Cancer Vaccines

Number: 0557

Policy

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.

Aetna considers helper multi-peptide (6MHP) vaccine for metastatic melanoma experimental and investigational because of insufficient evidence of its safety and effectiveness.

Aetna considers vaccine therapy including tumor-associated antigenic peptide-based vaccines in the treatment of the following cancers (not an all-inclusive list) experimental and investigational because the clinical evidence is not sufficient to permit conclusions on the health outcome effects of vaccine therapy in the treatment of these cancers:

  • Breast cancer
  • Central nervous system cancers (e.g., glioblastoma and neuroblastoma)
  • Colorectal cancer
  • Gallbladder cancer
  • Gastric cancer
  • Glioma
  • Head and neck cancer
  • Hepatic cancer
  • Lung cancer
  • Oral squamous cell carcinoma
  • Ovarian cancer
  • Pancreatic cancer.

Aetna considers HLA-A24-binding peptide vaccines experimental and investigational for gastric cancer because its effectiveness has not been established.

Aetna considers p16(INK4a-based peptide vaccine experimental and investigational for human papillomavirus-associated cancers (e.g., anal, cervical, oropharyngeal, penile, rectal, vaginal, and vulvar cancers) because its effectiveness has not been established.

Aetna considers p62 DNA vaccine (Elenagen) experimental and investigational for solid tumors (e.g., breast, kidney, lung, and ovary cancers as well as melanoma) because its effectiveness has not been established.

Background

Melanoma Vaccine

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:
  1. whole-cell vaccines,
  2. dendritic cell vaccines,
  3. peptide vaccines,
  4. ganglioside vaccines,
  5. DNA vaccines and
  6. 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 human leukocyte antigen (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).

Ovarian Cancer Vaccine

Ovarian cancer is cancer that begins in the ovaries. In general, ovarian tumors are named according to the kind of cells the tumor started from and whether the tumor is benign or cancerous. There are 3 main types of ovarian tumors
  1. germ cell tumors start from the cells that produce the ova (eggs);
  2. stromal tumors start from connective tissue cells that hold the ovary together and produce the female hormones estrogen and progesterone;
  3. epithelial tumors start from the cells that cover the outer surface of the ovary.

Therapeutic vaccines are intended to coerce the cellular components of the immune system to attack malignant tissue. Prophylactic vaccines are intended to induce the production of antibodies capable of neutralizing viral antigens before they infect host cells. 

The National Cancer Institute Ovarian Epithelial Cancer Treatment PDQ (2008) states that  vaccines are under clinical evaluation in the treatment of ovarian cancer, primarily as part of consolidation therapy.

According to a 2010 Cochrane database review, prognosis of ovarian cancer remains poor despite advances in chemotherapy. Antigen-specific active immunotherapy aims to induce a tumor-antigen-specific anti-tumor immune responses as an alternative treatment for ovarian cancer. The objective of this study was to assess feasibility of antigen-specific active immunotherapy for ovarian cancer. A systematic search of the Cochrane Central Register of Controlled Trials (CENTRAL) Issue 3, 2009, Cochrane Gynaecological Cancer Group Specialized Register, MEDLINE and EMBASE databases and clinicaltrials.gov was performed (1966 to July 2009). Randomized controlled trials, as well as non-randomized non-controlled studies that included patients with epithelial ovarian cancer, irrespective of stage of disease, and treated with antigen-specific active immunotherapy, irrespective of type of vaccine, antigen used, adjuvant used, route of vaccination, schedule, and reported clinical or immunological outcomes. Thirty-six studies were included. Response definitions showed substantial variation between trials, which makes comparison of trial results unreliable. Information on adverse events was frequently limited. However, three large randomised placebo-controlled trials did not show any clinical benefit despite induction of immune responses in approximately 60% of patients. Other small studies targeting many different tumour antigens showed promising immunological results. As these strategies have not yet been tested in randomized controlled trials (RCTs), no reliable inferences about clinical efficacy can be made. Given the promising immunological results, limited side effects and toxicity exploration of clinical efficacy in large well-designed RCTs may be worthwhile. It was concluded that despite promising immunological responses no clinically effective antigen-specific active immunotherapy is yet available for ovarian cancer. Furthermore, the adoption of guidelines to ensure uniformity in trial conduct, response definitions and trial reporting is recommended to improve quality and comparability of immunotherapy trials.

