Identification of a Germline Pyrin Variant in a Metastatic Melanoma Patient With Multiple Spontaneous Regressions and Immune-related Adverse Events.

Abstract

The mechanisms underlying tumor immunosurveillance and their association with the immune-related adverse events (irAEs) associated with checkpoint inhibitor immunotherapies remain poorly understood. We describe a metastatic melanoma patient exhibiting multiple episodes of spontaneous disease regression followed by the development of several irAEs during the course of anti-programmed cell death protein 1 antibody immunotherapy. Whole-exome next-generation sequencing studies revealed this patient to harbor a pyrin inflammasome variant previously described to be associated with an atypical presentation of familial Mediterranean fever. This work highlights a potential role for inflammasomes in the regulation of tumor immunosurveillance and the pathogenesis of irAEs.

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Description

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Citation

Published Version (Please cite this version)

10.1097/cji.0000000000000425

Publication Info

Oswalt, Cameron J, Rami N Al-Rohil, Bala Theivanthiran, Tarek Haykal, April KS Salama, Nicholas C DeVito, Alisha Holtzhausen, Dennis C Ko, et al. (2022). Identification of a Germline Pyrin Variant in a Metastatic Melanoma Patient With Multiple Spontaneous Regressions and Immune-related Adverse Events. Journal of immunotherapy (Hagerstown, Md. : 1997), 45(6). pp. 284–290. 10.1097/cji.0000000000000425 Retrieved from https://hdl.handle.net/10161/26401.

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Scholars@Duke

Al-Rohil

Rami Nayef Al-Rohil

Associate Professor of Pathology

I am dermatopathologist with special interest in melanocytic pathology (including molecular alterations and tests that aid in predicting their biologic behavior), and soft tissue pathology

Salama

April Kelly Scott Salama

Associate Professor of Medicine
Ko

Dennis Ko

Associate Professor in Molecular Genetics and Microbiology

Using Pathogens to Decipher Genetic Variation Connecting Cell Biology and Disease Susceptibility
Despite improvements in public health, advancements in vaccines, and the development of many classes of antibiotics, infectious disease is still responsible for over a quarter of all deaths worldwide. However, even for the most devastating of pandemics, individuals demonstrate a large variability in the severity of infection. The long-term goal of the lab is to understand the genetic basis for differences in susceptibility to infection and related inflammatory disorders. We approach this question through a combination of experimental and computational approaches that combine high-throughput cell biology with quantitative human genetics. The identified genetic differences serve as the starting point for exploring new cell biology and human disease susceptibility genes.

Hanks

Brent A. Hanks

Associate Professor of Medicine

We are interested in understanding the mechanisms that cancers have evolved to suppress the generation of tumor antigen-specific immune responses and how this knowledge can be exploited for the development of novel and more effective cancer immunotherapy strategies. This work involves the utilization of both autochthonous transgenic tumor model systems as well as clinical specimens to develop novel strategies to enhance the efficacy of immunotherapies while also developing predictive biomarkers to better guide the management of cancer patients with these agents. We strive to translate our understanding of the fundamental biochemical and metabolic pathways within the tumor microenvironment that are critical for driving immune evasion and resistance into early phase clinical trial testing.

Our work utilizes a variety of techniques and methodologies that span the breadth of basic biological research. This work integrates studies based on both 1) transgenic mouse tumor models that are monitored using bioluminescence and micro-CT imaging and 2) a variety of clinical specimens.

Our current areas of focus include:

  1. Investigating mechanisms of adaptive or acquired immunotherapy resistance in cancer
  2. Studying the relationship between EMT pathways and immunotherapy resistance.
  3. Elucidating mechanisms of dendritic cell tolerization in the tumor microenvironment and how these processes may contribute to immunotherapy resistance
  4. Development of novel pharmacologic and genetic strategies to overcome immunotherapy resistance
  5. Investigating mechanisms contributing to select immunotherapy-associated toxicities

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