important, evidence that melanoma responds to immunotherapy. The use of immunotherapy in the treatment of metastatic melanoma is a relatively late discovery for this malignancy. Recent studies have shown a significantly higher success rate with combination of immunotherapy and chemotherapy, radiotherapy, or targeted molecular therapy. Immunotherapy is associated to a panel of dysimmune toxicities called immune-related adverse events that can affect one or more organs and may limit its use. Future directions in the treatment of metastatic melanoma include immunotherapy with anti-PD1 antibodies or targeted therapy with BRAF and MEK inhibitors.

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“…To avoid such consequences, it is necessary to choose the safest dosage and frequency of administration of ICIs to patients, enabling the maximum effects with minimal toxicity to the body. In one study, researchers conducted a meta-analysis of RCTs for the treatment of progressive melanoma and found that using nivolumab, 3 mg/kg (3 milligrams of drug per kilogram of body weight) every 2 weeks, and pembrolizumab, 2 mg/kg every 3 weeks and 10 mg/kg every 3 weeks, the risk of serious irAEs is low [ 96 ]. In another article, researchers analyzed NSCLC patients who developed autoimmune encephalitis after using ICIs.…”

Section: Monoclonal Antibodiesmentioning

confidence: 99%

Current Trends in Cancer Immunotherapy

et al. 2020

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The search for an effective drug to treat oncological diseases, which have become the main scourge of mankind, has generated a lot of methods for studying this affliction. It has also become a serious challenge for scientists and clinicians who have needed to invent new ways of overcoming the problems encountered during treatments, and have also made important discoveries pertaining to fundamental issues relating to the emergence and development of malignant neoplasms. Understanding the basics of the human immune system interactions with tumor cells has enabled new cancer immunotherapy strategies. The initial successes observed in immunotherapy led to new methods of treating cancer and attracted the attention of the scientific and clinical communities due to the prospects of these methods. Nevertheless, there are still many problems that prevent immunotherapy from calling itself an effective drug in the fight against malignant neoplasms. This review examines the current state of affairs for each immunotherapy method, the effectiveness of the strategies under study, as well as possible ways to overcome the problems that have arisen and increase their therapeutic potentials.

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Immune Checkpoint Inhibitors and Immune-Related Adverse Events in Patients With Advanced Melanoma

Cited by 80 publications

References 36 publications

A novel mouse model for checkpoint inhibitor-induced adverse events

A novel mouse model for checkpoint inhibitor-induced adverse events

Immunotherapy in the Treatment of Metastatic Melanoma: Current Knowledge and Future Directions

Current Trends in Cancer Immunotherapy

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