Abstract
BackgroundDespite improved survival following checkpoint inhibitors, there is still a potential role for anti-cancer therapeutic vaccines. Because of biological heterogeneity and neoantigens resulting from each patient’s mutanome, autologous tumor may be the best source of tumor-associated antigens (TAA) for vaccines. Ex vivo loading of autologous dendritic cells with TAA may be associated with superior clinical outcome compared to injecting irradiated autologous tumor cells. We conducted a randomized phase II trial to compare autologous tumor cell vaccines (TCV) and autologous dendritic cell vaccines (DCV) loaded with autologous TAA.MethodsShort-term autologous tumor cell lines were established from metastatic tumor. Vaccines were admixed with 500 micrograms of GM-CSF and injected weekly for 3 weeks, then at weeks 8, 12,16, 20, and 24. The primary endpoint was overall survival. Secondary objectives were identification of adverse events, and results of delayed type hypersensitivity (DTH) reactions to intradermal tumor cell injections.ResultsForty-two patients were randomized. All were followed from randomization until death or for five years; none were lost to follow-up. DCV was associated with longer survival: median 43.4 versus 20.5 months (95% CI, 18.6 to > 60 versus 9.3 to 32.3 months) and a 70% reduction in the risk of death (hazard ratio = 0.304, p = 0.0053, 95% CI, 0.131 to 0.702). Tumor DTH reactions were neither prognostic nor predictive. The most common treatment-related adverse events were mild to moderate local injection site reactions and flu-like symptoms; but grade 2 treatment-related adverse events were more frequent with TCV. Serum marker analyses at week-0 and week-4 showed that serum markers were similar at baseline in each arm, but differed after vaccination.ConclusionsThis is the only human clinical trial comparing DCV and TCV as platforms for autologous TAA presentation. DCV was associated with minimal toxicity and long-term survival in patients with metastatic melanoma. DTH to autologous tumor cells was neither prognostic for survival nor predictive of benefit for either vaccine.Trial registrationClinical trials.gov NCT00948480 retrospectively registered 28 July 2009.
Highlights
Despite improved survival following checkpoint inhibitors, there is still a potential role for anti-cancer therapeutic vaccines
The mechanism of action for the anti-programmed death-1 (PD1) checkpoint inhibitors is blocking the suppression of an existing immune response, but many patients show no evidence of an existing immune response in their tumors [10, 11]
In the dendritic cell vaccines (DCV) arm tumor markers were only slightly increased from baseline, most inflammatory markers decreased from baseline, and some increased slightly. These results must be interpreted with caution because of the wide variability in assay results, and the use of only three donors for normalization. To our knowledge, this is the first and only study conducted in cancer patients that addresses the question of whether survival differs between cancer patients treated with an autologous DCV versus an autologous tumor cell vaccines (TCV) that both feature tumor-associated antigens (TAA) from short-term autologous tumor cell
Summary
Despite improved survival following checkpoint inhibitors, there is still a potential role for anti-cancer therapeutic vaccines. Relevance of therapeutic vaccine research During the past decade introduction of new therapies has been associated with increased survival for patients with metastatic melanoma [1]. These have included oral enzyme inhibitors of signal-transduction driver pathways [2, 3], and monoclonal antibodies that block immune checkpoint inhibitors [4,5,6]. Dendritic cell vaccines can induce or enhance immune responses to patient-specific neoantigens [14] For these and other reasons, vaccine research is still relevant for melanoma treatment [15]
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