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Melanoma

Melanoma Abstract Session

36: Development of Functional Biomarker Assays: Analysis of Neoadjuvant Intralesional Oncolytic Virus Response in High-Risk Stage II Melanoma

Monday, February 19, 2024
8:50 AM - 9:00 AM AST
Location: Miramar I & II
Disclosure(s):
Amanda R. Kirane, MD, PhD: No financial relationships to disclose
David Lee, B.A.: No financial relationships to disclose
Michael C. Lowe, MD, MA: BMS: Consultant (Terminated, August 31, 2023); Merck Sharp & Dohme: Consultant (Terminated, June 30, 2023)
Introduction: 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. 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. Tumor macrophage infiltrates and SLN characterization post-treatment reveals a divergent patient response profile and reinforces the contribution of non-tumor cells to PD-L1:PD-1 axis engagement.


Conclusions: 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.

Learning Objectives:

  • To understand the current landscape and the need for additional adjunct therapies in patients with high-risk early-stage melanoma besides standard-of-care surgery.
  • To understand the potential role of neoadjuvant TVEC in the management of high-risk early-stage melanoma.
  • To learn about a potential comprehensive biomarker analysis for effective patient stratification in a neoadjuvant setting in high-risk early-stage melanoma.