TYPE Editorial PUBLISHED 05 January 2023 DOI 10.3389/fmed.2022.1104382 Editorial: Multidisciplinary OPEN ACCESS management of cancer patients with immune-related adverse EDITED AND REVIEWED BY Victoria Bunik, Lomonosov Moscow State University, Russia *CORRESPONDENCE events from checkpoint Mar Riveiro-Barciela mar.riveiro@gmail.com inhibitors SPECIALTY SECTION This article was submitted to Translational Medicine, Mar Riveiro-Barciela1,2,3*, Enriqueta Felip4 and a section of the journal Frontiers in Medicine María E. Suarez-Almazor5 RECEIVED 21 November 2022 1 Liver Unit, Internal Medicine Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron ACCEPTED 30 November 2022 Barcelona Hospital Campus, Barcelona, Spain, 2 Centro de Investigación Biomédica en Red de PUBLISHED 05 January 2023 Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain, 3 CITATION Department of Medicine, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain, 4 Medical Riveiro-Barciela M, Felip E and Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Suarez-Almazor ME (2023) Editorial: Barcelona, Spain, 5 Department of Health Services Research and Section of Rheumatology and Multidisciplinary management of Clinical Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, cancer patients with immune-related United States adverse events from checkpoint inhibitors. Front. Med. 9:1104382. doi: 10.3389/fmed.2022.1104382 KEYWORDS COPYRIGHT immunotherapy, toxicity, cancer, oncology—discipline, special populations © 2023 Riveiro-Barciela, Felip and Suarez-Almazor. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other Editorial on the Research Topic forums is permitted, provided the Multidisciplinary management of cancer patients with original author(s) and the copyright immune-related adverse events from checkpoint inhibitors owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which Cancer immunotherapy with immune checkpoint inhibitors (ICI) has revolutionized does not comply with these terms. the management of many frequent advanced tumors, such as lung cancer (1). These therapies have markedly improved the survival of cancer patients decreasing the rates of recurrence and progression of the underlying malignancies (2, 3). However, the widespread use of ICIs has also lead to an exponential rise of immune-related adverse events (irAEs) associated with these drugs. As summarized in Figure 1, real-world practice has brought to light substantial challenges in many aspects of the management of irAEs, for instance in the diversity of clinical manifestations, the grading of severity and strategies for treatment, with concerns about the potential effect of immunosuppressants on the efficacy of ICIs. Furthermore, immunotherapy is now used in special cancer populations such as those infected by human immunodeficiency virus (HIV), patients who have received solid- organ transplantation, individuals with underlying autoimmune disorders, or patients with latent infections such as tuberculosis o viral hepatitis, who can develop reactivation of their infections when they receive therapy with ICIs. Altogether, these issues highlight the vital importance of collaborative teamwork in order to optimize the prognosis of patients who develop irAEs or other complications as a consequence of receiving ICI. These challenges are the theme of this Research Topic of Frontiers in Medicine entitled Frontiers in Medicine 01 frontiersin.org Riveiro-Barciela et al. 10.3389/fmed.2022.1104382 FIGURE 1 Pitfalls of real-world practice immune-related adverse events associated with immune checkpoint inhibitors (ICIs) and need of multidisciplinary teams for their management. The difficulties and differences between irAEs reported at the clinical trials and real-world practice highlight the importance of the multidisciplinary management of patients with severe irAEs. “Multidisciplinary Management of Cancer Patients with disease or rheumatoid arthritis, patients with good control of Immune-Related Adverse Events from Checkpoint Inhibitors.” their autoimmune disorder prior to beginning ICI therapy are less likely to develop exacerbations during immunotherapy (4) (Aguilar-Company et al.). Fortunately, concomitant treatment Immunotherapy in special with immunosuppressive drugs, including anti-TNF agents, populations seems safe in patients receiving ICIs (Robles-Alonso et al.). It is well-known that patients who have received solid- organ transplantation are at increased risk of subsequent Immune checkpoint inhibitors and cancer, and may be eligible to receive ICI. On this topic, risk of latent infections Bermejo et al. summarize the outcomes and controversies surrounding the treatment with ICIs in patients with prior Widespread use of ICI has highlighted the risk of kidney transplantation. One of the hot topics in this field is the reactivation of latent infections such as tuberculosis or viral risk of acute rejection associated with ICI therapy. Concomitant hepatitis with these agents. treatment with mTOR monotherapy, low-dose corticosteroids In registry studies all patients with hepatitis B and C had or even a “dynamic immunosuppression” scheme seems to to be virologically suppressed, with the exception of those reduce the incidence of rejection. The efficacy of this last with hepatocellular carcinoma. Although, ICIs have no impact approach will be assessed in a prospective cohort, and robust on hepatitis C virus (HCV) and could even decrease HCV- results may be available soon (Bermejo et al.). RNA, screening for HCV is highly recommended in cancer The increased survival of patients with HIV, currently patients to assess potential concomitant cirrhosis and further comparable to those non-infected, highlights the need to risk of decompensation (5). Concerning hepatitis B, patients provide access to effective therapeutic cancer therapies in this with chronic hepatitis B, that is those with positive HBsAg, are at population, as shown in the paper by Aguilar-Company et al. In risk of reactivation when receiving ICIs (6), so they can benefit this setting, incidence of irAEs seems similar to that observed in from concomitant antiviral prophylaxis, as is recommended for the general cancer