Medical Policies - Medicine

Melanoma Vaccines


Effective Date:10-15-2017



Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

Melanoma vaccines are considered experimental, investigational and/or unproven.


Tumor vaccines are a type of immunotherapy that attempts to stimulate the patient’s own immune system to respond to tumor antigens. There are a number of different tumor vaccines for the treatment of malignant melanoma in various stages of development.


Vaccines using crude preparations of tumor material were first studied by Ehrlich over 100 years ago, (1) but the first modern report suggesting benefit using these in cancer patients did not appear until 1967. (2) Melanoma has been viewed as a particularly promising tumor for this type of treatment because of its immunologic features, which include the prognostic importance of lymphocytic infiltrate at the primary tumor site, the expression of a wide variety of antigens, and the occasional occurrence of spontaneous remissions. (3) Melanoma vaccines can be generally categorized or prepared in the following ways (4):

Whole cell vaccines, prepared using melanoma cells or crude sub-cellular fractions of melanoma cell lines:

o Autologous whole-cell vaccines in which tumor cells are harvested from the tissues of excised cancers, irradiated, and potentially modified with antigenic molecules to increase immunogenicity and made into patient-specific vaccines (e.g., M-Vax®, AVAX Technologies); and

o Autologous heat-shock protein-peptide complexes vaccines in which patient’s tumor cells are exposed to high temperatures and then purified into patient-specific vaccines (e.g., Oncophage®, Vitaspin, Antigenics, Inc.); and

o Allogeneic whole-cell vaccines in which intact or modified allogeneic tumor cell lines from other patients are lysed by mechanical disruption or viral infection and used to prepare vaccine (e.g., Canvaxin®, CancerVaxCorp. or Melacine®, University of Southern California);

Dendritic cell vaccines in which autologous dendritic cells are pulsed with tumor-derived peptides, tumor lysates, or antigen encoding Ribonucleic acid (RNA) or Deoxyribonucleic acid (DNA) to produce immunologically enhanced vaccines;

Peptide vaccines consisting of short, immunogenic peptide fragments of proteins (e.g., Helper multi-peptide (6MHP) vaccine, melanoma antigen E or MAGE; B Melanoma antigen or BAGE) used alone or in different combinations to create vaccines of varying antigenic diversity, depending on the peptide mix;

Ganglioside vaccines in which glycolipids present in cell membranes are combined with an immune adjuvant (e.g. GM2) to create vaccines;

DNA vaccines created from naked DNA expression plasmids;

Viral vectors in which DNA sequences are inserted into attenuated viruses for gene delivery to patient immune systems; and

Anti-idiotype vaccine, consisting of monoclonal antibodies with specificity for tumor antigen-reactive antibodies.

Regulatory Status

At the present time, no preventive melanoma vaccine has received approval from the United States (U.S.) Food and Drug Administration (FDA). Melanoma vaccines are currently available only in clinical trials in the U.S.


The Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) evaluated the use of vaccines to treat melanoma in a 2001 TEC Special Report, “Vaccines for the Treatment of Malignant Melanoma.” (5) In spite of the fact that the literature contained hundreds of publications on this treatment at this time, there was a striking paucity of completed phase 3 clinical trials available for evaluation. The 2001 report highlighted the importance of such studies to control for patient characteristic, disease and treatment confounders. It also highlighted the value of long-term outcomes that measure disease progression or mortality instead of the use of less reliable surrogate measures of immune response. Of note, several phase 1 or 2 studies of melanoma vaccines (Canvaxin®, Melacine®) have not been replicated in subsequent phase 2 or 3 studies. (4)

In an article in Nature Medicine in 2004, Rosenberg et al. (6) noted that looking at the experience of the National Cancer Institute’s Surgery Branch in evaluating 450 patients treated for metastatic cancer with vaccines (most?422–with metastatic melanoma), only 2.6% exhibited a positive treatment response. Reviewing 35 carefully selected representative reports from the literature (one third in melanoma patients) involving 765 patients, the objective response rate to this treatment was again surprisingly low (only 3.8%).

Rosenberg et al. (6) suggested that an important reason for this poor performance was the inability of T cells generated by cancer vaccines to infiltrate tumors and become activated after an encounter with tumor antigen in vivo. He concluded “the lack of clinical effectiveness of currently available cancer vaccines should not be interpreted to mean that cancer vaccine approaches are at an investigational dead end. Rather, it emphasizes the need for profound changes in the application of this approach.” Among several suggestions proposed were mechanisms to increase the yield and activity of CD4+ cells and to eliminate-tumor induced or normally occurring lymphocyte-mediated immune suppressive mechanisms.