In a review, Gardner and Jewell (2011) wrote that future trials will determine the role of biologic agents and vaccine therapies for ovarian cancer, as well as their impact on quality of life.

Vaccines for Selected Types of Cancer

Krishnadas et al (2013) stated that patients with relapsed stage 4 neuroblastoma have an extremely poor long-term prognosis, making the investigation of new agents of interest.  These investigators reported the outcome of the first patient treated in a phase I study for relapsed neuroblastoma, using the chemotherapy agent decitabine to up-regulate cancer testis antigen expression, followed by a dendritic cell vaccine targeting the cancer testis antigens MAGE-A1, MAGE-A3, and NY-ESO-1.  The patient in this study had persistent tumor in his bone marrow after completion of standard therapy for neuroblastoma, including multi-agent chemotherapy, tumor resection, stem cell transplantation, radiation therapy, and anti-GD2 monoclonal antibodies.  His marrow disease persisted despite chemotherapy, which was given while the vaccine was being produced.  After 3 cycles of decitabine and vaccine, this patient achieved a complete remission and is now 1 year from his last treatment, with no evidence of tumor in his bone marrow or other sites.  This patient was noted to have an increase in MAGE-A3-specific T cells.  This was the first report combining demethylating chemotherapy to enhance tumor antigen expression followed by a cancer antigen vaccine.

An UpToDate review on “Treatment and prognosis of neuroblastoma” (Shohet and Nuchtern, 2014) states that “Novel therapies -- Development of new methods to treat high-risk neuroblastoma is an active area of research in pediatric oncology …. In general, novel treatments are given within a clinical trial because risks of such treatment are not fully known.  Examples of therapies under investigation include immunotherapies such as anti-GD2 antibodies modified to decrease toxicities, targeted autologous T-cells, and neuroblastoma vaccines”.  Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Central nervous system cancers” (Version 1.2014) does not mention the use of vaccine as a management tool.

Hall et al (2013) discussed recent clinical trials using immunotherapy techniques to treat both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) and high-lighted ongoing immunotherapy research efforts at the authors’ center.  For NSCLC, phase II clinical trials have examined allogeneic vaccines that target either mucin 1 (MUC1), epidermal growth factor or melanoma-associated antigen 3.  These vaccines are now undergoing larger phase III trials.  An autologous cellular therapy directed against transforming growth factor beta-2 and a recombinant protein with antitumor properties have also shown promise in prolonging survival in NSCLC in phase II trials.  The monoclonal antibodies ipilimumab, BMS-936558 (anti-PD-1), and BMS936559 (anti-PD-L1) lead to enhanced T-cell-mediated anti-tumor effects and have produced objective responses in early-phase clinical trials.  Studies for SCLC also exist, such as a novel vaccine therapy targeting p53.  The authors concluded that recent clinical trials in lung cancer demonstrated the potential of immunotherapeutics to increase overall survival in patients with lung cancer compared with the current standard of care.

An UpToDate review on “Immunotherapy for non-small cell lung cancer” (Gettinger, 2014) states that “Several other vaccines are currently being evaluated in Phase III studies.  Additional efforts are concentrating of developing new vaccines and combining vaccines with other immunologic agents, chemotherapy or targeted agents.  Advances in DNA and RNA sequencing and drug development may also ultimately allow for the creation of personalized vaccines consisting of several antigens uniquely expressed by an individual’s tumor …. Two immunotherapeutic approaches showing promise in NSCLC are immune checkpoint inhibition and cancer vaccination.  Multiple agents are currently in advanced clinical development, and the results of ongoing randomized clinical trials will define the role of immunotherapy in the treatment of NSCLC”.  Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Non-small cell lung cancer” (Version 3.2014) does not mention the use of vaccine as a management tool.

