Lightning Talk + Poster ESA-SRB-ANZBMS 2024 in conjunction with ENSA

Identifying conventional and novel biomarkers to predict checkpoint inhibitor associated autoimmune diabetes (#498)

Linda Wu 1 2 , John Wentworth 3 , Christopher Liddle 4 , Matteo Carlino 4 5 6 , David Brown 4 5 , Roderick Clifton-Bligh 1 4 , Georgina Long 1 4 6 , Sarah Sasson 4 5 , Venessa Tsang 1 4 , Alexander Menzies 1 4 , Jenny Gunton 2 4 5
  1. Royal North Shore Hospital, St Leonards, New South Wales, Australia
  2. Westmead Institute for Medical Research, Westmead, New South Wales, Australia
  3. Walter Eliza Hall Institute, Melbourne
  4. University of Sydney, Camperdown, New South Wales, Australia
  5. Westmead Hospital, Ryde, NEW SOUTH WALES, Australia
  6. Melanoma Institute Australia, North Sydney, New South Wales, Australia

Introduction

Checkpoint inhibitor-associated autoimmune diabetes (CIADM) is a rare but highly morbid complication of immune checkpoint inhibitor (ICI) therapy. The ability to predict CIADM-risk before ICIs would have huge clinical value.

 

Aim: To identify potential biomarkers for prediction of CIADM.

 

Methods

14 patients with metastatic melanoma treated with ICI who subsequently developed CIADM were identified. 28 controls matched for ICI, gender, cancer-response and other ICI-related adverse events were identified. Pre-treatment, on-ICI and post-CIADM serum and peripheral blood mononuclear cells (PBMCs) were analysed. Serum was analysed for type 1 diabetes autoantibodies, C-peptide, glucose and a cytokine panel of TNFα, IL-2, IL-4, IL-6, IL-10, CXCL10, IL-1β, CCL2, IL-17A, CXCL8, TGF-B1, and IL-12p70. PBMCs were sorted using a BD Influx III into 1000 CD8 cell subsets. PBMCs from each group were further analysed using flow cyometry. RNA was extracted and sequenced using a NovaSeq X with ~10 million 150bp paired-end reads. RNA-Seq analysis was performed using edgeR.

 

Results

Pre-ICI-treatment anti-GAD had predictive value for CIADM and was significantly higher in CIADM patients than in controls (p=0.0002). Anti-IA2, anti-IAA and anti-ZnT8 were not predictive. C-peptide fell rapidly from 1.8nmol/L on ICI to 0.18nmol/L post diagnosis for CIADM-patients and remained normal in controls.  IFNɣ, TNFα and IL-4 were significantly higher at CIADM diagnosis in comparison to controls. Flow cytometry analysis of PBMCs is underway.

Pathway enrichment analysis of differentially expressed RNA-seq genes in CIADM-patients identified significant regulation in pathways for B cell receptor and interferon signalling, RAS signalling and IGF1R signalling. These changes were not observed in controls.

 

Conclusion

Anti-GAD-antibodies have predictive value for CIADM but are incompletely sensitive. Further research is needed to prospectively test the predictive value of GAD Ab in combination with cytokines and other markers such as pancreatic volumetry as we have previously published.