Melanoma
Amanda R. Kirane, MD, PhD (she/her/hers)
Assistant Professor
Stanford University
PALO ALTO, California, United States
David Lee, B.A. (he/him/his)
Medical Student
Loma Linda University School of Medicine
Palo Alto, California, United States
M. Usman Ahmad, MD (he/him/his)
Research Fellow
Stanford University, United States
Saurabh Sharma, Ph.D.
Postdoctoral Scholar
Stanford University, United States
Mamatha Serasanambati, Ph.D.
Senior Scientist
Stanford University, United States
.jpg "Michael C. Lowe, MD, MA photo")
Michael C. Lowe, MD, MA
Associate Professor of Surgery, Disease Team Lead and Co-Chair Melanoma Working Group
Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University
Atlanta, Georgia, United States
Christopher Applebee, Ph.D.
Postdoctoral Scholar
University of Bath, United States
Elena Safrygina, Ph.D.
Postdoctoral Scholar
University of Bath, United States
Susan Swetter, M.D.
Professor
Stanford University, United States
Sunil Reddy, M.D.
Associate Professor
Stanford University, United States
Alison Warner, M.D., Ph.D.
Assistant Professor
Stanford University, United States
Pauline Funchain, M.D.
Associate Professor
Stanford University, United States
Jennifer Wang, M.D.
Assistant Professor
Stanford University, United States
Ronald Levy, M.D.
Professor
Stanford University, United States
Banafshe Larijani, n/a
Professor
University of Bath, United States
Emanual Maverakis, M.D.
Professor
UC Davis, United States
Biomarkers predictive of response to immunotherapy (ICB) are urgently needed with no currently validated markers for optimal clinical use. As such, the use of ICB in Stage II melanoma remains controversial. Talimogene Iaherparepvec (TVEC) has shown promise within the neoadjuvant setting in advanced melanoma with a 34% complete response rate and a diminished need for systemic ICB. Herein, we present a novel, functional biomarker analysis from our phase II clinical trial involving TVEC administration in high-risk stage II melanoma through the use of immune time-resolved-resonance energy transfer (iFRET) and mass cytometry (CyTOF).
Methods:
We conducted an open-label, phase 2 clinical trial (NCT04427306) of neoadjuvant TVEC prior to wide local excision and sentinel lymph node biopsy. Tumor and PBMC sampling were collected before and after therapy to dissect pre-treatment features and immune shifts associated with response exploring endpoints of histologic response, sentinel lymph node positivity, functional checkpoint engagement (time-resolved iFRET), and mass cytometry (CYTOF) analysis of on-treatment PBMCs.
Results:
All patients completed TVEC therapy without experiencing any adverse effects beyond grade I. Observed sentinel lymph node positivity (+SLN) was less than the predicted rate (12-60%). No relapses were observed upon follow-up in patients without +SLN. iFRET showed varying alterations in PDL-1: PD-1 receptor engagement both before and after TVEC with statistically significant increases (p=0.007) correlating with improved pathologic response. iFRET was not correlated to previous biomarkers of TVEC response measured by CD8 or PD-L1 expression. Mass cytometry (CyTOF) profiling revealed multiple early shifts in immune cell populations from specific divergences in monocyte subsets, innate profiles, and unique T cell subsets that corresponded with response to oncolytic virus. SLN post-treatment reveals a divergent profile from the treated tumor bed and reinforces the contribution of non-tumor cells to PD-L1:PD-1 axis engagement. Our study demonstrates that neoadjuvant intralesional TVEC in stage II melanoma is safe and can induce systemic immune changes in early, high risk disease with low risk profile. Our functional assay design provides a comprehensive biomarker foundation that has the potential to stratify patients and warrants further development as a companion diagnostic toward the goal of accurate, predictive biomarkers to improve precision immunotherapy.
Conclusions: Learning Objectives: