Background Although survival remains significantly poorer for thick, ulcerated melanoma, application of immunotherapy is controversial in the absence of nodal disease. Talimogene Laherparpvec (TVEC) is the only FDA approved intralesional therapy for melanoma and has demonstrated overall response and bystander effect (34% complete response in uninjected lesions) in late stage melanoma. We hypothesize neoadjuvant TVEC in stage II melanoma will treat local and subclinical regional disease and still allow standard of care surgery.
Methods We present an open-label, Phase 2 pilot study (NCT04427306) of TVEC in stage II melanoma patients with residual disease prior to wide excision and sentinel lymph node biopsy (SLNB). Primary endpoints were safety and efficacy of TVEC with secondary objective to identify of immunologic and molecular predictors of response by immuneFRET (iFRET), digital spatial profiling, serum luminex, and immune-typing of PBMCs.
Results To date, 6 patients were enrolled and treated. All patients completed therapy, adverse events were limited to grade I, there were no surgical complications. 3 patients had at least partial pathologic response (<50% viable tumor), 1 complete response, and 1 positive for sentinel disease. No patients experienced relapse or conversion to systemic therapy at follow up. iFRET revealed dynamic shifts in functional PD-1 receptor engagement with increases correlating to positive therapeutic response and serum pro-inflammatory profile and decreases reflected immunosuppressive profiles. PD-1 expression alone did not correlate to response. Cytof profiling revealed common trends in T cell population shifts (CD3, CD4, CD8) that did not correlate to therapeutic response, but significant divergences in monocyte subsets (alternatively vs classically activated), regulatory cells (Treg, NKreg, MDSC), T cell activation, and migratory T cell subsets (figure 1).
Conclusions This study is the first to neoadjuvantly target earlier-stage melanoma with intra-tumoral immunotherapy and mechanistically dissect immune factors responsible for response and bystander effect in draining nodes. Neoadjuvant TVEC was safe and well tolerated. Baseline characteristics and early functional shifts may differ between patients likely to benefit from oncolytic virus versus checkpoint blockade. We expect the granularity of our data to contribute significantly to future studies of precision application of immunotherapy in high risk patients.
Ethics Approval Ethics approval was obtained via IRB committee (IRB 68118). All participants provided informed consent for study participation.
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