Treatment of the Immune-Related Adverse Effects of Immune Checkpoint Inhibitors

Friedman, Claire F.; Proverbs-Singh, Tracy; Postow, Michael A.

doi:10.1001/jamaoncol.2016.1051

Cited by 705 publications

(740 citation statements)

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“…12,13 Clinically, corticosteroids are routinely used in the management of cancer for fatigue, night sweats, appetite stimulation, antiemesis, and the reduction of side effects associated with certain chemotherapies (platinum-based agents and taxanes) and immune checkpoint inhibitors. 14,15 Corticosteroids are especially important in the management of tumors residing in the central nervous system (CNS), since they can effectively palliate neurological deficits and reduce complications caused by cerebral edema through restoring the integrity of the blood-brain barrier (BBB). 16 Moreover, cerebral edema is often potentiated by the additive pro-inflammatory effects of brain radiation plus immunotherapy, even when not given concurrently, thus necessitating the use of corticosteroids post-treatment.…”

Section: Introductionmentioning

confidence: 99%

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

et al. 2018

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Immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) is emerging as an important treatment strategy in a growing list of cancers, yet its clinical benefits are limited to a subset of patients. Further investigation of tumor-intrinsic predictors of response and how extrinsic factors, such as iatrogenic immunosuppression caused by conventional therapies, impact the efficacy of anti-PD-1 therapy are paramount. Given the widespread use of corticosteroids in cancer management and their immunosuppressive nature, this study sought to determine how corticosteroids influence anti-PD-1 responses and whether their effects were dependent on tumor location within the periphery versus central nervous system (CNS), which may have a more limiting immune environment. In well-established anti-PD-1-responsive murine tumor models, corticosteroid therapy resulted in systemic immune effects, including severe and persistent reductions in peripheral CD4+ and CD8 + T cells. Corticosteroid treatment was found to diminish the efficacy of anti-PD-1 therapy in mice bearing peripheral tumors with responses correlating with peripheral CD8/Treg ratio changes. In contrast, in mice bearing intracranial tumors, corticosteroids did not abrogate the benefits conferred by anti-PD-1 therapy. Despite systemic immune changes, anti-PD-1-mediated antitumor immune responses remained intact during corticosteroid treatment in mice bearing intracranial tumors. These findings suggest that anti-PD-1 responses may be differentially impacted by concomitant corticosteroid use depending on tumor location within or outside the CNS. As an immune-specialized site, the CNS may potentially play a protective role against the immunosuppressive effects of corticosteroids, thus sustaining antitumor immune responses mediated by PD-1 blockade.

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Section: Introductionmentioning

confidence: 99%

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

et al. 2018

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“…Guidelines for the management of imAEs have been proposed in expert reviews [144,145,151,152] but are also available within the prescribing information for each agent and in brochures that can be downloaded from the manufacturers' websites [11][12][13][14][15][16][153][154][155][156][157]. Most moderate and severe immune-mediated toxicities can be managed effectively with corticosteroids and can be resolved within 6 to 12 weeks [146].…”

Section: Adverse Events Associated With Icbsmentioning

confidence: 99%

Immune Checkpoint Blockade: The New Frontier in Cancer Treatment

et al. 2018

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Immune checkpoint blockers have revolutionized cancer treatment in recent years. These agents are now approved for the treatment of several malignancies, including melanoma, squamous and non-squamous non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, and head and neck squamous cell carcinoma. Studies have demonstrated the significant impact of immunotherapy versus standard of care on patient outcomes, including durable response and extended survival. The use of immunotherapy-based combination therapy has been shown to further extend duration of response and survival. Immunotherapies function through modulation of the immune system, which can lead to immune-mediated adverse events (imAEs). These include a range of dermatologic, gastrointestinal, endocrine, and hepatic toxicities, as well as other less common inflammatory events. ImAEs are typically low grade and manageable when identified early and treated with appropriate measures. Identifying the right patient for the right therapy will become more important as new immunotherapies and immunotherapy-based combinations are approved and costs of cancer care continue to rise.