In a phase II clinical trial, Morse et al (2013) examined if 1 of 2 vaccines based on dendritic cells (DCs) and poxvectors encoding CEA (carcinoembryonic antigen) and MUC1 (PANVAC) would lengthen survival in patients with resected metastases of colorectal cancer (CRC).  Patients, disease-free after CRC metastasectomy and peri-operative chemotherapy (n = 74), were randomized to injections of autologous DCs modified with PANVAC (DC/PANVAC) or PANVAC with per injection GM-CSF (granulocyte-macrophage colony-stimulating factor).  End-points were recurrence-free survival, overall survival (OS), and rate of CEA-specific immune responses.  Clinical outcome was compared with that of an unvaccinated, contemporary group of patients who had undergone CRC metastasectomy, received similar peri-operative therapy, and would have otherwise been eligible for the study.  Recurrence-free survival at 2 years was similar (47 % and 55 % for DC/PANVAC and PANVAC/GM-CSF, respectively) (χ P = 0.48).  At a median follow-up of 35.7 months, there were 2 of 37 deaths in the DC/PANVAC arm and 5 of 37 deaths in the PANVAC/GM-CSF arm.  The rate and magnitude of T-cell responses against CEA was statistically similar between study arms.  As a group, vaccinated patients had superior survival compared with the contemporary unvaccinated group.  The authors concluded that both DC and poxvector vaccines had similar activity.  Survival was longer for vaccinated patients than for a contemporary unvaccinated group, suggesting that a RCT of poxvector vaccinations compared with standard follow-up after metastasectomy is warranted.

Ding and Ming (2014) noted that lung cancer is the most common malignancy worldwide in terms of incidence and mortality.  The vast majority of cases (85 to 90 %) are NSCLC.  Immunotherapy consists of mainly therapeutic vaccination designed to induce or amplify the immune responses directed against tumor-associated antigens.  However, there is no conclusion to date for its strengths and weaknesses.  Assessing the objective safety and effectiveness of the therapeutic vaccination for NSCLC patients will help to figure out the future development of therapeutic vaccination.  These investigators performed a meta-analysis of 6 RCTs including 2,239 patients (1,363 patients in the therapeutic vaccination group and 876 patients in the control group) with NSCLC.  Quantitative analysis was carried out to evaluate OS and toxicity of therapeutic vaccination.  The vaccine group had produced significant improvement in OS compared with the control group (hazard ratio [HR] 0.83, 95 % confidence interval [CI]: 0.76 to 0.91; Z = 3.79, p = 0.0002].  Subgroup analysis showed a more significant improvement of OS in the subgroup compared with the control group (HR 0.70, 95 % CI: 0.59 to 0.82; Z = 4.42, p < 0.00001).  No increased incidence of adverse events was obtained in the therapeutic vaccination group compared with the control group.  The authors concluded that therapeutic vaccination added benefits to NSCLC patients and may become a standard complementary therapeutic approach in the future if the associated toxicity is reduced.

Wang et al (2014) stated that glioblastoma multiforme (GBM) has a poor prognosis.  In a systematic review and meta-analysis, these investigators analyzed the outcomes of clinical trials that compared immunotherapy with conventional therapy for the treatment of malignant gliomas.  PubMed, Cochrane and Google Scholar databases were searched for relevant studies.  The 2-year survival rate was used to evaluate effectiveness of immunotherapy.  Of 171 studies identified, 6 comparative trials were included in the systematic review.  Immunotherapy was associated with a significantly longer OS and 2-year survival compared to conventional therapy.  The authors concluded that immunotherapy may improve the survival of patients with GBM.

