Coverage Policy Manual
Policy #: 2003029
Category: Pharmacy
Initiated: July 2003
Last Review: May 2024
  Tumor Vaccines

Description:
Tumor (or Cancer) Vaccines claim to arm the immune system and shrink specific cancers, including melanoma, neuroblastoma, lymphoma, multiple myeloma, sarcoma, and cancers of the breast, cervix, lungs, esophagus, prostate, kidney, colorectal, and ovaries.  Unlike traditional vaccines, tumor (or cancer) vaccines do not prime the immune system to prevent illness.  They combat existing tumors and they also work in the same way as traditional vaccines, by activating disease-fighting white blood cells of the immune system to mount a counterattack.
 
Tumor cells express unique antigens to inform the immune system that something about these cells is foreign.  The vaccine is a way to deliver an antigen to the immune system so that immune cells can recognize the antigen as foreign and destroy any cells bearing that antigen.  These vaccines are thought to arm white blood cells (T-cells) and to destroy microscopic metastatic cells that have migrated from the primary tumor (even after the primary tumor has been removed).  This type of T-cell response is also known as a tumor-associated antigen.  
 
Additional tumor or cancer vaccine therapy categories include:
    • Dendritic cell vaccines, which seek out foreign tissue and alert the immune system to launch an attack; and
    • Genetically altered tumor cells, which "supercharge" the immune system to seek and destroy tumor cells throughout the body.  This is done by vaccinating the patient with their own tumor cells that have been injected with genetic material from altered bacteria or glycoproteins.
 
On April 29, 2010, the U.S. Food and Drug Administration (FDA) approved Provenge® (sipuleucel-T, Dendreon Corp.) via a Biologics Licensing Application (BLA) for "the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer (for autologous use only)." Approval was contingent on agreement of the manufacturer to conduct a postmarketing study, based on a registry design, to assess the risk of cerebrovascular events in 1,500 patients with prostate cancer who receive sipuleucel-T.  Coverage for Sipuleucel-T (Provenge®) is handled in policy # 2010028.
 

Policy/
Coverage:
Effective May 2010
 
Tumor (or cancer) vaccines are currently being studied in Phase I, II, and III clinical trials and laboratory studies and only sipuleucel-T (e.g., Provenge®) has received FDA approval.
 
Therefore, tumor (or cancer) vaccines with the exception of FDA approved indications for sipuleucel-T (e.g., Provenge®) do not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following, but not limited to, cancers or tumors:
    • Melanoma,
    • Neuroblastoma,
    • Lymphoma,
    • Multiple Myeloma,
    • Sarcoma,
    • Breast,
    • Cervix,
    • Lungs,
    • Esophagus,
    • Prostate (other than FDA approved indications for sipuleucel-T [Provenge®]),
    • Kidney,
    • Colon, and
    • Ovaries
 
For contracts without primary coverage criteria, the following tumor (or cancer) vaccines with the exception of FDA approved indications for sipuleucel-T (e.g., Provenge®) are considered investigational including but not limited to the following:  
    • Melanoma,
    • Neuroblastoma,
    • Lymphoma,
    • Multiple Myeloma,
    • Sarcoma,
    • Breast,
    • Cervix,
    • Lungs,
    • Esophagus,
    • Prostate (other than FDA approved indications for sipuleucel-T [e.g., Provenge®]),
    • Kidney,
    • Colon, and
    • Ovaries
 
Investigational services are an exclusion in most member benefit certificates of coverage.
 
Effective July 2003 through April 2010
 
At the present time, there are no tumor or cancer vaccines with FDA approval.  Some tumor vaccines that use autologous tumor tissue from the patient may not be subject to FDA approval.  Phase I, II, and III clinical trials and laboratory studies are currently being conducted.  
 
The following tumor (or cancer) vaccines:
    • Melanoma,
    • Neuroblastoma,
    • Lymphoma,
    • Multiple Myeloma,  
    • Sarcoma, and
    • Vaccines targeted for cancer of the -
      • Breast,
      • Cervix,
      • Lungs,
      • Esophagus,
      • Prostate,
      • Kidney,
      • Colon, and
      • Ovaries
do not meet benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For contracts without primary coverage criteria, the following tumor (or cancer) vaccines:
    • Melanoma,
    • Neuroblastoma,
    • Lymphoma,
    • Multiple Myeloma,  
    • Sarcoma, and
    • Vaccines targeted for cancer of the -
      • Breast,
      • Cervix,
      • Lungs,
      • Esophagus,
      • Prostate,
      • Kidney,
      • Colon, and
      • Ovaries
are considered investigational.  Investigational services are an exclusion in the member certificate of coverage.