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“…The manipulation of the immune system using immunotherapeutic interventions has changed the therapeutic landscape in many type of cancers [1][2][3][4]. However, immunotherapy carries immune-related adverse effects (irAEs) which can be significant [5][6][7]. irAEs are usually reversible but occasionally can be life-threatening [5][6][7].…”

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confidence: 99%

“…For instance in grade 1 rash, namely localised rash or pruritus (less than 10% BSA), topical corticosteroid creams of medium to high potency, sun protection creams as well as oral antihistamines can be used [5,7,14,23]. Pruritic symptoms can also be relieved with the use of cold compresses, oatmeal baths as well as oral or topical doxepin hydrochloride or oral aprepitant if the active daily living activities have been affected [5,11,23]. If the rash is stable or responding to the local treatments, ICPI can be continued [7].…”

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confidence: 99%

“…Finally, in rare cases, such as Stevens Johnson syndrome and toxic epidermal necrolysis, a multidisciplinary approach should be followed in conjunction with the dermatology and critical care teams. These patients should be admitted in hospital for supportive care with intravenous fluids and electrolyte replacement and the drug should be permanently discontinued [5,7,11,23]. …”

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confidence: 99%

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2016

JCPCR

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Background: Over the last 5 years ever since Ipilimumab received FDA approval for the treatment of metastatic melanoma, immunotherapy as a treatment modality is making its presence felt in oncology clinics across the globe. While initially approved for the treatment of metastatic melanoma alone, the immunotherapy repertoire is ever expanding with its' utility being assessed for in the metastatic and adjuvant setting. The adverse effect profile from immunotherapy drugs differs from that of conventional chemotherapy that oncological services have trained in managing over the last few decades. This raises the need for educating health care professionals as the scenarios that patients present with at acute admissions or in clinic secondary to immune related adverse effects (iRAEs) can often be misleading. Aims:This review aims to synopsise the common and less common iRAEs and highlight their varied presentations, in addition to stressing the need to institute timely immunosuppression, which forms the cornerstone in the management of iRAEs.Recommendations: iRAEs have been recognised more frequently and in greater severity in dose dense and combination treatment regimens. While dermatological, gastrointestinal, hepatic toxicities in addition to endocrinopathies are the most commonly encountered iRAEs though other organ systems can be involved. The appropriate grading of an iRAEs' severity, delaying or discontinuing immunotherapy based treatment, supportive care, commencement of immunosuppression (with corticosteroids and/or steroid sparing agents) and a multidisciplinary approach are key constituents in the treatment pathway of iRAEs. Conclusion:Early recognition of iRAEs and timely commencement of appropriate immunosuppression is imperative in order to reduce the risk of significant morbidity and potential mortality. The management of iRAEs warrants a multidisciplinary approach which would be aided by the development of local guidelines and educational activities directed at providing health care professionals with the information and tools required to recognise and appropriately treat iRAEs. IntroductionOver the last few decades there has been an increasing interest in the field of cancer immunotherapy. The manipulation of the immune system using immunotherapeutic interventions has changed the therapeutic landscape in many type of cancers [1][2][3][4]. However, immunotherapy carries immune-related adverse effects (irAEs) which can be significant [5][6][7]. irAEs are usually reversible but occasionally can be life-threatening [5][6][7]. A retrospective study on the irAEs of Ipilimumab showed that 85% of patients experienced irAEs of any grade of whom 19% discontinued therapy [8]. 35% patients required systemic corticosteroids and 10% required anti-TNF therapy for irAEs [8]. There were no significant differences in overall survival in those with and without irAEs or between those who received corticosteroids or not [8,9]. Hence, this requires the development of treatment protocols and training of the healthcar...

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Treatment of the Immune-Related Adverse Effects of Immune Checkpoint Inhibitors

Cited by 705 publications

References 71 publications

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

Immune Checkpoint Blockade: The New Frontier in Cancer Treatment

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