A phase III randomized, doúble-blind, multiinstitutional trial of vaccinia melanoma oncolysate-active specific immunotherapy for patients with stage II melanoma

Abstract

Background. In a Phase II trial, surgical adjuvant active specific immunotherapy using a live vaccinia virus‐augmented allogeneic polyvalent melanoma cell lysate, vaccinia melanoma oncolysate (VMO), produced a significant disease free interval (DFI) in patients with International Union Against Cancer Stage II melanoma with positive lymph nodes. Therefore, a Phase III randomized prospective, double‐blind, multiinstitutional, surgical adjuvant VMO trial was performed to determine the efficacy of VMO to increase the DFI and the overall survival in this group of patients with Stage II disease. Methods. Two hundred and fifty patients with Stage II melanoma were divided into two postsurgical groups. One group received VMO (total protein equals 2 mg/ml) and the other received the placebo of live vaccinia vaccine virus (V) (105.4 TCID50/ml), an adjuvant component of the VMO. Patients initially received these biologies once a week for 13 weeks and then once every 2 weeks for an additional 39 weeks or until recurrence. All surviving patients have been followed for at least 30 months. Results. Statistical analysis of survival data (n = 217) for this first interim analysis shows that there is no statistically significant (P = 0.99) increase in DFI of patients treated with VMO (n = 104) when compared with V (n = 113). The median DFI is 38.0 months for patients treated with VMO and 37.0 months for patients treated with V. At 2‐ and 4‐year intervals, 70 and 38%, respectively, of patients treated with VMO vs. 66 and 36%, respectively, of patients treated with V were free of melanoma. The median overall survival is not available because the pa‐tients treated with VMO have not yet reached the 50% mark and the median overall survival is 45.0 months for patients treated with V. At 2‐ and 4‐year intervals, 70 and 38%, respectively, of VMO‐treated patients survived when compared with 66 and 36%, respectively, of pa‐tients treated with V. Although the overall survival of pa‐tients treated with VMO is not statistically significant (P = 0.88) at this point, there is an increasing trend in the overall survival of patients treated with VMO; a 10% increase at the 4‐year time point. Moreover, in the subset analysis, VMO‐treated male patients (n = 63) showed a 17% improvement in survival at 4‐year time point when compared with male patients treated with V (n = 67) (P = 0.19) at the same time point and male patients (n = 20) between the ages of 44 and 57 having 1‐5 positive lymph nodes showed a 37% difference in overall survival at the 4‐year time point when compared with those patients treated with V (n = 18) (P = 0.13) at the same time point. Conclusion. In this first interim analysis, active specific immunotherapy with VMO vs. V showed no difference in the disease free interval or overall survival. Subset analyses likewise showed no significant differences in outcome but the data suggest a potential difference in immunoreactivity between male and female patients with melanoma that awaits further follow up and may merit further inve...

Natural and genetically engineered viral agents for oncolysis and gene therapy of human cancers

“…For the validity of such a comparison, nearly identical patients in the compared cadres are needed. In patients with stage III melanoma, active "tumor-specific" immunization with vaccinia viral oncolysates yielded slightly better results than direct oncolysis induced by vaccinia virus injected into the patients [155,201,370,[436][437][438]. The hope for the success of virotherapy with naturally oncolytic viruses for human cancers rests on the fact that both immunization with viral oncolysates prepared ex vivo and viral oncolysis accomplished in vivo induce specific postoncolytic anti-tumor immunity [213,234,358,372].…”

“…Nevertheless, this clinical trial inadvertently showed a favorable trend for MVO immunotherapy over direct VV oncolysis. In comparison with surgically treated control groups of several other prominent clinical trials (testing IFN-α or IFN-γ against surgically treated controls), the VMO and the VV groups together and the VV group in itself performed better than the surgically treated control groups [201,[435][436][437][438]. Thus, in the VV group, live vaccinia virus exerted some oncolytic effect, but less than the VMO.…”

“…A "favorable trend" emerged toward the continuation of viral oncolysate therapy for melanoma with the aim to eradicate micrometastases after the surgical removal of all gross disease. Most elaborate clinical trials [50,201,[376][377][378][435][436][437][438] in which academic standards had been strictly adhered to support this effort.…”

Novel dendritic cell-based vaccination in late stage melanoma

“…Both peptide and tumor lysate-loaded dendritic cells have been previously utilized to vaccinate patients. [43][44][45][46][47][48][49] A preferred method to manufacture such a hybrid uses un-cultured, post-irradiation, tumor cells to produce a non-proliferative hybrid cell or dendritoma that retains both the character of the tumor cells in addition to the ability to act as an effective APC. Animal studies have shown these hybrid cells capable of producing an anti-tumor specific immune response.…”

Tumor Biology for the Clinician: Melanoma Peptide Vaccines

“…However, convincing therapeutic efficacy has not yet been demonstrated in prospective randomized trials. [7] Early efforts to evaluate responses to tumor vaccines focused on humoral responses. The result was the identification of many antigens that could be defined serologically on melanoma cells, including glycoproteins and gangliosides.…”