Rationale:
This policy references a 2001 Blue Cross Blue Shield Association Technology Evaluation Center Special Report, Vaccines for the Treatment of Malignant Melanoma.  The purpose of this report was to review the completed, active, or closed phase III trials of melanoma vaccine and to summarize and evaluate the evidence from phase I/II trials of those melanoma vaccines currently in phase III trials. The report looked separately at patients with stage II disease (locally advanced), stage III disease (limited nodal metastases), and stage IV disease (advanced regional or distant metastases). The report offered the following observations and conclusions:
 
Stage II disease
Studies of vaccine in patients with stage II melanoma (localized disease) suggest a benefit for vaccine, however, there are insufficient data to permit conclusions regarding the outcomes of vaccine use in this disease stage. In addition, only historical controls from other studies are available for comparison, and patients' characteristics and non-vaccine treatments are not matched, making valid comparisons difficult. The results of phase III trials of vaccine therapy are necessary to determine whether or not vaccines will benefit stage II and in-transit melanoma patients compared to standard therapy.
 
Stage III disease
Studies of a variety of vaccines in resected stage III melanoma patients have reported generally favorable survival comparisons to historical outcomes. Resected stage III patients have a low tumor burden, but a poor long-term prognosis, and so might benefit from vaccine therapy. However, improvements in staging and treatment over time make unmatched, historical comparison unreliable for accurate assessment of efficacy. The results of randomized, controlled phase III trials of vaccine therapy are necessary to determine whether or not vaccines will benefit resected stage III melanoma patients compared to standard therapy. Although phase III trials may not show the same degree of benefit for vaccine as phase II trials, vaccines that result in outcomes that equal standard therapy and are significantly less toxic may be attractive alternative for some patients.
 
Stage IV disease
Stage IV melanoma patients who can be rendered clinically disease free by resection may have survival outcomes similar to resected stage III patients, and make good candidates for vaccine therapy clinical trials. However, for stage IV patients, with tumors that cannot be completely resected, survival is poor; tumor burden is high; and regimens involving combination chemotherapy or chemo immunotherapy have not significantly improved survival compared to dacarbazine therapy. Vaccines are unlikely to obtain a significant response, especially as evidence suggests that high tumor burden may induce immunosuppression, and may be more likely to escape immune detection due to tumor heterogeneity developing over time. The results of phase I/II trials in stage IV or stage III-IV patient groups in general appear to be as good as, but show little added benefit compared to standard therapy (although vaccine therapy has low toxicity). Response rates and disease-free survival results tend to overlap with those expected for dacarbazine therapy; in some trials, the range of results appears to extend beyond that of dacarbazine. However, it is not possible to know if this represents a true benefit of vaccine therapy, or an artifact due to comparison to unmatched, historical controls. The results of phase III trials are needed to determine efficacy for melanoma patients compared to standard therapy.
 
2002 Update
At the present time, no phase III vaccine trial of adequate power has as yet demonstrated a statistically significant improvement in health outcomes for vaccine compared to standard therapy. In addition, no melanoma vaccine has received approval from the U.S. Food and Drug Administration (FDA) (although some vaccines, such as those prepared from autologous tumor cells, are not subject to FDA approval). For example, Melacine, a cell lysate vaccine made from allogeneic tumor cell lines, currently in phase III clinical trials, is subject to FDA approval. (This product is marketed in Canada.) An initial phase III trial (SWOG-9035) suggested that Melacine vaccine was effective in prolonging relapse-free survival and overall survival compared to observation in patients who expressed HLA A2 and/or HLA C3. A second recently initiated phase III trial will study overall survival as the primary endpoint in a similar group of patients. According to the manufacturer, Corixa, the results of these 2 trials will be presented to the FDA as part of the FDA-approval process.  Other melanoma vaccines that are subject to FDA regulation include Canvaxin (CancerVax), GMK (Progenics Pharmaceuticals) and Oncophage (Antigenics, Inc).
 
2009 Update
Presently there are no tumor or cancer vaccines with FDA approval.  Numerous clinical trials are ongoing with over 170 phase I and II trials of melanoma vaccines listed in the NIH clinical trials database.
 
