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  1. Advancing Regulatory Science

Whole exome sequencing to predict immune related adverse events and response to checkpoint inhibitors

CERSI Collaborators: University of California, San Francisco: Elad Ziv, MD: Zoe Quandt, MD: Pooja Middha, PhD.; Vanderbilt University Medical Center: Melinda Aldrich, PhD.; Memorial Sloan Kettering Cancer Center: Adam Schoenfeld, MD

FDA Collaborators: : Marc Theoret, MD, Abhilasha Nair, MD, Wenming Xiao, PhD, Patrick DeMoss, MD, Caitlin Drew, MSN, RN

Project Start Date: August 2022

Regulatory Science Challenge

Immunotherapies have improved the survival of patients with multiple types of metastatic cancer including metastatic melanoma, lung cancer, head and neck cancer, bladder cancer, and renal cell carcinoma among others. However, most patients have an extremely limited or no response to these drugs. In addition, a portion of patients have significant side effects from immunotherapy drugs including immune related adverse events (irAEs). Approximately 20% of patients develop (irAE's)1, and some irAE's have similarity to autoimmune disorders (PMID 37493210).2 Few biomarkers have been developed to determine who will develop irAEs, and none are currently in clinical use. These irAEs frequently require cessation of therapy and in some cases can lead to life-threatening illness. Being able to identify who is at an increased risk of developing irAE(s) before giving immunotherapy will be extremely helpful to clinicians and patients.

Project Description and Goals

Researchers aim to investigate the effect of inherited genetic variation on treatment response to checkpoint inhibitors. They will investigate the effect of inherited variants that affect the protein sequence of genes using an approach called “whole exome sequencing” (WES). Their focus will be on irAEs and treatment outcomes among patients with non-small cell lung cancer (NSCLC) since this is one of the most common indications for Immune Checkpoint Inhibitors. WES will be used to identify genes associated with increased risk of irAEs, as well as identify patients who are more likely to respond to immunotherapy.

References

  1. Ik Shin Chin, Khan, A., Olsson-Brown, A., Papa, S., Middleton, G., & Palles, C. (2022). Germline genetic variation and predicting immune checkpoint inhibitor induced toxicity. Npj Genomic Medicine, 7(1). https://doi.org/10.1038/s41525-022-00345-6
  2. Singh, N., Hocking, A. M., & Buckner, J. H. (2023). Immune‐related adverse events after immune check point inhibitors: Understanding the intersection with autoimmunity. Immunological Reviews. https://doi.org/10.1111/imr.13247

 

 
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