Genetic risk analysis of a patient with fulminant autoimmune type 1 diabetes mellitus secondary to combination ipilimumab and nivolumab immunotherapy

Abstract

BackgroundCheckpoint 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.Case presentationWe 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.ConclusionsWhile 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.

Is autoimmunity the Achilles' heel of cancer immunotherapy?

“…With regard to the latter, although existing observations of immune-related toxicity are helpful, most literature reporting autoimmune-associated disease consists of case reports 54,55 , in which, for example, autoantibodies are often not described. Moreover, frequently, autoantibodies are negative when reported and autoimmune disease presents rapidly, as seen with diabetic ketoacidosis and T1D; because subsequent longitudinal data are often not reported, scientists have generally been unable to assess whether autoantibodies, such as GAD-65, ICA-512, and ZnT8, become detectable over time.…”

“…By contrast, biomarker studies are just beginning to identify patients who are at increased risk for immunotoxicity 71 . A recent SNP analysis of high-risk loci for T1D in a human case of fulminant T1D treated with combination ipilimumab and nivolumab failed to reveal a high-risk genetic profile, and so the role of genetic predisposition is unclear with regard to identifying those who might develop autoimmunity when treated with checkpoint blockade 54 . More accurate predictions of irAEs require the development of better insights into the genetics, epigenetics, and environmental elements that control immunity in both animal models and humans 72 .…”

New onset diabetes after nivolumab treatment

“…Other authors also reported the onset of DM after anti-PD-1 therapy,6 some of them in patients under treatment with nivolumab 3–5 7–17. The time of onset varied between 1 and 48 weeks 5–15 15–23…”

Painless Thyroiditis and Fulminant Type 1 Diabetes Mellitus in a Patient Treated with an Immune Checkpoint Inhibitor, Nivolumab

“…In contrast, twelve cases of anti-PD-1 therapy-induced type 1 diabetes mellitus with positive islet-related autoantibodies (type 1A) have been reported in the literatures (Table 4) (Hughes et al 2015;Martin-Liberal et al 2015;Mellati et al 2015;Hansen et al 2016;Hofmann et al 2016;Lowe et al 2016;Li et al 2017;Araujo et al 2017;Chae et al 2017). Thyroid dysfunction accompanied by positive thyroid autoantibodies occurred in at least three out of these twelve cases of type 1 diabetes mellitus with positive isletrelated autoantibodies.…”

“…Some of the literatures reported cases of insulindependent diabetes mellitus with positive islet-related autoantibodies (type 1A, autoimmune diabetes mellitus) after anti-PD-1 therapy as fulminant type 1 diabetes mellitus (Lowe et al 2016;Araujo et al 2017). But it is difficult to conclude that these cases were typical fulminant type 1 diabetes mellitus because of the presence of positive islet- related autoantibodies.…”