Nonspecific immunostimulants and vaccines

BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)

Multiple different immunostimulant and vaccine strategies have been pursued as adjuvant therapy for patients with high risk melanoma over the past 40 years with none showing convincing or reproducible benefits. Some of the most promising of these approaches are described below.

Observation of regression in intradermal metastases of melanoma after intralesional injection of Bacillus Calmette-Guerin (BCG) led to adjuvant trial with BCG in high-risk patients [65]. In the EORTC 18781 trial, 353 patients were randomized to two different BCG preparations or to follow-up only [66]. Although the treatment was generally well tolerated, there was no benefit in patient survival and time to relapse. Corynebacterium parvum is another micro-organism which stimulates the immune system. In a randomized clinical trial of C. parvum compared to observation in 260 patients with clinically localized melanoma, there was no significant difference in survival between the two treatment arms [67]. Levamisole, an antihelminthic agent with immunomodulatory effects, was tested in a few randomized controlled trials. It failed to show any benefit in all except one study. This study demonstrated statistically insignificant reduction in the death rate and the recurrence rate in levamisole group compared with observation [68]. Levamisole has never been adopted widespread as a therapeutic agent.

In the wake of negative studies with nonspecific immunostimulants, investigators switched course and attempted to develop vaccines capable of eliciting a specific host immune response against melanoma. A variety of vaccination strategies using autologous or allogeneic melanoma cells have been tested over the last few decades. Technical complexities inherent in harvesting tumor and preparing a vaccine made it difficult to test autologous cellular vaccine in large multi-institutional trials. Allogeneic tumor cell vaccines, conversely, are generally prepared from cultured cell lines or lysates allowing the conduct of large-scale, multi-institutional clinical trials. The Southwest Oncology Group (SWOG) conducted one such, large randomized trial of an allogenic melanoma vaccine (melacine) compared to observation in patients with intermediate-thickness, node-negative melanoma [69]. There was no evidence of improved disease-free survival among patients randomized to receive vaccine. Canvaxin, a polyvalent cell vaccine composed of a combination of allogeneic cell lines, showed great promise in a variety of phase II trials [70]. However, it also failed to show improvement in progression-free or overall survival in randomized phase 3 trials comparing canvaxin plus BCG to placebo plus BCG in patients with resected melanoma stage III and stage IV disease [71].

Melanoma vaccines based on peptides or gangliosides also have been developed and examined in clinical trials in the adjuvant setting. The GM2 ganglioside is expressed in the majority of melanomas and could induce an antibody response. A GM2 vaccine was shown to be associated with freedom from disease recurrence in patients who developed an antibody response to the vaccine. Combining the vaccine with GM2-KLH/QS-21 adjuvant led to enhanced immunogenicity suggesting it might be an even more potent adjuvant therapy. However a randomized phase III trial comparing standard HD IFN to the GM2/KLH/QS-21 vaccine in patients with Stage IIB and III melanoma (E1694) conducted in the US Intergroup, had to be closed early because there were 50% more relapses and deaths on the vaccine arm relative to the IFNα arm [72]. In a second randomized phase II study, E2696, patients with stage III melanoma were randomized to receive two different schedules of IFNα, IFNα + the GM2/KLH/QS-21 vaccine or the vaccine alone [73]. In this small study the two IFNα containing arms showed a significant improvement in relapse free survival (RFS) over the vaccine only arm. This same vaccine was also compared to placebo by the EORTC in a randomized Phase III trial involving 1314 patients with stage II melanoma [74]. A trend toward adverse overall survival outcome for the vaccine arm led to trial termination at the 2nd interim analysis; however, more mature data has suggested no significant difference in any outcome.

The majority of patients with melanoma have the MAGE-A3 antigen expression on the tumors and MAGE-3 vaccination is an attractive strategy. A phase I/II study demonstrated MAGE-3-specific antibody and T-cell responses following vaccination in patients with MAGE-3-positive tumors [75]. This led to a randomized phase III clinical trial (DERMA) in patients with stage III nodal metastases and detectable MAGE-3 expression in resected lymph nodes. A recent sponsor-led press release from September 2013 based on an independent analysis failed to show significant extension of DFS in Stage III patients with MAGE-A3 tumors who were on the vaccine versus placebo. However, the trial will continue to assess its second co-primary endpoint of DFS in the gene signature positive patients. Results from this analysis are expected in 2015. The National Cancer Institute surgery branch reported vaccination efforts in 95 HLA-A*0201 patients at high risk for recurrence of melanoma who received prolonged immunization with a peptide vaccine, gp100209-217 [76]. Vaccination was highly effective at inducing large numbers of self/tumor-Antigen reactive T cells, however, there was no difference in the levels of antitumor Antigen-specific T cells in patients who recurred compared with those who remained disease-free. Based on the results of this extensive research effort, one must conclude that adjuvant vaccine strategies in patients with resected high and intermediate risk melanoma have yet to show efficacy and newer approaches and a better understanding of tumor immunology are necessary to advance this field.

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