Jakub, James

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 .

Background: Tumoral melanosis clinically resembles metastatic melanoma, occurs in the context of regressed disease, and requires evaluation to rule out underlying melanoma and metastatic disease. Histopathology demonstrates a nodular infiltrate of melanophages in the dermis, subcutaneous tissue, deep soft tissue, or lymph nodes in the absence of viable melanocytes. Recent limited reports of tumoral melanosis in the context of immunotherapy with ipilimumab (monoclonal antibody targeting CTLA-4) as well as nivolumab and pembrolizumab (humanized monoclonal antibodies against programmed death 1 receptor) highlight a unique presentation representative of treatment-related tumor regression and an association with a favorable clinical response. Objective: To describe our experience with tumoral melanosis in the setting of immunotherapy for metastatic melanoma and elucidate the clinical and histopathological features. Methods: Retrospective case series from a single tertiary care institution. Results: We describe 10 cases of patients with metastatic melanoma who received treatment with immunotherapy before the development of tumoral melanosis. Length of time between the initiation of therapy and the onset of tumoral melanosis ranged from 2 to 20 months with a mean time of 10 months. At the end of the follow-up period, 8 patients were classified as having a complete or partial response to treatment with immunotherapy. One patient had progression of visceral and cutaneous disease on ipilimumab despite developing tumoral melanosis, and 1 patient had yet to undergo repeat imaging. Furthermore, at the end of follow-up, 3 patients were alive with no evidence of active disease, 5 patients were alive with disease, and 1 patient was deceased, although this patient died of a cardiovascular event unrelated to his underlying melanoma. Of the patients who were classified as alive with disease, 2 patients had minimal remaining disease, and 2 patients had an almost complete response on immunotherapy with recurrence of visceral metastases after immunotherapy was discontinued. One patient developed new peritoneal and cutaneous metastases on pembrolizumab despite development of tumoral melanosis. Conclusions: The underlying biologic mechanisms and prognostic implications of tumoral melanosis in the setting of immunotherapy remain to be elucidated. Further prospective studies with a larger cohort and prolonged follow-up are necessary to better understand the incidence, prevalence, and oncologic outcomes in patients with tumoral melanosis who receive immunotherapy.