Abstract
As cutaneous melanoma (CM) currently remains with a bleak prognosis, thorough investigation of new treatment options are of utmost relevance. In the phase II/III randomized clinical trial (CASVAC-0401), the repeated immunization of stages IIB-III CM patients with the irradiated, allogeneic cellular CSF-470 vaccine plus the adjuvants bacillus Calmette-Guerin (BCG) and recombinant human granulocyte macrophage colony-stimulating factor (rhGM-CSF) demonstrated a significant benefit over IFN-alpha2B treatment in distant metastasis-free survival. Here we present on the short and long term immune monitoring results after completing the 2-year protocol; a continuation of the previous report by Mordoh et al. (1). We demonstrate that the repeated CSF-470 vaccinations stimulated a long term cellular and humoral immunity response directed against the vaccine antigens. In the case of 2 patients, we are able to show that a similar immune response was generated against autologous antigens. Evaluation of inhibitory receptor co-expression on patient's T cells indicates that the vaccination protocol did not stimulate T cell exhaustion. In order to better understand the basis for the efficacious vaccine responses observed, we investigated the short term immune events following vaccine injection. A significant increase in C-reactive protein (CRP) and IL-6 was observed 24 h after vaccination, with in vitro studies suggesting IL-6 production occurs in the vaccine site. We demonstrate that CRP enhances the cytotoxicity of peripheral blood mononuclear cells (PBMC) against melanoma cells in an in vitro model. Additionally, CRP stimulates the release of pro and anti-inflammatory cytokines from PBMC. As our results demonstrate that successive vaccinations with CSF-470 plus adjuvants promoted an increase in both anti-tumor innate and adaptive immunity, we propose a subsequent model of action.
Highlights
Cutaneous melanoma (CM) is responsible of most skin cancer deaths [2]
Recent therapeutic advances based in targeted therapies for BRAF-mutated CM and of anti-PD1 monoclonal antibodies (MAbs) have changed the somber prognosis of metastatic CM [3], the challenges are still great
Peripheral blood mononuclear cells (PBMC) were purified using a Ficoll density gradient (GE Healthcare, UK) from 200 ml of peripheral blood collected at each time-point, and kept cryopreserved in freezing medium consisting of 40% Albumin (UNC Hemoderivados, Argentina), 50% Dulbecco’s Modified Eagle’s Medium (Gibco, ThermoFisher, USA) and 10% Dimethyl Sulfoxide (Merck, USA) (1 × 107 cells per cryotube) until use
Summary
Cutaneous melanoma (CM) is responsible of most skin cancer deaths [2]. recent therapeutic advances based in targeted therapies for BRAF-mutated CM and of anti-PD1 monoclonal antibodies (MAbs) have changed the somber prognosis of metastatic CM [3], the challenges are still great. With respect to adjuvant therapies in stage III patients, it has been reported that mutated BRAF inhibitors and anti-PD1 MAbs increase relapse-free survival, follow-up is short and about two thirds of patients at risk of recurrence are unprotected [4, 5]. Since CM is an immunogenic tumor, most probably due to its high mutation rate [6], the use of vaccines as immunogens have been assayed for a long time. Based on the idea that a single Ag-based vaccine may permit escape from immune response precisely due to the high mutation rate of CM, we have used multi-Ag allogeneic vaccines to foster immunity against commonly shared melanocytic differentiation Ags and cancer testis Ags, expecting that epitope spreading might be a mechanism of further including private Ags in the immune response
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
