Multiple antigen-engineered DC vaccines with or without IFNα to promote antitumor immunity in melanoma

Abstract

Background Cancer vaccines are designed to promote systemic antitumor immunity and tumor eradication. Cancer vaccination may be more efficacious in combination with additional interventions that may build on or amplify their effects. Methods Based on our previous clinical and in vitro studies, we designed an antigen-engineered DC vaccine trial to promote a polyclonal CD8 + and CD4 + T cell response against three shared melanoma antigens. The 35 vaccine recipients were then randomized to receive one month of high-dose IFNα or observation. Results The resulting clinical outcomes were 2 partial responses, 8 stable disease and 14 progressive disease among patients with measurable disease using RECIST 1.1, and, of 11 surgically treated patients with no evidence of disease (NED), 4 remain NED at a median follow-up of 3 years. The majority of vaccinated patients showed an increase in vaccine antigen-specific CD8 + and CD4 + T cell responses. The addition of IFNα did not appear to improve immune or clinical responses in this trial. Examination of the DC vaccine profiles showed that IL-12p70 secretion did not correlate with immune or clinical responses. In depth immune biomarker studies support the importance of circulating Treg and MDSC for development of antigen-specific T cell responses, and of circulating CD8 + and CD4 + T cell subsets in clinical responses. Conclusions DC vaccines are a safe and reliable platform for promoting antitumor immunity. This combination with one month of high dose IFNα did not improve outcomes. Immune biomarker analysis in the blood identified several predictive and prognostic biomarkers for further analysis, including MDSC. Trial registration NCT01622933 . Electronic supplementary material The online version of this article (10.1186/s40425-019-0552-x) contains supplementary material, which is available to authorized users.

Clinical and Immunological Outcomes in High-Risk Resected Melanoma Patients Receiving Peptide-Based Vaccination and Interferon Alpha, With or Without Dacarbazine Preconditioning: A Phase II Study

“…Because no significant differences were observed between arm 1 and arm 2 patients either in terms of clinical outcome or of Melan-A-specific immune responses, the immunological analyses were conducted cumulatively in arm 1 and arm 2 patients. Overall, our combination strategies enhanced the vaccine-specific CD8 + T cell frequencies in ∼69% of patients, but this rise did not correlate with the patient clinical outcome [similar to results obtained by Butterfield et al (44)]. On the contrary, the investigation of the quality of the immune response, carried out by means of a functional multiparameter assay (34), showed that the polyfunctionality of Melan-A-specific T cells is associated with disease control.…”

“…In a small melanoma vaccine trial testing the combination of high-dose IFN-α with autologous DC, transduced with three shared/nonmutated melanoma antigens, it was observed that among the 11 stage III/IV resected patients NED at baseline, seven recurred, and four remained NED (36.3 %) up to 3 years (3.7-37.5+ months). No indications of the OS of these patients are given in the article (44).…”

Impact of Influenza on Pneumococcal Vaccine Effectiveness during Streptococcus pneumoniae Infection in Aged Murine Lung

“…As recent work has illustrated differential efficacy of Prevnar vaccination in modulating the immune responses of adult mice to a post-influenza infection with a serotype 3 strain of Streptococcus pneumoniae, we chose to examine the impact of Pneumovax on these responses [30,40]. Given these findings, it would be plausible that other vaccines, designed with specific bacterial components, such as pneumococcal surface protein A (PspA) and pneumolysin (Ply) or liposomal encapsulation of polysaccharides (LEPS), may improve efficacy to post-influenza S. pneumoniae infection [31,[43][44][45]. Future work will need to evaluate if additional vaccine types can prove efficacious and further reduce inflammatory cytokine production while improving bacterial clearance post-influenza infection.…”

Impact of checkpoint blockade on cancer vaccine–activated CD8+ T cell responses

“…Clinical trial and patient samples A phase 1 single-site study was performed to evaluate the immunological effects of autologous monocyte-derived DCs transduced with tyrosinase, MART-1, and MAGE-A6 genes (by replication-defective AdV AdVTMM2) in 35 subjects with recurrent, unresectable stage III or IV melanoma (Butterfield et al, 2019). The clinical trial reported was fully approved by the University of Pittsburgh protocol review committee and institutional review board (PRO12010416, #UPCI09-021) and had Food and Drug Administration investigational new drug #15044 and NCT01622933 (clinical data finalized April 2018).…”