Description:
Tumor vaccines are a type of active immunotherapy that attempts to stimulate the patient's own immune system to respond to tumor cell antigens. A wide range of vaccine types 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 areas of investigation include new and different vaccine preparations, as well as various forms of immune modulation to enhance vaccine effectiveness.

The evidence for melanoma vaccines in patients who have stage II-IV melanoma includes studies 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. Relevant outcomes include overall survival, disease-specific survival and morbid events. Despite considerable activity in numerous studies over the past 20 years, no melanoma vaccine has received U.S. Food and Drug Administration marketing approval. One randomized controlled trial (RCT) of a gp100 melanoma vaccine has reported a significant increase in response rate and progression-free survival. However, several other RCTs have reported no improvements in disease-free survival or overall survival rates with the use of study vaccines. Additionally, other RCTs were closed early due to inferiority of results with study vaccines. Other phase 3 RCTs are underway or in the planning stages to further investigate vaccine preparations to treat malignant melanoma. For use of melanoma vaccines for treatment of patients with stage II-IV melanoma, the body of evidence is insufficient to conclude that anti-melanoma vaccines of any type, alone or in combination with immunomodulating agents, significantly improve survival outcomes compared with non-vaccine therapies. The evidence is insufficient to determine the effects of the technology on health outcomes.

Background
Vaccines using crude preparations of tumor material were first studied by Ehrlich over 100 years ago.¹ However, the first modern report to suggest benefit in cancer patients did not appear until 1967.² Melanoma has been viewed as a particularly promising target for vaccine 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 ways⁴:

• Whole-cell vaccines prepared using melanoma cells or crude subcellular fractions of melanoma cell lines 
  • Autologous whole-cell vaccines in which tumor cells are harvested from the tissue 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) 
  • Autologous heat-shock protein-peptide complexes vaccines in which a patient's tumor cells are exposed to high temperatures and then purified to make patient-specific vaccines (e.g., Oncophage^®, Antigenics Inc.), and
  • 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^®, CancerVax Corp.; 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 RNA or DNA to produce immunologically enhanced vaccines.
• Peptide vaccines consisting of short, immunogenic peptide fragments of proteins (e.g., melanoma antigen E [MAGE]; B melanoma antigen [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.
• Anti-idiotype vaccines made from monoclonal antibodies with specificity for tumor antigenreactive antibodies.  

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

Related Policies
80101 Adoptive Immunotherapy

Policy:
Melanoma vaccines (also known as Theraccine vaccine or Oncophage vaccine) are investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY.    

Policy Guidelines:

There are no specific CPT codes for this service. The administration of the vaccine might be reported with code 96372 as a therapeutic, prophylactic, or diagnostic injection. The use of 96405 or 96406 may also be used to indicate the administration. The unlisted immunology procedure code 86849 might be used for creating the vaccine. J code J9325 is specific to IMLYGIC^®.

Benefit Application
BlueCard/National Account Issues
Melanoma vaccines are currently available only in clinical trials in the United States. 

Rationale
In a 2011 systematic review and meta-analysis of 4,375 patients in 56 phase 2 and phase 3 studies, no evidence was found that vaccine therapy yields better overall disease control or overall survival (OS) compared with other treatments.⁶ Currently, there are 12 phase 3 clinical studies that have evaluated melanoma vaccines^{7,8,9,10,11,12,13,14,15,16,17,18}: 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, vaccine treatments appeared to demonstrate superior performance in unique populations identified during post hoc data evaluation.^7,10 However, no published study to date has shown a statistically significant survival benefit in the general population selected for study. In 2 reports, outcomes using vaccines appeared inferior to those observed in controls.^9,12 Table 1 provides a summary of trials that showed lack of efficacy of melanoma vaccines.  

Several explanations have been offered as to why melanoma vaccines have not produced clinically significant improvements in clinical outcomes.¹⁹ 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 molecular adhesion 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. One potential solution to this problem is to use molecular profiling to identify relevant immune resistance in the tumor microenvironment.²⁰ If confirmed in future studies, this approach toward identifying subsets of patients likely to benefit from specific treatment choices may help improve treatment outcomes with the use of tumor vaccines.

Table 1. Phase 3 Randomized, Controlled Trials of Vaccine Therapy Evaluating Cancer Outcomes

BCG: Bacille Calmette-Guérin; DFS: disease-free survival; GMK: guanylate kinase; HLA: human leukocyte antigen; IL-2: interleukin‒2; OS: overall survival.  

No new phase 3 randomized controlled trial (RCT) evidence has been published in the period since the last evidence review. In single-arm series published in 2013 – 2015, combinations of immunotherapeutic agents (nivolumab, pegylated interferon) and study vaccines have been investigated in patients with unresectable or resected stage III and IV malignant melanoma.^21,22,23 Results from these studies suggest combined immunotherapeutic approaches are tolerable and may have clinical efficacy reflected by tumor regression. However, no valid conclusions can be drawn from this evidence as to the effectiveness of the combinations relative to other treatments. 

A randomized, phase 2 clinical trial published in 2014 evaluated the activity of interleukin-2 (IL-2) alone or IL-2 in combination with allogeneic large multivalent immunogen (LMI) vaccine in patients with stage IV melanoma.²⁴ The primary objective of this trial was to evaluate the effect of the treatments on progression-free survival (PFS), with a secondary objective to evaluate median OS and 1- and 2-years rates of OS. The study was halted after enrolling 21 patients after a preplanned analysis established that it was unlikely to meet its primary objective of improved PFS with additional accrual. Per-protocol analysis of data from the 21 accrued patients showed median PFS of 2.20 months in the IL-2 plus LMI group versus 1.95 months in the IL-2 controls (p = NS). Median OS was 11.89 months in the IL-2 plus LMI group and 9.97 months in the IL-2 group (p = NS).  