Kobayashi et al (2014) stated that DC-based cancer vaccines may have a significant benefit to patients with advanced pancreatic cancer.  However, variations among clinical studies make it difficult to compare clinical outcomes.  These investigators identified factors that determined the clinical benefits by analyzing data obtained at 7 Japanese institutions that employed the same DC preparation and treatment regimens.  Of 354 patients who met the inclusion criteria, 255 patients who received standard chemotherapy combined with peptide-pulsed DC vaccines were analyzed.  The mean survival time from diagnosis was 16.5 months (95 % CI: 14.4 to 18.5) and that from the first vaccination was 9.9 months (95 % CI: 8.0 to 12.9).  Known prognostic baseline factors related to advanced pancreatic cancer, namely ECOG-PS, peritoneal metastasis, liver metastasis, and the prognostic nutrition index, were also representative.  Importantly, these researchers found that erythema reaction after vaccination was an independent and treatment-related prognostic factor for better survival and that OK-432 might be a good adjuvant enhancing the anti-tumor immunity during DC vaccination.  The authors concluded that this was the first report of a multi-center clinical study suggesting the feasibility and possible clinical benefit of an add-on DC vaccine in patients with advanced pancreatic cancer who are undergoing chemotherapy.  They stated that these findings need to be addressed in well-controlled, prospective randomized trials.

Helper Multi-Peptide (6MHP) Vaccine for Metastatic Melanoma

Hu and colleagues (2015) stated that a multi-peptide vaccine (6MHP), designed to induce helper T cells against melanocytic and cancer-testis antigens, has been shown to induce specific Th1-dominant CD4+ T cell responses. These researchers compared the long-term outcome of patients with metastatic melanoma vaccinated with 6MHP to that of a group of unvaccinated historical controls.  The 6MHP vaccine was given to patients with metastatic melanoma.  Circulating CD4+ T cell responses were measured by proliferation or direct IFN-gamma ELIspot assay.  Overall survival of vaccinated patients was compared to a group of clinically comparable historical controls using multi-variable Cox regression analysis and Kaplan-Meier survival analysis, taking into account age, metastatic site, and resection status.  Across 40 vaccinated patients and 87 controls, resection status (HR 0.54, p = 0.004) and vaccination (HR 0.24, p < 0.001) were associated with improved OS.  Forty pairs of vaccinated patients and controls were matched by metastatic site, resection status, and age within 10 years.  Median survival was significantly longer for vaccinated patients (5.4 versus 1.3 years, p < 0.001).  Among the vaccinated patients, the development of a specific immune response after vaccination was associated with improved survival (HR 0.35, p = 0.040).  The authors concluded that helper peptide vaccination was associated with improved OS among patients with metastatic melanoma; they stated that these data support a randomized prospective trial of the 6MHP vaccine.

Tumor-Associated Antigenic Peptide-Based Vaccines for Cancers

Peres Lde and associates (2015) discussed peptide-based vaccines in breast cancer, immune responses and clinical outcomes, which include studies on animal models and phase I, phase I/II, phase II and phase III clinical trials. These researchers stated that peptide-based vaccines are powerful neoadjuvant immunotherapies that can directly target proteins expressed in tumor cells, mainly tumor-associated antigens (TAAs).  The most common breast cancer TAA epitopes are derived from MUC1, HER2/neu and CEA proteins.  Peptides derived from TAAs could be successfully used to elicit CD8 and CD4 T cell-specific responses.  Thus, choosing peptides that adapt to natural variations of HLA genes is critical.  The most attractive advantage is that the target response is more specific and less toxic than for other therapies and vaccines.  Prominent studies on NeuVax - E75 (epitope for HER2/neu and GM-CSF) in breast cancer and DPX-0907 (HLA-A2-TAAs) expressed in breast cancer, ovarian and prostate cancer have shown the efficacy of peptide-based vaccines as neoadjuvant immunotherapy against cancer.  The authors concluded that future peptide vaccine strategies, although a challenge to be applied in a broad range of breast cancers, point to the development of degenerate multi-epitope immunogens against multiple targets.

