Genetic risk analysis of a patient with fulminant autoimmune type 1 diabetes mellitus secondary to combination ipilimumab and nivolumab immunotherapy.
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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. CASE PRESENTATION: 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.
Genetic risk analysis
HLA risk allele
Single nucleotide polymorphism
Type I diabetes
Published Version (Please cite this version)10.1186/s40425-016-0196-z
Publication InfoHanks, Brent A; Lowe, JR; Mathews, CE; Moss, LG; Perry, DJ; & Salama, April KS (2016). Genetic risk analysis of a patient with fulminant autoimmune type 1 diabetes mellitus secondary to combination ipilimumab and nivolumab immunotherapy. J Immunother Cancer, 4. pp. 89. 10.1186/s40425-016-0196-z. Retrieved from http://hdl.handle.net/10161/13294.
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Assistant Professor of Medicine
My lab is interested in elucidating the molecular and cellular mechanisms involved in tumor-mediated immune suppression and cancer immunotherapy resistance. Our overriding hypothesis is that tumor cells and/or their associated stromal elements elicit soluble factors that tolerize local dendritic cell populations and/or recruit other immunosuppressive cell populations to the tumor bed; thereby, interfering with the generation of an effective anti-tumor immune response. This work has both basic an