Ongoing and Unpublished Clinical Trials
A search of the online site www.ClinicalTrials.gov in June 2015 identified a number of small phase 2 trials. Ongoing phase 3 clinical trials that might influence this review are listed in Table 2. 

Table 2. Summary of Key Trials 

NCT: national clinical trial.
ª Denotes industry-sponsored or cosponsored trial.  

Summary of Evidence
The evidence for melanoma vaccines in patients who have stage II-IV melanoma includes studies 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. Relevant outcomes include overall survival, disease-specific survival and morbid events. Despite considerable activity in numerous studies over the past 20 years, no melanoma vaccine has received U.S. Food and Drug Administration marketing approval. One randomized controlled trial (RCT) of a gp100 melanoma vaccine has reported a significant increase in response rate and progression-free survival. However, several other RCTs have reported no improvements in disease-free survival or overall survival rates with the use of study vaccines. Additionally, other RCTs were closed early due to inferiority of results with study vaccines. Other phase 3 RCTs are underway or in the planning stages to further investigate vaccine preparations to treat malignant melanoma. For use of melanoma vaccines for treatment of patients with stage II-IV melanoma, the body of evidence is insufficient to conclude that anti-melanoma vaccines of any type, alone or in combination with immunomodulating agents, significantly improve survival outcomes compared with non-vaccine therapies. The evidence is insufficient to determine the effects of the technology on health outcomes. 

Practice Guidelines and Position Statements
The National Comprehensive Cancer Network guideline on the treatment of melanoma (v.3.2015) does not reference the use of vaccines in clinical trials in any of its treatment algorithms.²⁵ The guidelines do discuss clinical trials that have reported inferiority in melanoma vaccine treatment arms.  

U.S. Preventive Services Task Force Recommendations
Not applicable

References:

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. Nov-Dec 2009;27(6):603-613. PMID 19880048
2. Cunningham TJ, Olson KB, Laffin R, et al. Treatment of advanced cancer with active immunization. Cancer. Nov 1969;24(5):932-937. PMID 4187652
3. Eggermont AM. Therapeutic vaccines in solid tumours: can they be harmful? Eur J Cancer. Aug 2009;45(12):2087-2090. PMID 19477117
4. Lens M. The role of vaccine therapy in the treatment of melanoma. Expert Opin Biol Ther. Mar 2008;8(3):315-323. PMID 18294102
5. Blue Cross Blue Shield Association Technology Evalaution Center. Special Report: Vaccines for the Treatment of Malignant Melanoma. TEC Assessments. 2001;Volume 16, Tab 4. PMID
6. Chi M, Dudek AZ. Vaccine therapy for metastatic melanoma: systematic review and meta-analysis of clinical trials. Melanoma Res. Jun 2011;21(3):165-174. PMID 21537143
7. Livingston PO, Adluri S, Helling F, et al. Phase 1 trial of immunological adjuvant QS-21 with a GM2 gangliosidekeyhole limpet haemocyanin conjugate vaccine in patients with malignant melanoma. Vaccine. Nov 1994;12(14):1275-1280. 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. Jul 1998;187(1):69-77; discussion 77-69. 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. May 1 2001;19(9):2370-2380. 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. Apr 15 2002;20(8):2058-2066. 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. Oct 15 2002;20(20):4181-4190. 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. PMID
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. May 20 2007;25(15):2078-2085. PMID 17513813
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. Feb 20 2008;26(6):955-962. 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. 2009 ASCO Annual Meeting. 2009. PMID
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. Apr 2006;17(4):563-570. 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. Aug 19 2010;363(8):711-723. 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. Jun 2 2011;364(22):2119-2127. PMID 21631324
19. Chapman PB. Melanoma vaccines. Semin Oncol. Dec 2007;34(6):516-523. PMID 18083375
20. Gajewski TF. Molecular profiling of melanoma and the evolution of patient-specific therapy. Semin Oncol. Apr 2011;38(2):236-242. PMID 21421113
21. Gibney GT, Kudchadkar RR, DeConti RC, et al. Safety, correlative markers, and clinical results of adjuvant nivolumab in combination with vaccine in resected high-risk metastatic melanoma. Clin Cancer Res. Feb 15 2015;21(4):712-720. PMID 25524312
22. Riker AI, Rossi GR, Masih P, et al. Combination immunotherapy for high-risk resected and metastatic melanoma patients. Ochsner J. Summer 2014;14(2):164-174. PMID 24940124
23. Weber JS, Kudchadkar RR, Yu B, et al. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. Dec 1 2013;31(34):4311-4318. PMID 24145345
24. Jha G, Miller JS, Curtsinger JM, et al. Randomized phase II study of IL-2 with or without an allogeneic large multivalent immunogen vaccine for the treatment of stage IV melanoma. Am J Clin Oncol. Jun 2014;37(3):261-265. PMID 23241505
25. National Comprehensive Cancer Network N. Clinical Practice Guidelines in Oncology, Melanoma (v3.2015). http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. Accessed June 2, 2015. 

Coding Section 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.  

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

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