Author ORCID Identifier
https://orcid.org/0000-0002-6271-0337
Date of Graduation
12-2020
Document Type
Dissertation (PhD)
Program Affiliation
Immunology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Michael Davies, M.D., Ph.D.
Committee Member
Chantale Bernatchez, Ph.D.
Committee Member
Navin Varadarajan, Ph.D.
Committee Member
Michael Curran, Ph.D.
Committee Member
Scott Woodman, M.D.
Abstract
With the growing use of both cellular and antibody-based immunotherapies, it has become more important to uncover biomarkers to predict patient response to therapy and ideally aid in patient selection for specific therapeutics, thereby enhancing treatment outcome. At MD Anderson, we have a 43% response rate to therapy when treating metastatic melanoma patients with adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TIL), but it is unknown what makes the other 57% of patients not respond to therapy. It is further unknown how particularly early doses of checkpoint inhibitors, like anti-PD-1, attribute to TIL functionality, adding another confounding factor in determining a unanimous response rate. Therefore, the overall goal of this study has been to identify biomarkers for patient response to TIL ACT in melanoma and to deeply study the impact of anti-PD-1 on TIL functionality, a front line therapy that a vast majority of patients now receive prior to TIL therapy. We obtained tumor tissue from a variety of rare tumor types after early exposure to anti-PD-1 on a clinical trial. We studied the functional effects of one dose of anti-PD-1 therapy on TIL by examining growth, phenotype, and soluble factor production post cellular activation, and observed enhanced CTLA-4 expression on CD4 TIL with a diminished soluble factor profile by CD8 TIL post exposure. To uncover biomarkers for TIL ACT within metastatic melanoma that are indicative of response and survival to TIL therapy, we interrogated pre-treatment samples using genomics and transcriptomics, whereby we observed neoantigen load significantly correlates with overall survival (OS) and identify particularly the gene ELFN1 associated with unfavorable outcome to therapy. Through this research, we hope to further provide insight to understanding TIL and the tumor microenvironment and help to increase the efficacy of using immunotherapy to treat cancer patients. Therefore, our work will provide significant impact in the usage of ACT and antibody based immunotherapies as a whole.
Keywords
adoptive cellular therapy, tumor infiltrating lymphocytes, biomarkers, immunotherapy, anti-PD-1, ELFN1