Archived Policies - Medicine


Melanoma Vaccines

Number:MED203.010

Effective Date:10-15-2008

End Date:04-14-2011

Coverage:

Melanoma Vaccines are considered experimental, investigational and unproven.

Description:

Tumor vaccines are a type of immunotherapy that attempts to stimulate the patient’s own immune system to respond to tumor antigens.  Tumor vaccines have been principally investigated as a treatment of melanoma, due to the recognition that melanoma can induce an immune response, and the overall ineffectiveness of chemotherapy.  Melanoma vaccines can be generally categorized or prepared in the following ways:

  • Purified antigen vaccines, consisting of single, purified proteins or gangliosides, or short, immunogenic peptide fragments of proteins (e.g., GMK (ganglioside) vaccine, Progenics);
  • Cell lysate vaccines, in which allogeneic tumor cell lines are lysed by mechanical disruption or viral infection;
  • Whole cell vaccines, consisting of whole killed allogeneic cells from tumor cell lines.
  • Autologous whole-cell vaccines, in which tumor cells are harvested from the patients, irradiated, and potentially modified with antigenic molecules to increase immunogenicity (e.g., M-Vax®, AVAX Technologies).
  • Heat-shock protein-peptide complexes purified from autologous tumor cells (e.g., Oncophage®, Antigenics, Inc.).
  • Shed antigen vaccines, consisting of a mixture of cell surface antigens shed into tissue culture supernatant by melanoma cell lines.
  • Dendritic cell vaccines, consisting of autologous, dendritic cells pulsed with tumor-derived peptides, tumor lysates, antigen encoding Ribonucleic acid (RNA) or Deoxyribonucleic acid (DNA).
  • Genetically modified tumor vaccines, consisting of autologous or allogeneic tumor cell lines transduced with retroviral vectors containing cytokine genes, tumor antigen genes, co-stimulatory molecules, or human leukocyte antigen (HLA) proteins.
  • Anti-idiotype vaccine, consisting of monoclonal antibodies with specificity for tumor antigen-reactive antibodies.

NOTE:  At the present time, no melanoma vaccine has received approval from the U.S. Food and Drug Administration (FDA).

Rationale:

A 2001 Blue Cross Blue Shield Technology Association Evaluation Center (TEC) Special Report, “Vaccines for the Treatment of Malignant Melanoma” reviewed the completed, active, or closed phase III trials of melanoma vaccine and evaluated the evidence from phase I/II trials of those melanoma vaccines in phase III trials at that time.  The report focused on phase III (randomized, controlled) clinical trials because concurrent control patients are necessary to control for patient characteristic, disease, and treatment confounders.  Long-term outcomes that measure disease progression or mortality are also essential to such trials; surrogate measures of immune response may not be directly related to long-term outcomes, and may be confounded by other factors.

Results from the TEC Special Report and from subsequent searches of MedLine through June 2008 have identified several relatively large (100 patients or more), phase III randomized, controlled clinical trials of vaccine therapy that evaluated cancer outcomes.  These trials are summarized in the table shown below; part A describes completed or discontinued trials, and part B of the table below describes trials that are listed as ongoing in the National Institute of Health (NIH) clinical trials database.

The results in part A of the table below show that a diversity of vaccine types, with or without immunotherapy, have been tested against a variety of control treatments, and that none have shown a statistically significant improvement in progression-free or overall survival outcomes. Development of several specific vaccines was terminated after the trials were evaluated, some after interim evaluation.

Part B of the table lists three trials from the NIH clinical trials database that are currently recruiting patients.  Two of the vaccines being tested in these trials are purified antigen vaccines consisting of immunogenic peptides, delivered in conjunction with immunotherapy.  The third trial is testing M-Vax™ (AVAX Technologies, Inc.), which consists of autologous tumor cells conjugated to dinitrophenyl, a highly immunogenic hapten.  The trial identified as NCT00005034 is listed as ongoing, but no longer recruiting patients.  It was initiated in 1999, but no information on current status was found.  NCT00036816 is also listed as ongoing, but no longer recruiting patients.  It was initiated in 2002, but no information on current status was found.

A recent review of melanoma vaccines concludes that important parameters have yet to be conclusively established:

  • which melanoma antigens are most effective as rejection antigens;
  • the most effective method of immunization; and
  • an in vitro assay that correlates with clinical effects, to indicate when a vaccine is sufficiently immunogenic to warrant testing in large, randomized, controlled trials.

Approximately 170 phase I and II trials of melanoma vaccines are currently listed in the NIH clinical trials database, many of which are hopefully addressing these issues.

Phase III randomized, controlled, clinical trials of vaccine therapy evaluating cancer outcomes

A.  Completed or Terminated Trials

Study or Principal Investigator (PI)

ClinicalTrials.gov

Identifier (status)

 

Patient Population

 

N

 

Vaccine

 

Control

 

Results

Livingston et al. 1994

 

Stage III, resected

122

GM2 + BCG

BCG

Disease-free survival and overall survival at nearly 5 years were longer in the vaccine arm, but not statistically significant.

