Clinical and immunological responses in metastatic melanoma patients vaccinated with a high-dose poly-epitope vaccine

Abstract

DNA.Mel3 and MVA.Mel3 in a prime-boost protocol generated high rates of immune response to melanoma antigen epitopes. The treatment was well tolerated and the correlation of immune responses with patient outcomes encourages further investigation.

Is the “3+3” Dose-Escalation Phase I Clinical Trial Design Suitable for Therapeutic Cancer Vaccine Development? A Recommendation for Alternative Design

“…In the remaining 15 trials, only 6 reported the toxicities at the highest dose level (10 systemic toxicities). Two out of these 6 trials that reported toxicities at the highest dose level used bacterial vaccines (17, 18), and the rest used autologous (19), DNA (20), viral (21), or liposomal vaccines (22). Two toxicities occurred in the middle dose level in one trial that used a bacterial vaccine, with no further toxicity occurring when the dose was escalated (23).…”

“…The results for tetramer assay and T-cell proliferation were of borderline significance, with a two-tailed significance level of about 10%. The borderline significance of the tetramer result was driven by a single study reported by Dangoor et al that used plasmid DNA and a recombinant modified Vaccinia Virus Ankara (MVA), both expressing epitopes from five melanoma antigens (18). Without the Dangoor et al study, the two-sided p value for the remaining 10 studies did not approach significance.…”

Deletion of Specific Immune-Modulatory Genes from Modified Vaccinia Virus Ankara-Based HIV Vaccines Engenders Improved Immunogenicity in Rhesus Macaques

“…The resulting inability of MVA to replicate in human hosts likely contributes substantially to its excellent safety profile as both a smallpox vaccine as well as a recombinant vaccine vector (17,22,64,79). Given its high level of safety and ability to accommodate large foreign gene inserts, MVA has been an attractive candidate as a vector for clinical development into vaccines against a number of infectious diseases in addition to HIV/AIDS, including malaria (9,28,42,59,60) and tuberculosis (TB) (39,54,55,63), as well as cancers (20,23,48,72 (10,39,65).…”

Clinical Application of Plasmid-Based Cancer Vaccines

“…A previous phase I study of the same approach in melanoma patients had demonstrated safety but inadequate immunogenicity [60]. In the subsequent multicenter, nonrandomized, openlabel, dose-escalation study, the dose was escalated (20-fold) and the dosing period extended (by increasing the interval between primary pDNA immunizations and using additional, less frequent MVA boosters) [59]. The group tested the safety and cellular immunogenicity of the vaccination in 41 late-stage metastatic melanoma patients randomized into seven groups (5À8 patients per group) that differed with respect to dose and number of pDNA and MVA immunizations.…”

“…Considering that use of plasmid DNA vaccines alone had shown only modest immune responses and little clinical efficacy in cancer patients, Dangoor and colleagues tried a different ("heterogeneous prime-boost") approach [59]. The group evaluated rising doses and varying regimens of a plasmid-based DNA (pDNA) immunization followed by booster immunizations with recombinant modified vaccinia virus Ankara (MVA), both expressing a string of seven epitopes from five melanoma antigens.…”