Prospective, randomized, double-blind phase 2B trial of the TLPO and TLPLDC vaccines to prevent recurrence of resected stage III/IV melanoma: a prespecified 36-month analysis

Abstract

Background: The tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is made by ex vivo priming matured autologous dendritic cells (DCs) with yeast cell wall particles (YCWPs) loaded with autologous tumor lysate (TL). The tumor lysate, particle only (TLPO) vaccine uses autologous TL-loaded YCWPs coated with silicate for in vivo DC loading. Here we report the 36-month prespecified analyses of this prospective, randomized, double-blind trial investigating the ability of the TLPO and TLPLDC (±granulocyte-colony stimulating factor (G-CSF)) vaccines to prevent melanoma recurrence in high-risk patients.

Methods: Patients with clinically disease-free stage III/IV melanoma were randomized 2:1 initially to TLPLDC versus placebo (n=124) and subsequently TLPO versus TLPLDC (n=63). All patients were randomized and blinded; however, the placebo control arm was replaced in the second randomization scheme with another novel vaccine; some analyses in this paper therefore reflect a combination of the two randomization schemes. Patients receiving the TLPLDC vaccine were further divided by their method of DC harvest (with or without G-CSF pretreatment); this was not randomized. The use of standard of care checkpoint inhibitors was not stratified between groups. Safety was assessed and Kaplan-Meier and log-rank analyses compared disease-free (DFS) and overall survival (OS).

Results: After combining the two randomization processes, a total of 187 patients were allocated between treatment arms: placebo (n=41), TLPLDC (n=103), or TLPO (n=43). The allocation among arms created by the addition of patients from the two separate randomization schemes does not reflect concurrent randomization among all treatment arms. TLPLDC was further divided by use of G-CSF in DC harvest: no G-CSF (TLPLDC) (n=47) and with G-CSF (TLPLDC+G) (n=56). Median follow-up was 35.8 months. Only two patients experienced a related adverse event ≥grade 3, one each in the TLPLDC+G and placebo arms. DFS was 27.2% (placebo), 55.4% (TLPLDC), 22.9% (TLPLDC+G), and 60.9% (TLPO) (p<0.001). OS was 62.5% (placebo), 93.6% (TLPLDC), 57.7% (TLPLDC+G), and 94.6% (TLPO) (p=0.002).

Conclusions: The TLPO and TLPLDC (without G-CSF) vaccines were associated with improved DFS and OS in this clinical trial. Given production and manufacturing advantages, the efficacy of the TLPO vaccine will be confirmed in a phase 3 trial.

Trial registration number: NCT02301611.

Keywords: Clinical Trials, Phase II as Topic; Immune Checkpoint Inhibitors; Immunogenicity, Vaccine; Melanoma.

Figure 1

CONSORT diagram. CONSORT, Consolidated Standards of Reporting Trials; CPI, checkpoint inhibitor; G-CSF, granulocyte-colony stimulating factor; TLPLDC, tumor lysate, particle-loaded, dendritic cell; TLPLDC+G, TLPLDC with G-CSF; TLPO, tumor lysate, particle only.

Figure 2

Kaplan-Meier curves demonstrating DFS (A) and OS (B) between placebo (n=41), TLPLDC+G (n=56), TLPLDC (n=47), and TLPO (n=43). DFS, disease-free survival; OS, overall survival; TLPLDC, tumor lysate, particle-loaded, dendritic cell; TLPLDC+G, TLPLDC with granulocyte-colony stimulating factor; TLPO, tumor lysate, particle only.

Figure 3

DFS (A) and OS (B) for patients receiving CPI therapy (placebo (n=9), TLPLDC (n=16), TLPLDC+G (n=18), and TLPO (n=35)). CPI, checkpoint inhibitor; DFS, disease-free survival; OS, overall survival; TLPLDC, tumor lysate, particle-loaded, dendritic cell; TLPLDC+G, TLPLDC with granulocyte-colony stimulating factor; TLPO, tumor lysate, particle only.

Figure 4

DFS (A) and OS (B) for patients who did not receive CPI therapy (placebo (n=32), TLPLDC (n=31), TLPLDC+G (n=38), and TLPO (n=8)). CPI, checkpoint inhibitor; DFS, disease-free survival; OS, overall survival; TLPLDC, tumor lysate, particle-loaded, dendritic cell; TLPLDC+G, TLPLDC with granulocyte-colony stimulating factor; TLPO, tumor lysate, particle only.