One vaccine has recently shown a statistically significant improvement in outcomes.  Schwartzentruber et al reported the initial findings of their phase III trial of gp100:209-217(210M) peptide plus high-dose IL-2 (Vacc) vs. high-dose IL-2 alone (Ctl). The Vacc arm showed significant improvement in response rate (p=0.02), progression-free survival (PFS; p=0.01), but not median overall survival (p=0.09). Complete evaluation of the results awaits full publication.
 
A trial testing M-Vax™ (AVAX Technologies, Inc.) is currently recruiting subjects with Stage IV melanoma.  M-Vax™ consists of autologous tumor cells conjugated to dinitrophenyl, a highly immunogenic hapten.  AVAX Technologies is also sponsoring a Phase I/II trial of O-Vax®, an autologous, hapten-modified vaccine for patients with ovarian cancer.
 
Schuster et al, reported results of a phase III randomized trial of BiovaxID, a tumor-specific protein vaccine for patients with advanced follicular lymphoma with complete response to chemotherapy (Schuster et al, 2009).   The results indicated that BiovaxID prolonged disease free survival in patients that received the vaccine to 44months compared to 31 months for those who received the control vaccine.  However, the trial was terminated early due to difficulty with patient accrual.  This was due in part because rituximab became the standard of care for patients with follicular lymphoma.
 
In summary, although there is a vast amount of research being done in the area of tumor vaccines, there are no vaccines with FDA approval at this time.   The policy remains unchanged.
 
2010 Update
On April 29, 2010, the U.S. Food and Drug Administration (FDA) approved Provenge® (sipuleucel-T, Dendreon Corp.) via a Biologics Licensing Application (BLA) for "the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer (for autologous use only)." Approval was contingent on agreement of the manufacturer to conduct a postmarketing study, based on a registry design, to assess the risk of cerebrovascular events in 1,500 patients with prostate cancer who receive sipuleucel-T.  Coverage for Sipuleucel-T (Provenge®) is handled in policy # 2010028.
 
Sipuleucel-T (Provenge®, Dendreon Corp.) is a new class of therapeutic agent used in the treatment of asymptomatic or minimally symptomatic, androgen-independent (hormone-refractory), metastatic prostate cancer. It consists of specially treated dendritic cells obtained from the patient with leukapheresis. The cells are then exposed in vitro to proteins that contain prostate antigens and immunologic stimulating factors, and then reinfused back into the patient. The proposed mechanism of action is that the treatment stimulates the patient’s own immune system to resist spread of the cancer.
 
Sipuleucel-T ((Provenge®) is discussed in detail in a separate policy #2010028.
 
2011 Update
A review of the Medline Database was conducted through July 2011. The search did not identify any new literature that would prompt a change in the coverage statement.
 
In a recent systematic review of medical treatments in melanoma, two pending studies were highlighted (Garbe, 2011). The first is a Phase III 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 III 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.
 
2012 Update
A literature search was conducted through September 2012.  There was no new literature identified that would prompt a change in the coverage statement. There are numerous ongoing clinical trials assessing the use of vaccines in the treatment of patients with various types of malignancies. Since the last policy update, no new vaccines have been approved by the U.S. FDA.
 
2013 Update
A search of the MEDLINE database did not reveal any new information that would prompt a change in the coverage statement.
 
2014 Update
A literature search conducted through April 2014 did not reveal any new information that would prompt a change in the coverage statement.
  
2015 Update
A literature search conducted through April 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
No new phase 3 RCT evidence has been published in the period since the last evidence review for this Policy. In recent single-arm series, 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 (Gibney, 2015; Riker, 2014; Weber, 2013). 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 (Jha, 2014). 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).
 
The body of evidence reviewed for this Policy is insufficient to conclude that anti-melanoma vaccines of any type alone or in combination with immunomodulating agents significantly improve survival outcomes compared with nonvaccine therapies in any clinical setting. Phase 3 RCTs are underway or in the planning stages to further investigate vaccine preparations to treat malignant melanoma.
 
2016 Update
A literature search conducted through April 2016 did not reveal any new information that would prompt a change in the coverage statement.     
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2018. No new literature was identified that would prompt a change in the coverage statement.
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2019. No new literature was identified that would prompt a change in the coverage statement.
 
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2020. No new literature was identified that would prompt a change in the coverage statement.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2023. No new literature was identified that would prompt a change in the coverage statement.
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2024. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
86849Unlisted immunology procedure

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Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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