population, without changes in plasma viral those undergoing chemotherapy (5). Hitherto, data on the risk loads (Aguilar-Company et al.). of hepatitis B reactivation on patients with resolved infection i.e., The coexistence of an autoimmune disorder with cancer is testing negative for HBsAg but positive for anti-HBc, is scarce. of special relevance for therapy with ICIs, as there are risks In this Research Topic, Aceituno et al. reported the absence of of flares of the pre-existing autoimmune disease, as well as a hepatitis B reactivation in a cohort of 75 subjects with resolved potential for higher incidence of irAEs (Aguilar-Company et al.). HBV infection. Interestingly, authors also reported the relatively As learnt from studies of patients with inflammatory bowel low awareness of oncologists about the risk of viral hepatitis Frontiers in Medicine 02 frontiersin.org Riveiro-Barciela et al. 10.3389/fmed.2022.1104382 reactivation in patients on ICIs, with only 55% of subjects having against retreatment after a severe irAE. However, a few reports the complete serology panel performed before immunotherapy have suggested a strong correlation between the development was started (Aceituno et al.). of irAEs and a better response to ICIs (12); [Cardeña-Gutiérrez There is a need for further studies regarding the risk-benefit and López Barahona]. Moreover, for many patients there are no and the proper strategy for management of latent tuberculosis further alternatives for therapy beyond ICIs. Altogether, these in individuals about to initiate ICIs. Current evidence does not have led to rechallenge with ICIs after recovery from a severe clearly support routine latent tuberculosis infection screening, irAE. Real-world data from subjects with history of a severe and treatment for latent tuberculosis should be weighed on gastrointestinal irAE have revealed that relapse is not universal, an individual basis, accounting for potential pharmacological ranging from 24% among patients with prior immune-related interactions, risk of hepatotoxicity and expected survival colitis to 35% in those with previous immune-related hepatitis (Aguilar-Company et al.). (13, 14). Despite this data, retreatment with ICIs after a severe irAE, as many other aspects about immunotherapy, remains a hot topic, with low agreement even among experts on their Treatment of severe immune-related management (15). adverse events In summary, several challenges remain in the management of severe irAEs which require collaborative multidisciplinary One of the hottest topics on the management of irAEs is efforts. As clinical trials of ICIs did not include special the treatment of severe grade-3 and grade-4 adverse events. populations such as those with pre-exiting autoimmune Corticosteroids have been the backbone of therapy of severe diseases or transplants, or patients with chronic infections, irAEs in both registry studies and international guidelines (7, 8). initially there were concerns about treating with ICIs cancer However, real-world practice has revealed that for many patients patients with these disorders. As new real-world evidence with severe irAEs, temporal discontinuation of ICIs may result emerges, it is becoming increasingly clear, that cancer patients in improvement without need of immunosuppressant therapy, with these concomitant comorbidities can also benefit from for instances in immune-mediated hepatitis (9, 10). Moreover, immunotherapy and should not be denied treatment in most data on some irAEs has shown the potential benefits of early cases. Careful multidisciplinary management with an emphasis access to corticosteroid-sparing agents. On this regard, studies in controlling concomitant comorbidities can result in successful of real-world clinical practice indicate that specific therapy for therapy in these patients, for many of whom immunotherapy irAEs in accordance with the autoimmune disorders they mimic will be their last therapeutic alternative. may be beneficial. For example, in the case of immune-related colitis, early access to endoscopy can identify subjects with ulcers or pancolitis who will benefit from infliximab therapy (4). Author contributions Similarly individuals with severe immune-related arthritis could benefit from early therapy with TNF or IL-6 inhibitors (11). Drafting of the manuscript: MR-B. Critical revision of However, an outstanding issue associated with the use of the manuscript for important intellectual content: EF and immunosuppressant drugs is their potential harm on cancer MS-A. All authors contributed to the article and approved the progression, especially taking into account the advanced stage submitted version. of tumors in the majority of patients undergoing ICIs. As summarized by Bruera et al., the potential deleterious effect of corticosteroids on cancer progression seems to be associated Conflict of interest with dose and timing of use. Concomitant treatment with corticosteroids at the initiation of ICIs can negatively impact The authors declare that the research was conducted in the overall and progression-free survival, whereas temporal or absence of any commercial or financial relationships that could intermittent corticosteroids such as are used often for irAEs, do be construed as a potential conflict of interest. not seem to negatively impact survival (Bruera et al.). Rechallenge with immune Publisher’s note checkpoint inhibitors after a severe All claims expressed in this article are solely those of the irAE authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the Once an irAE is resolved, the next step is to assess the reviewers. Any product that may be evaluated in this article, or possibility of ICI rechallenge. The majority of clinical trials claim that may be made by its manufacturer, is not guaranteed and, in consequence, the international guidelines, recommend or endorsed by the publisher. Frontiers in Medicine 03 frontiersin.org Riveiro-Barciela et al. 10.3389/fmed.2022.1104382 References 1. Felip E, Altorki N, Zhou C, Csoszi T, Vynnychenko I, Goloborodko O, et al. immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol. 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