Aetna considers melanoma vaccine (also known as Theraccine vaccine or Oncophage vaccine) experimental and investigational for any indication because of insufficient evidence of its safety and effectiveness.

Melanoma vaccine is prepared from melanoma cell lines that are cultured in-vitro.  The vaccine product is designed to contain 1 or more antigens that are unique to melanoma cells; some preparations also contain "adjuvants" (such as bacillus Calmette-Guerin [BCG]) thought to enhance immunogenicity of the preparation.

Currently, no melanoma vaccine products are licensed for marketing in the United States.  Until a commercial preparation is available, there is significant potential for variability between products and batches.  Effects that are seen in patients to whom these products are administered may be due to the components thought to be active, or to other components which are contaminants, adjuvants or excipients.  In those studies lacking a concurrent control group, it is impossible to distinguish which components are active.  Ribi Immunochem Research has developed a standardized melanoma vaccine called Melacine.  As a biological, this product would be evaluated and licensed by the Center for Biological Evaluation and Research of the Food and Drug Administration (FDA).  At this time, no application for licensure has been filed for this product.

Several published studies have suggested that melanoma vaccine may be effective in the treatment of malignant melanoma and/or prevention of metastasis of melanoma; however, these studies are not adequate to establish the safety and/or efficacy of this therapy.  In addition, there have been a number of reports of phase I and phase II studies that have demonstrated increases in tumor-specific cytotoxic T lymphocytes and other immune responses in patients vaccinated with various melanoma vaccines.  A number of these studies have incorporated interleukin-2 and other adjuvants to improve immune response to melanoma vaccine.  The second interim report from a phase III, multi-center randomized controlled clinical trial of a melanoma vaccine, however, showed no significant overall survival benefit in vaccinated melanoma patients.  A retrospective analysis of clinical trial results identified subsets of patients that appeared to have improved survival with the vaccine; this retrospective analysis suggests that a vaccine may be effective in selected subgroups of melanoma patients.

Randomized controlled clinical trials, where subgroups of patients are identified prospectively, are necessary to confirm the efficacy of melanoma vaccine in selected patient subgroups.  Kuhn and Hanke (1997) concluded in a recent review of the current status of melanoma vaccines that "[t]he clinical effectiveness of melanoma vaccines is unclear and adequately controlled studies need yet to be performed".  A former President of the American Cancer Society stated that "[t]he success of melanoma vaccines has been inhibited by the large number of potential antigen targets on the melanoma cell, which may vary from tumor to tumor.  In addition, the lack of intermediate end points for assessment of the effect of immunotherapy has impeded research in this field."

The FDA has deemed the Antigenics Inc. (New York, NY) Oncophage late-stage investigational cancer vaccine an orphan drug for metastatic melanoma.  The FDA orphan drug designation was designed to encourage the development of therapies for conditions affecting fewer than 200,000 people in the United States.  The designation entitles the sponsor to aid with the development program, tax breaks, waivers from certain regulatory fees and 7 years of additional marketing exclusivity if the product eventually is approved.

The Oncophage vaccine is prepared by removing a tumor from the patient and isolate specific antigens of the particular cancer.  The vaccine is composed of heat-shock proteins that are bound to other proteins specific to tumor antigens.  According to Antigenics, Inc., studies have shown that the protein complex, when purified from tumor cells and reintroduced to the patient, appears to stimulate cellular immunity.  The immune response appears to be directed specifically to cancer cells, leaving the patient's healthy tissue intact.  In May 2002, Antigenics reported that it had begun enrolling patients in the United States and Europe in a pivotal phase III trial of Oncophage for stage IV metastatic melanoma.

Elliott and Dalgleish (2004) stated that melanoma vaccines offer new hope to patients with metastatic melanoma, although convincing survival advantages have yet to be reported.  Bystryn and Reynolds (2005) stated that vaccines are a promising but still experimental treatment for melanoma.

Guidelines on malignant melanoma from the National Institute for Health and Clinical Excellence (2006) have concluded that "[v]accine therapy for advanced [malignant melanoma] remains uncertain and its use should only be in the context of a clinical trial."  A systematic evidence review in BMJ Clinical Evidence (Savage, 2006) concluded that adjuvant vaccines in people with malignant melanoma are of "unknown effectiveness."

Lens and colleagues (2008) assessed different vaccines tested in stage III and/or IV melanoma patients.  Systematic review of the published evidence on vaccine therapy in melanoma was carried out.  Melanoma vaccines can be classified into 6 groups: (i) whole-cell vaccines, (ii) dendritic cell vaccines, (iii) peptide vaccines, (iv) ganglioside vaccines, (v) DNA vaccines and (vi) viral vectors.  The main characteristics of these vaccines including their advantages and disadvantages and the results from conducted trials were presented.  Clinical responses to melanoma vaccines are still poor and currently there is no melanoma vaccine with a proven efficacy.  The authors concluded that vaccine therapy still remains an experimental therapy in patients with metastatic melanoma.  Further research is needed although a future therapy for advanced melanoma is probably a multi-modal approach including vaccines, adjuvants and negative co-stimulatory blockade.  This is in agreement with the observations of Stein and Brownell (2008) who noted that advanced melanoma has a poor prognosis, and standard adjuvant treatment offers little survival advantage.  Current efforts are aimed at combining chemotherapy and novel immunomodulators, which include vaccines, cytokines, and anti-CTLA4 antibodies.  Hundreds of combination therapies are currently undergoing clinical trials.  All advanced melanoma patients should be considered for enrollment in a trial for their own benefit as well as for the advancement of melanoma treatment.  Thus far, no single investigative approach stands out as highly effective, however, they all hold promise with rare patients showing durable responses.  Most treatment protocols are evaluating combinations of adjuvant therapies, hoping to achieve a synergistic effect.