While more than 1700 publications on melanoma vaccine use in both animals and humans have appeared since the 2001 BCBSA TEC Special Report, there were only 12 phase 3 clinical studies evaluating melanoma vaccines (7-18): 4 using allogeneic vaccines, 2 autologous whole-cell vaccines, 2 ganglioside vaccines, 1 autologous heat shock protein, and 3 peptide vaccines—1 pulsed with dendritic cells, 1 administered with ipilimumab, and 1 administered with concomitant IL-2. In 2 studies, (7, 10) vaccine treatments appeared to demonstrate superior performance in unique populations identified during post hoc data evaluation. However, no published study to date has shown a statistically significant survival benefit in the general population selected for study. In 2 reports, (9, 12) outcomes using vaccines appeared inferior to those observed in controls. A summary of trials showing lack of efficacy are provided in Table 1.

Hodi et al. (17) performed a phase 3 study of ipilimumab, an agent that blocks cytotoxic T lymphocyte-associated antigen 4 to potentiate an antitumor T cell response. This agent was administered in a 3-arm study comparing ipilimumab to ipilimumab with gp100 peptide vaccine to gp100 peptide vaccine alone. Ipilimumab, when used alone or with gp100, exhibited improved OS compared with gp100 alone in patients with previously treated melanoma. Ipilimumab has subsequently been approved by the FDA for this use.

Schwartzentruber et al. (15, 18) reported findings of their phase 3 trial of gp100:209-217(210M) peptide vaccine plus high-dose IL-2 (vaccine) versus high-dose IL-2 alone (control). The vaccine arm showed significant improvement in response rate (p=0.03) and PFS (p=0.008) but not median OS (p=0.06). The authors reached the guarded conclusion that “additional data are needed to ascertain whether the finding in our study was due to a direct effect of the vaccine or to the possibility that vaccinated patients were more responsive to salvage regimens or that the nature of progression differed between the two groups or that other factors were involved.”

In a systematic review and meta-analysis of 4375 patients in 56 phase 2 and phase 3 studies, no evidence was found that vaccine therapy provides better overall disease control or OS compared with other treatments. (19) However, in a second review of medical treatments in melanoma, 2 pending studies were highlighted. (20) The first is a phase 3 vaccine trial of patients with stage IIIB melanoma whose tumors express MAGE-A3 antigen in lymph node metastasis. This allogeneic vaccine is unique in targeting a specific cancer germline family antigen. The second is a phase 3 trivalent vaccine prepared using 3 peptides (gp100, MART-1/Melan, and tyrosine HLA-A2). Preliminary reports suggest patients exhibiting antibodies to any of the 3 peptides had insignificantly improved survival. More definitive results from both studies are pending.

There are a variety of explanations as to why, to date, melanoma vaccines have not been able to produce clinically significant improvements in treatment outcomes. (21) One possible mechanism is immune ignorance and the ability of melanoma cells to escape detection through loss of antigens or loss of HLA expression. A second mechanism is immune tolerance. This may result from the ability of the melanoma tumor to prevent a local accumulation of active helper and/or effector T cells as a result of high interstitial pressure in the tumor or lack of appropriate adhesion molecular on tumor vasculature. This may also occur as a result of normal down-regulation of the immune system at the site of T cell tumor interaction. A wide range of immune-modulating techniques are being explored to find mechanisms for enhancing the immune response induced by tumor vaccines.

Gajewski (22) published a preliminary or exploratory report on the value of molecular profiling to identify relevant immune resistance in the tumor microenvironment. This approach toward identifying subsets of patients likely to benefit from specific treatment choices, if confirmed in future studies, may help improve treatment outcomes with the use of tumor vaccines.

TABLE 1: Phase III randomized, controlled, clinical trials of vaccine therapy evaluating cancer outcomes.







Livingston et al., 1994 (7)

Stage III n=122



DFS and OS showed no statistically significant differences

COMMENT: Patients with no pre-treatment anti-GM2 antibody showed improved PFS with vaccine

Wallack et al., 1998 (8)

Stage III n=217

Vaccinia melanoma oncolysate

Vaccinia oncolysate from normal cell

DFS and OS showed no statistically significant differences.

Kirkwood et al., 2001 (9)

Stage IIB/III n=774

Ganglioside GM2-KLH21 (GMK [guanylate kinase])

Interferon alpha

Trial closed after interim analysis indicated GMK inferiority.

Sondak et al., 2002 (10)

Stage II n=600

Allogeneic melanoma vaccine (Melacine®)


No evidence of DFS.

COMMENT: Patients with 2 or more HLA matches showed improved PFS .