Wallack et al

 

Stage III

217

Vaccinia melanoma oncolysate

Vaccinia virus vaccine

No difference in disease-free or overall survival.

Mitchell 1998

 

Stage III-IV unresec-table

140

Allogeneic whole cell lysate administered with Detox™ (Melacine®)

Dacarbazine (DTIC) + cisplatin + carmustine + tamoxifen

No significant differences in response or survival; toxicity much lower in vaccine arm.

Kirkwood et al. 2001

 

Stage IIb-III, resected

774

Ganglioside GM2-KLH21 (GMK)

Interferon alpha

The trial was closed after interim analysis indicated inferiority of GMK compared with Interferon.

Hersey et al. 2002

 

Stage IIb-III, resected

700

Vaccinia melanoma cell lysate

Observation

Vaccine therapy was not associated with a statistically significant improvement in recurrence-free or overall survival.

Sondak et al 2002

 

Stage II

600

Allogeneic melanoma vaccine

Observation

No evidence of improved disease-free survival.

[Corixa Corp]

 

Stage II, resected

572

Allogeneic whole cell lysate administered with Detox™ (Melacine®)

Detoxified endotoxin (Detox™ )

No survival advantage to vaccine; further development terminated.

 

NCT00002767 (ongoing not recruiting)

Stage IV

300

Melacine® + Interferon alpha

Interferon alpha

Further development terminated.

Mitchell et al 2007

 

Stage III

604

Melacine® + Interferon alpha

Interferon alpha

No survival advantage to vaccine; fewer severe adverse events in vaccine arm; further development terminated.

Schadendorf et al 2006

 

Stage IV

108

autologous peptide-pulsed dendritic cells

Dacarbazine

Discontinued after interim analysis showed likely lack of vaccine efficacy.

Morton et al 2007

 

 

 

(ASCO abstract)

NCT000052130

NCT000052156

Stage III-IV, resected

1656

BCG + allogeneic melanoma cell vaccine (Canvaxin™; CancerVax Corp)

BCG + Placebo

Discontinued after interim analysis showed likely lack of vaccine efficacy.

Eggermont et al 2008

 

 

(ASCO abstract)

NCT00005052 (ongoing, not recruiting)

Stage II

1314

Ganglioside GM2-KLH21

(GMK, Progenics Pharmaceuticals, Inc.)

Observation

2nd interim analysis and early disclosure of results; concludes vaccination is ineffective and possibly detrimental.

Testori et al 2008

NCT000039000 (completed)

Stage IV

322

Heat shock protein gp96 peptide complex vaccine (Oncophage®; Antigenics, Inc.

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

No significant difference in overall survival; no significant toxicity in vaccine arm.

 

B.  Active Trials

Study or Principal Investigator (PI)

ClinicalTrials.gov

Identifier (status)

 

Patient Population

 

N

 

Vaccine

 

Control

 

Results

Rosenberg S (PI; NCI)

NCT00019682 (currently recruiting)

Stage III-IV

185

GP100: 209-217 (210M) Peptide + IL-2

IL-2

 

Yellin M (PI; Medarex

NCT00094653 (currently recruiting)

Stage III-IV

750

MDX-1379 Melanoma Pedtide Vaccine + Ipilmumab

Ipilimumb

 

Berd D (PI; AVAX Technologies)

NCT00477906 (currently recruiting)

Stage IV

387

M-Vax™ +IL2

Placebo vaccine + IL-2

 

Lawson D, Margolin, K (Pls; NCI, ECOG

NCT00005034 (ongoing, not recruiting)

Locally advanced or stage IV

800

(1) Peptide vaccine (2) Peptide vaccine + GM-CSF

(1) GM-CSF (2) Placebo

No publications under either PI name.

Brichard, V, Prause J (Pls; EORTC)

NCT00036816 (ongoing, not recruiting)

Patients with primary ocular mela-noma at high risk of relapse

600

Vaccine with NA17-A (patient-derived ocular melanoma antigen) and melanoma differentiation peptides

Observation

No publications under either PI name.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

None


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.

A national coverage position for Medicare may have been developed or changed since this medical policy document was written.  See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

Livingston, P.O., Wong, G.Y., et al.  Improved survival in stage III melanoma patients with GM2 antibodies: a randomized trial of adjuvant vaccination with GM2 ganglioside.  Journal of Clinical Oncology (1994) 12(5):1036-44.

Wallack, M.K., Sivanandham, M., 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.  Journal of the American College of Surgeons (1998) 187(1):69-79.

Mitchell, M.S.  Perspective on allogeneic melanoma lysates in active specific immunotherapy. Seminars in Oncology (1998) 25(6):623-35.

Vaccines for the Treatment of Malignant Melanoma.  Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (2001 May) 16(4):1-45.

Kirkwood, J.M., Ibrahim, J., et al.  High-dose interferon alfa-2b does not diminish antibody response to GM2 vaccination in patients with resected melanoma: results of the multicenter Eastern Cooperative Oncology Group phase II trial E2696.  Journal of Clinical Oncology (2001) 19(5):1430-6.