Nishimura and co-workers (2015) noted that recent genome-wide cDNA microarray analysis of gene expression profiles in comprehensive tumor types coupled with isolation of cancer tissues by laser-microbeam microdissection have revealed ideal TAAs that are frequently over-expressed in various cancers including head and neck squamous cell cancer (HNSCC) and lung cancer, but not in most normal tissues except for testis, placenta, and fetal organs. Pre-clinical studies using HLA-transgenic mice and human T cells in-vitro showed that TAA-derived CTL-epitope short peptides (SPs) are highly immunogenic and induce HLA-A2 or -A24-restricted CTLs.  Based on the accumulated evidence, these researchers carried out a phase II clinical trial of the TAA-SP vaccine in advanced 37 HNSCC patients.  This study showed a significant induction of TAA-specific CTLs in the majority of patients without serious adverse effects.  Importantly, clinical responses including a complete response were observed in this study.  Another phase II clinical trial of therapeutic TAA-SP vaccine, designed to evaluate the ability of prevention of recurrence, is ongoing in HNSCC patients who have received curative operations.  Further studies in human pre-clinical studies and in-vivo studies using HLA class I transgenic mice showed TAA-derived long peptides (TAA-LPs) have the capacity to induce not only promiscuous HLA class II-restricted CD4(+) T helper type 1 cells but also tumor-specific CTLs through a cross-presentation mechanism.  Moreover, these investigators observed an augmentation of TAA-LP-specific T helper type 1 cell responses and tumor antigen-spreading in HNSCC patients vaccinated with TAA-SPs.  The authors concluded that this accumulated evidence suggested that therapeutic TAA-SPs and LPs vaccines may provide a promising cancer immunotherapy.

Chamani and colleagues (2018) noted that the E75 peptide vaccine, derived from tumor-associated antigen HER2, is the most frequently studied anti-HER2 vaccination strategy for the treatment of breast cancer patients.  It has been investigated in the several phases Ι/Π of the clinical trials and is currently being evaluated in a randomized multi-center phase III clinical trial.  These researchers conducted a systematic review and meta-analysis to clarify the outcomes of the E75 peptide vaccine including the therapeutic efficacy, the disease recurrence, the survival rate, and the side effects; 3 peer-reviewed literature databases including the PubMed, Web of Science, and Scopus were sought.  Of 29 trials assessed for eligibility, 16 were considered based on inclusion criteria.  Statistical analyses were performed by the Excel and STATA v.11.0.  Meta-analysis of delayed-type hypersensitivity (DTH) reactions and CD8+-T cell levels, as immune responses, displayed the significant differences in the vaccinated groups compared to their non-vaccinated counterparts.  In addition, the recurrence, and the OS and the disease-free survival (DFS) were significantly different in the vaccinated subjects versus the control.  The authors concluded that the valuation of the local and systemic toxicity of the E75 peptide vaccine demonstrated the minimal side effects.  It appeared that the E75 peptide vaccine is safe and effective, and can be used for further randomized clinical trials.

HLA-A24-Binding Peptide Vaccines for Gastric Cancer

Fujiwara and colleagues (2017) performed a clinical trial using HLA-A24-binding peptide vaccines containing a combination of novel cancer-testis antigens and anti-angiogenic peptides for advanced gastric cancer (GC).  A total of 35 GC patients who had shown resistance to the standard therapy were enrolled in this clinical trial using vaccinations with a mixture of multiple peptides derived from DEPDC1, URLC10, FoxM1, Kif20A and VEGFR1.  The safety, OS, and the immunological responses based on an ELISPOT assay were determined to assess differences in patients who were HLA-A24-positive [24(+)] and HLA-A24-negative [24(-)].  No severe adverse events (AEs) were observed except for severe skin reactions in 4 patients.  The differences in OS were not significant between patients who were 24(+) and 24(-).  In the 24(+) group, patients who showed T cell responses specific to antigen peptides had a tendency towards better survival than those who showed no response, especially to the DEPDC1 peptide.  The patients with local skin reactions had significantly better OS than the others.  The authors concluded that peptide vaccine therapy was found to be safe and is expected to induce specific T cell responses in patients with advanced GC.  They stated that the survival benefit of peptide vaccine monotherapy may not have been shown and further trials are needed to confirm these results.