Hersey et al., 2002 (11)

Stage IIB/III n=700

Vaccinica melanoma oncolysate


Recurrence-free and OS not statistically improved in vaccine patients.

Morton et al., 2006 (12)

Stage III n=1,160

Canvaxin® + BCG + placebo

BCG + placebo

Trial closed after interim analysis indicated Canvaxin® inferiority.

Morton et al., 2006 (12)

Stage IV n=496

Canvaxin®+ BCG + placebo

BCG + placebo

Trial closed after interim analysis showed lack of efficacy.

Mitchell et al., 2007 (13)

Stage III n=604

Allogeneic whole-cell lysate administered with Detox™ (Melacine®) + interferon alpha

Interferon alpha

No survival advantage but fewer adverse events in patients on vaccine.

Testori et al., 2008 (14)

Stage IV n=322

Heat shock protein gp96 complex vaccine (Oncophage®)

Physician’s choice of dacarbazine, temozolomide, IL-2 and/or resection

No survival advantage in patients on vaccine.

Schadendorf et al., 2006 (16)

Stage IV n=108

Peptide-pulsed dendritic cells


Trial closed after interim analysis showed lack of efficacy.

Hodi et al., 2010 (17)

Stage III

or IV n=676

Ipilimumab alone or with GP100

GP100 peptide alone

Ipilimumab showed improved OS with or without GP100 compared to GP100 treatment alone.

Schwar-zentruber et al., 2011 (18)

Stage III/IV n=185

GP100 peptide + IL2

High-dose IL2

Objective response and increased in patients on vaccine and IL2 treatment.

Table Key:DFS: disease free survival; PFS progression free survival;OS: overall survival; HLA: human leukocyte antigen; IL-2: interleukin-2: BCG: Bacillus Calmette-Guerin.

Ongoing Clinical Trials

A review of identified no new studies that address preventive melanoma vaccines.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN)

The 2017 NCCN guidelines on the treatment of melanoma do not reference the use of preventive or therapeutic vaccines. (23)


Tumor vaccines are a type of active immunotherapy that attempts to stimulate the patient’s own immune system to respond to tumor antigens. There are a number of different tumor vaccines for the treatment of malignant melanoma in various stages of development.

A wide range of vaccine choices are available including use of autologous tumor cells, allogeneic tumor cells, and tumor-specific moieties including peptides, gangliosides, and DNA plasmids. A variety of mechanisms appear to exist as possible obstacles to successful active immunotherapy using vaccines. Current studies are focused on the use of new and different vaccine preparations, as well as on various forms of immune-modulation as potential techniques for enhancing vaccine effectiveness.

Despite considerable interest and numerous studies over the past 20 years, to date, no preventive melanoma vaccine has been approved by the FDA. One randomized, controlled trial (RCT) of a gp100 melanoma vaccine has reported a significant increase in response rate and progression free survival (PFS), and many other trials are underway or in the planning stages. However, several other RCTs have reported no improvements in disease-free survival and overall survival (OS) rates with the use of study vaccines. Additionally, other RCTs have closed early due to inferiority of results with study vaccines. Therefore, the use of melanoma vaccines is considered experimental, investigational and/or unproven.


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Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

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1. Ray S, Chhabra A, Mehrotra S et al. Obstacles to and opportunities for more effective peptide-based therapeutic immunization in human melanoma. Clin Dermatol 2009; 27(6):603-13. PMID: 19880048.

2. Cunningham TJ, Olson KB, Laffin R et al. Treatment of advanced cancer with active immunization. Cancer 1969; 24(5):932-7. PMID: 4187652.

3. Eggermont AM. Therapeutic vaccines in solid tumours: can they be harmful? Eur J Cancer 2009; 45(12):2087-90. PMID: 19477117.

4. Lens M. The role of vaccine therapy in the treatment of melanoma. Expert Opin Biol Ther 2008; 8(3):315-23. PMID: 18294102.

5. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Special Report: Vaccines for the Treatment of Malignant Melanoma. TEC Assessments 2001; Volume 16, Tab 4.

6. Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med 2004; 10(9):909-15. PMID: 15340416.

7. Livingston PO, Adluri S, Helling F et al. Phase 1 trial of immunological adjuvant QS-21 with a GM2 ganglioside-keyhole limpet haemocyanin conjugate vaccine in patients with malignant melanoma. Vaccine 1994; 12(14):1275-80. PMID: 7856291.

8. Wallack MK, Sivanandham M, Balch CM et al. Surgical adjuvant active specific immunotherapy for patients with stage III melanoma: the final analysis of data from a phase III, randomized, double-blind, multicenter vaccinia melanoma oncolysate trial. J Am Coll Surg 1998; 187(1):69-77; discussion 77-9. PMID: 9660028.

