Checkpoint immunotherapies targeting the CTLA-4 andPD-1/PD-L1 pathways have provided breakthroughs in a number of cancer types. However, up to 40% of patients will experience side effects such as a skin rash. In certain cases, this rash can be severe enough to cause patients to discontinue treatment, which may compromise its effectiveness, but the underlying mechanisms causing these rashes are still unknown. A novel hypothesis is that the rash may represent a tumor-specific response that is misdirected towards the skin or may represent unmasking of a latent autoimmune response. What is still missing, and of critical importance, is an improved understanding of the mechanism of rash and how it compares to the anti-tumor response.
Therefore, Dr. Kulkarni aims to identify the molecular basis of immune responses against tumors and compare them with the responses within rashes. Using both a DNA sequencing approach to identify mutations in the tumor likely to drive an immune response, as well as a mass spectrometry approach to identify the portions of proteins directly presented (in both tumors and the rashes), his team will work to identify the molecular signatures of the immune response and determine any potential overlap. Overall, this project aims to provide a better understanding of the specificity of checkpoint immunotherapy responses and subsequently aid the development of develop strategies to mitigate their harmful effects and allow for more effective use of these potentially lifesaving treatments.
Projects and Grants
Elucidating the molecular basis of skin-directed irAEs
Oregon Health & Science University | All Cancers | 2018
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