Clinical Activity of Combined Telomerase Vaccination and Pembrolizumab in Advanced Melanoma: Results from a Phase I Trial

Abstract

Purpose: Cancer vaccines represent a novel treatment modality with a complementary mode of action addressing a crucial bottleneck for checkpoint inhibitor (CPI) efficacy. CPIs are expected to release brakes in T-cell responses elicited by vaccination, leading to more robust immune responses. Increased antitumor T-cell responses may confer increased antitumor activity in patients with less immunogenic tumors, a subgroup expected to achieve reduced benefit from CPIs alone. In this trial, a telomerase-based vaccine was combined with pembrolizumab to assess the safety and clinical activity in patients with melanoma.

Patients and methods: Thirty treatment-naïve patients with advanced melanoma were enrolled. Patients received intradermal injections of UV1 with adjuvant GM-CSF at two dose levels, and pembrolizumab according to the label. Blood samples were assessed for vaccine-induced T-cell responses, and tumor tissues were collected for translational analyses. The primary endpoint was safety, with secondary objectives including progression-free survival (PFS), overall survival (OS), and objective response rate (ORR).

Results: The combination was considered safe and well-tolerated. Grade 3 adverse events were observed in 20% of patients, with no grade 4 or 5 adverse events reported. Vaccination-related adverse events were mostly mild injection site reactions. The median PFS was 18.9 months, and the 1- and 2-year OS rates were 86.7% and 73.3%, respectively. The ORR was 56.7%, with 33.3% achieving complete responses. Vaccine-induced immune responses were observed in evaluable patients, and inflammatory changes were detected in posttreatment biopsies.

Conclusions: Encouraging safety and preliminary efficacy were observed. Randomized phase II trials are currently ongoing.

Figure 1.

Efficacy read-out. Kaplan–Meier plots of (A) progression-free survival (iPFS) and (B) OS in all patients (N = 30). C, Donut plot showing the ORRs in the total population (N = 30) and subgroups according to tumor biopsy PD-L1 positivity. D, Kaplan–Meier plot showing the DOR (n = 17).

Figure 2.

Spider and waterfall plots. A, Spider plot showing the percent change in tumor size from baseline. One line represents 1 patient, color- and symbol-coded by best overall response according to iRECIST. B, Waterfall plot depicting the maximum percent change in tumor size from baseline. One bar represents one patient, color-coded according to the best overall responses according to iRECIST. Symbols indicate patients with baseline LDH-high, TMB-low, and PD-L1–negative tumor biopsies.

Figure 3.

Baseline tumor characteristics in clinical responders and nonresponders. A, TMB and (B) predicted neoantigen in all patients with available baseline biopsy. C, Baseline multiplex immunofluorescence staining of T cells (CD4⁺ and CD8⁺), regulatory CD4 T cells (CD4⁺/FoxP3⁺), granzyme B⁺, hTERT⁺, Ki67⁺, and melanoma cells (Sox10⁺/S100⁺). Two samples with no Sox10/S100 stained cells were excluded from the analysis of co-staining melanoma cells and hTERT and Ki67. D, Among all available biopsies (both baseline and week 14), there was a significant correlation between signal intensity of Ki67 and TERT within melanoma cells (simple linear regression, R² = 0.267; P = value 0.002). E, Baseline levels of the 18-gene IFNγ gene signature expression according to iRECIST category. Heat map shows the calculated z-score, representing the relative expression levels across patient samples. Unless otherwise described, all reported P values represent results from the unpaired nonparametric test (Mann–Whitney). ND, not detected. R, clinical responder. NR, clinical nonresponders.

Figure 4.

Anti-hTERT immune responses and impact of therapy on tumor gene expression, infiltration of lymphocytes, and tumor markers. A, Vaccine-induced T-cell responses against hTERT were documented in 10 patients. Figure shows the difference between baseline sample and highest SI achieved. B, Immune response development over time. C, TMB and neoantigen load in pre- and posttreatment biopsies. D, Change in tumor expression of genes related to T-cell function and activation, cytokine activity, immune checkpoint molecules, and hTERT. Heat map reflects the relative change in expression (transcripts per million) from baseline to week 14. The log₂(fold change) was uncalculable for cells marked with “X” (zero transcripts per million in either baseline or week 14 biopsy). E, Comparison of immunofluorescence staining of biopsies at baseline and week 14. In the analysis of Sox10/S100 co-stained with Ki67 and TERT, six biopsies without any Sox10/S100 stained cells were excluded. All reported P values represent results from the unpaired nonparametric test (Mann–Whitney). ND, not detected.