Lesterhuis and associates (2008) stated that dendritic cells are the directors of the immune system, capable of inducing tumor antigen-specific T-cell and B-cell responses.  As such, they are currently applied in clinical studies in cancer patients.  Early small clinical trials showed promising results, with frequent induction of anti-cancer immune reactivity and clinical responses.  In recent years, additional trials have been carried out in melanoma patients, and although immunological responses are often reported, objective clinical responses remain anecdotal with objective response rates not exceeding 5 to 10 %.  Thus, dendritic cells vaccination research has now entered a stage in between "proof of principle" and "proof of efficacy" trials.  Crucial questions to answer at this moment are why the clinical responses remain scarce and what can be done to improve the efficacy of vaccination.

Faries et al (2009) examined the effect of the addition of granulocyte/macrophage colony-stimulating factor (GM-CSF) to vaccination with a melanoma vaccine.  A total of 97 patients with resected melanoma (stage II-IV) were enrolled, stratified by stage, and randomized to receive a cellular melanoma vaccine with or without GM-CSF.  The primary endpoint was delayed-type hypersensitivity (DTH) response to melanoma cells.  Antibody responses, peripheral leukocyte counts, and survival were also examined.  The GM-CSF arm showed enhanced antibody responses with an increase in IgM titer against the TA90 antigen and increased TA90 immune complexes.  This arm also had diminished anti-melanoma cell delayed-type hypersensitivity response.  Peripheral blood leukocyte profiles showed increases in eosinophils and basophils with decreased monocytes in the GM-CSF arm.  These immune changes were accompanied by an increase in early melanoma deaths and a trend toward worse survival with GM-CSF.  The authors concluded that these findings suggested that GM-CSF is not helpful as an immune adjuvant in this dose and schedule and raised concern that it may be harmful.  Based on the discordant findings of an immune endpoint and clinical outcome, the use of such surrogate endpoints in selecting treatments for further evaluation must be done with a great deal of caution.

In a phase II, multi-center, randomized trial, Slinglull et al (2009) examined whether local administration of GM-CSF augments immunogenicity of a multi-peptide vaccine.  It also assessed immunogenicity of administration in 1 versus 2 vaccine sites.  A total of 121 eligible patients with resected stage IIB to IV melanoma were vaccinated with 12 major histocompatibility complex class I-restricted melanoma peptides to stimulate CD8+ T cells plus a HLA-DR-restricted tetanus helper peptide to stimulate CD4+ T cells, emulsified in incomplete Freund's adjuvant, with or without 110 microg GM-CSF.  Among 119 evaluable patients, T-cell responses were assessed by IFN-gamma ELIspot assay and tetramer analysis.  Clinical outcomes were recorded.  CD8+ T-cell response rates to the 12 MHC class I-restricted melanoma peptides (by day 50) with or without GM-CSF were 34 % and 73 %, respectively (p < 0.001), by direct ELIspot assay.  Tetramer analyses corroborated the functional data.  CD4+ T-cell responses to tetanus helper peptide were higher without GM-CSF (95 % versus 77 %; p = 0.005).  There was no significant difference by number of vaccine sites.  Three-year overall and disease-free survival estimates (95 % confidence interval) were 76 % (67 % to 83 %) and 52 % (43 % to 61 %), respectively, with too few events to assess differences by study group.  The authors concluded that high immune response rates for this multi-peptide vaccine were achieved, but CD8+ and CD4+ T-cell responses were lower when administered with GM-CSF.  These data challenge the value of local GM-CSF as a vaccine adjuvant in humans.

Kaufman (2012) noted that the inherent immunogenicity of melanoma and renal cell carcinoma (RCC) has made these tumors a focus of considerable research in vaccine development.  Recent data from murine studies of immuno-surveillance have highlighted the importance of both innate and adaptive immune responses in shaping a tumor's inherent susceptibility to immune surveillance and immunotherapy.  Melanoma has been a useful model for the identification of tumor-associated antigens and a number of putative renal cell antigens have been described more recently.  These antigens have been targeted using a variety of vaccine strategies, including protein- and peptide-based vaccines, recombinant antigen-expressing vectors, and whole cell vaccine approaches.  While evidence for clinical benefit has been disappointing to date, several current phase III clinical trials are in progress based on promising results from phase II studies.  Accumulating data suggest that the tumor microenvironment and mechanisms of immunological escape by established tumors are significant barriers that must be overcome before vaccine therapy can be fully realized.  The author discussed the basis for vaccine development, described some of the more promising vaccine strategies in development, and mentioned some of the tumor escape mechanisms that block effective anti-tumor immunity for melanoma and RCC.  The author listed 4 phase III clinical trials  in melanoma vaccine (1 completed, and 3 in progress).