Co-occurring infections in cancer patients treated with checkpoint inhibitors significantly increase the risk of immune related adverse events

Abstract Therapeutic antibodies designed to target immune checkpoint proteins such as PD-1, PD-L1, and CTLA-4 have been applied in the treatment of various tumor types, including small and non-small cell lung cancers, melanoma, renal cell carcinoma, and others. These treatments combat cancers by reactivating CD8 cytotoxic T-cells. Nevertheless, this unique targeted mode of action was found to be associated with a broader range of immune-related adverse events, irAEs, affecting multiple physiological systems. Depending on their severity, these irAEs often necessitate the suspension or discontinuation of treatment and, in rare instances, may lead to fatal consequences. In this study we investigated over eighty thousand adverse event reports of irAEs in patients treated with PD-1, PD-L1, and CTLA-4 inhibitors. FDA Adverse Event Reporting System MedWatch submissions were used as the data source. These therapeutics included pembrolizumab, nivolumab, cemiplimab, avelumab, durvalumab, atezolizumab, and ipilimumab. The data analysis of these reports revealed a statistically significant association of immune related adverse events, including serious and life-threatening events in patients who experienced infectious disease during treatment. Additionally, the association trend was preserved across all the three classes of checkpoint inhibitors and each of the seven individual therapeutic agent cohorts. Competing Interest Statement The authors have declared no competing interest. Funding Statement The study was funded in part by NIH R35GM131881. The study was in part funded by FAST Armenia. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability The datasets analyzed for this study can be found in the FAERS database. For online access to FAERS/AERS datasets, please refer to the following link: https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html The FDA Medical Queries tables were made available online in September 2022 and may be accessed at: https://downloads.regulations.gov/FDA-2022-N-1961-0001/attachment_1.xlsm https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html Abbreviations - AE - adverse event - AERS - adverse event reporting system - AD - autoimmune disease - CI - confidence interval - CTLA-4 - cytotoxic T-lymphocyte–associated antigen 4 - FDA - Food and Drug Administration - FAERS - FDA Adverse Event Reporting System - FMQs - FDA medical queries - ICI - immune checkpoint inhibitors - irAE - immune-related adverse events - PD-1 - programmed cell death protein 1 - PD-L1 - programmed cell death protein 1 ligand - ROR - Reporting odds ratios - PT - Preferred term