title: Genetic risk analysis of a patient with fulminant autoimmune type 1 diabetes mellitus secondary to combination ipilimumab and nivolumab immunotherapy.
abstract: BACKGROUND
  Checkpoint inhibitor immunotherapy is becoming an effective treatment modality for an increasing number of malignancies. As a result, autoinflammatory side-effects are also being observed more commonly in the clinic. We are currently unable to predict which patients will develop more severe toxicities associated with these treatment regimens.
  
  
  METHODS
  We present a patient with stage IV melanoma that developed rapid onset autoimmune type 1 diabetes (T1D) in response to combination ipilimumab and nivolumab immunotherapy. At the time of the patient's presentation with diabetes ketoacidosis, a confirmed anti-GAD antibody seroconversion was noted. Longer-term follow-up of this patient has demonstrated a durable complete response based on PET CT imaging along with a persistently undetectable C-peptide level. Single nucleotide polymorphism gene sequencing and HLA risk allele analysis has revealed the patient to lack any established genetic predisposition to the development of autoimmune T1D.
  
  
  CONCLUSIONS
  While larger studies are necessary to better understand the role of genetic risk factors for the development of autoimmune toxicities in those patients undergoing checkpoint inhibitor immunotherapy, these results suggest that pre-screening patients for known T1D risk alleles may not be indicated. Additional investigation is needed to determine whether an approach such as T cell receptor clonotypic analysis to identify the presence of autoreactive T cell clones may be an effective approach for predicting which patients are at risk for the development of autoinflammatory toxicities while undergoing checkpoint inhibitor immunotherapy.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710 USA.
authors.forename: Jared R
authors.initials: JR
authors.lastname: Lowe
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610 USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Perry
authors.affiliation: Department of Medicine, Division of Medical Oncology, Melanoma Program, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710 USA.
authors.forename: April K S
authors.initials: AK
authors.lastname: Salama
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610 USA.
authors.forename: Clayton E
authors.initials: CE
authors.lastname: Mathews
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism, & Nutrition, Duke University Medical Center, Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Durham, NC 27701 USA.
authors.forename: Larry G
authors.initials: LG
authors.lastname: Moss
authors.affiliation: Department of Medicine, Division of Medical Oncology, Melanoma Program, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710 USA.
authors.forename: Brent A
authors.initials: BA
authors.lastname: Hanks
keywords: Advanced melanoma; Autoimmune endocrinopathy; Genetic risk analysis; HLA risk allele; Ipilimumab; Nivolumab; Single nucleotide polymorphism; Type I diabetes