Hersey, P., Coates, A.S., et al.  Adjuvant immunotherapy of patients with high-risk melanoma using vaccinia viral lysates of melanoma: results of a randomized trial.  Journal of Clinical Oncology (2002) 20(20):4181-90.

Sondak, V.K., Liu, P.Y., 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.  Journal of Clinical Oncology (2002) 20(8):2058-66.

Hsueh, E.C., Essner, R., et al.  Prolonged survival after complete resection of disseminated melanoma and active immunotherapy with a therapeutic cancer vaccine.  Journal of Clinical Oncology (2002) 20(23):4549-54.

Mitchell, M.S., Abrams, J., et al.  Interim analysis of a phase III stratified randomized trial of melamine + low-dose intron-a versus high-dose intron-a for resected stage III melanoma. Chicago, Illinois.  American Society of Clinical Oncology (ASCO) Annual Meeting (2003 May 31-June 3) Abstract 2851.

Paczesny, S., Shi, H., et al.  Measuring melanoma-specific cytotoxic T lymphocytes elicited by dendritic cell vaccines with a tumor inhibition assay in vitro.  Journal of Immunotherapy (2005 March-April) 28(2):148-57.

Spaner, D.E., Hammond, C., et al.  A phase I/II trial of oxidized autologous tumor vaccines during the 51watch and wait51 phase of chronic lymphocytic leukemia.  Cancer Immunology, Immunotherapy (2005 July) 54(7):635-46.

Mocellin, S.  Cancer vaccines:  the challenge of developing an ideal tumor killing system.  Frontiers of Bioscience (2005 September 1) 10:2285-305.

Emens, L.A., and E.M. Jaffee.  Leveraging the activity of tumor vaccines with cytotoxic chemotherapy.  Cancer Research (2005 September 15) 65(18):8059-64.

Suckow, M.A., Wolter, W.R., et al.  Prevention of de novo prostate cancer by immunization with tumor-derived vaccines.  Cancer Immunology, Immunotherapy (2005 January) 54(6): 571-6.

Sondak,V.K., Sabel, M.S., et al.  Allogeneic and autologous melanoma vaccines: where have we been and where are we going?  Clinical Cancer Research (2006) 12(7 Supplement):2337s-41s.

Schadendorf, D., Ugurel, S., 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.  Annals of Oncology (2006) 17(4):563-70.

Baxevanis, C.N., Sotiriadou, N.M., et al.  Immunogenic HER-2/neu peptides as tumor vaccines.  Cancer Immunology, Immunotherapy (2006 January) 55(1):85-95.

Chen, P.W. and R.R. Keander.  Termination of systemic immunity in the presence of intraocular tumors: influence of ocular immune privilege on tumor vaccines.  Current Eye Research (2006 January) 31(1):43-55.

Zhou, G., Drake, C.G., et al.  Amplification of tumor-specified regulatory T cells following therapeutic cancer vaccines.  Blood (2006 January 15) 107(2):628-36.

Dolan, B.P., Gibbs, K.D., et al.  Tumor-specific CD4+ T cells are activated by 51cross-dressed51 dendritic cells presenting peptide-MHC class II complexes acquired from cell-based cancer vaccines.  Journal of Immunology (2006 February 1) 176(3):1447-55.

Garza, E., and C.Y. Okada.  Adjuvant IL-15 does not enhance the efficacy of tumor cell lysate-pulsed dendritic cell vaccines for active immunotherapy of T-cell lymphoma.  Cancer Immunology, Immunotherapy (2006 April) 55(4):420-32.

Schadendorf, D., Ugurel, S., 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.  Annals of Oncology (2006) 17(4):563-70.

Hahn, T., Alvares, I., et al.  Short-term dietary administration of celecoxib enhances the efficacy of tumor lysate-pulsed dendritic cell vaccines in treating murine breast cancer.  International Journal of Cancer (2006 May 1) 118(9):2220-31.

Morton, D.L., Mozzillo, N., et al.  An international, randomized, phase III trial of bacillus Calmette-Guerin (BCG) plus allogeneic melanoma vaccine (MCV) or placebo after complete resection of melanoma metastatic to regional or distant sites.  Journal of Clinical Oncology (2007) 25(18S):8508.

Chapman, P.B.   Melanoma vaccines.  Seminars in Oncology (2007) 34(6):516-23.

Mitchell, M.S., Abrams, J., 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.  Journal of Clinical Oncology (2007) 25(15):2078-85.

Eggermont, A.M., Suciu, S., et al.  EORTC 18961: Post-operative adjuvant ganglioside GM2-KLH21 vaccination treatment vs observation in stage II (T3-T4N0M0) melanoma: 2nd interim analysis led to an early disclosure of the results.  Journal of Clinical Oncology (2008) 26(15 supplement): abstract 9004.

Testori, A., Richards, J., 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.  Journal of Clinical Oncology (2008) 26(6):955-62.

Melanoma Vaccines.  Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2008 July) Medicine 2.03.04.

Policy History:

10/15/2008      Revised/updated entire document

9/15/2006        Revised/updated entire document

10/2003           Revised/updated entire document

1/2000             Revised/updated entire document

4/1999             Revised/updated entire document

8/1998             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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