9. Kirkwood JM, Ibrahim JG, Sosman JA et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol 2001; 19(9):2370-80. PMID: 11331315.

10. Sondak VK, Liu PY, Tuthill RJ et al. Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with an allogeneic tumor vaccine: overall results of a randomized trial of the Southwest Oncology Group. J Clin Oncol 2002; 20(8):2058-66. PMID: 11956266.

11. Hersey P, Coates AS, McCarthy WH et al. Adjuvant immunotherapy of patients with high-risk melanoma using vaccinia viral lysates of melanoma: results of a randomized trial. J Clin Oncol 2002; 20(20):4181-90. PMID: 12377961.

12. Morton Dl MN, Thompson JF et al. An international, randomized phase III trial of bacillus Calmette-Guerin (BCG) plus allogenic melanoma vaccine (MCV) or placebo after complete resection of melanoma metastatic to regional or distant sites. J Clin Oncol 2007; 25(18S):8508.

13. Mitchell MS, Abrams J, Thompson JA et al. Randomized trial of an allogeneic melanoma lysate vaccine with low-dose interferon Alfa-2b compared with high-dose interferon Alfa-2b for Resected stage III cutaneous melanoma. J Clin Oncol 2007; 25(15):2078-85.

14. Testori A, Richards J, Whitman E et al. Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician's choice of treatment for stage IV melanoma: the C-100-21 Study Group. J Clin Oncol 2008; 26(6):955-62. PMID: 18281670.

15. Schwartzentruber DJ LD, Richards J et al. A Phase III multi-institutions randomized study of immunization with the gp100.209-217 (210M) peptide followed by high-dose IL-2 compared with high-dose IL-2 alone in patients with metastatic melanoma. A Phase III multi-institutions randomized study of immunization with the gp100.209-217 (210M) peptide followed by high-dose IL-2 compared with high-dose IL-2 alone in patients with metastatic melanoma. ASCO Annual Meeting 2009.

16. Schadendorf D, Ugurel S, Schuler-Thurner B et al. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG. Ann Oncol 2006; 17(4):563-70. PMID: 16418308.

17. Hodi FS, O'Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363(8):711-23. PMID: 20525992.

18. Schwartzentruber DJ, Lawson DH, Richards JM et al. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med 2011; 364(22):2119-27. PMID: 21631324.

19. Chi M, Dudek AZ. Vaccine therapy for metastatic melanoma: systematic review and meta-analysis of clinical trials. Melanoma Res 2011; 21(3):165-74. PMID: 21537143.

20. Garbe C, Eigentler TK, Keilholz U et al. Systematic review of medical treatment in melanoma: current status and future prospects. Oncologist 2011; 16(1):5-24. PMID: 21212434.

21. Chapman PB. Melanoma vaccines. Semin Oncol 2007; 34(6):516-23. PMID: 18083375.

22. Gajewski TF. Molecular profiling of melanoma and the evolution of patient-specific therapy. Semin Oncol 2011; 38(2):236-42. PMID: 21421113.

23. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology, Melanoma (v1.2017). Available at: <>. Accessed November 30, 2016.

24. Melanoma Vaccines-Archived. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2015 August) Medicine 2.03.04.

Policy History:

Date Reason
10/15/2017 Reviewed. No changes.
1/15/2017 Document updated with literature review. Coverage unchanged.
8/1/2015 Reviewed. No changes.
10/15/2014 Document updated with literature review. Coverage unchanged.
4/15/2013 Document updated with literature review. Description and Rationale significantly revised. Coverage unchanged.
4/15/2011 Document updated with literature review. Coverage unchanged.
10/15/2008 Revised/updated entire document
9/15/2006 Revised/updated entire document
10/1/2003 Revised/updated entire document
1/1/2000 Revised/updated entire document
4/1/1999 Revised/updated entire document
8/1/1998 New medical document

Archived Document(s):

Title:Effective Date:End Date:
Melanoma Vaccines10-15-201706-30-2018
Melanoma Vaccines01-15-201710-14-2017
Melanoma Vaccines08-01-201501-14-2017
Melanoma Vaccines10-15-201407-31-2015
Melanoma Vaccines04-15-201310-14-2014
Melanoma Vaccines04-15-201104-14-2013
Melanoma Vaccines10-15-200804-14-2011
Melanoma Vaccines09-15-200610-14-2008
Tumor Vaccines08-15-200609-14-2006
Tumor Vaccines10-24-200308-14-2006
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