p16(INK4a)-Based Peptide Vaccine for Human Papillomavirus-Associated Cancers

Reuschenbach and colleagues (2016) stated that the cyclin-dependent kinase inhibitor p16(INK4a) is strongly and consistently over-expressed in all human papillomavirus (HPV)-associated cancers.  These researchers hypothesized that p16(INK4a) may be a vaccine target antigen for HPV-associated cancers.  To test this hypothesis, these investigators performed a phase I/IIa first-in-human trial to evaluate the safety and immunogenicity of a p16(INK4a)-based peptide vaccine.  A total of 26 patients with different, advanced, p16(INK4a)-overexpressing, HPV DNA-positive cancers were included after the completion of standard treatment.  According to protocol, 12 subcutaneous injections of a p16(INK4) peptide (P16_37-63) mixed in a water-in-oil emulsion with immuno-adjuvant activity (Montanide ISA-51 VG) were administered over a 6-month period.  A total of 20 patients received at least 4 injections and were evaluable for immune responses against P16_37-63.  Clusters of differentiation (CD) 4 T cells were detected in 14 of 20 patients (3 of whom had pre-existing CD4 T cells before vaccination), CD8 T cells were detected in 5 of 20 patients, and antibodies were detected in 14 of 20 patients (1 of whom had pre-existing antibodies).  No suspected unexpected serious adverse reaction or serious adverse drug reaction was documented.  All reported serious AEs were expected and not considered to be related to study therapy.  None of the patients discontinued trial participation due to unacceptable toxicities and no dose-limiting toxicities occurred.  Tumor response could be assessed in 14 patients.  Of these, 9 patients (64 %) had stable disease (SD) as their best overall response and 5 patients (36 %) developed progressive disease.  The authors concluded that vaccination with the p16(INK4a -derived peptide P16_37-63 appeared to induce cellular and humoral immune responses and did not cause severe toxicities.  They stated that the findings of the current study paved the way for the further clinical development of p16(INK4a -based cancer immuno-therapeutics.

p62 DNA Vaccine (Elenagen) for Solid Tumors (e.g., Breast, Kidney, Lung, and Ovary Cancers as well as Melanoma)

Ponomarenko and colleagues (2017) noted that Elenagen is a plasmid encoding p62/SQSTM1, the first DNA vaccine possessing 2 mutually complementing mechanisms of action:
  1. it elicits immune response against p62, and
  2. it mitigates systemic chronic inflammation.
Previously, Elenagen demonstrated anti-tumor safety and effectivness in rodent tumor models and spontaneous tumors in dogs.  This multi-center phase I/IIa clinical trial evaluated safety and clinical activity of Elenagen in patients with advanced solid tumors.  A total of 15  patients were treated with escalating doses of Elenagen (1 to 5 mg per doses, 5 times weekly) and additional 12 patients received 1-mg dose; 10 patients with breast and ovary cancers that progressed after Elenagen were then treated with conventional chemotherapy; AEs were of Grade 1; no severe AEs were observed.  Cumulatively, 12 patients (44 %) with breast, ovary, lung, renal cancer and melanoma achieved SD for at least 8 weeks, with 4 of them (15 %) had tumor control for more than 24 weeks, with a maximum of 32 weeks.  Patients with breast and ovary cancers achieved additional tumor stabilization for 12 to 28 weeks when treated with chemotherapy following Elenagen treatment.  The authors concluded that Elenagen demonstrated good safety profile and ant-itumor activity in advanced solid tumors; especially encouraging is its ability to restore tumor sensitivity to chemotherapy.  These preliminary findings need to be validated by well-designed phase III studies.

Vaccine for Ovarian Cancer

In a pilot clinical trial, Tanyi and co-workers (2018) tested a personalized vaccine generated by autologous DCs pulsed with oxidized autologous whole-tumor cell lysate (OCDC), which was injected intranodally in platinum-treated, immunotherapy-naïve, recurrent ovarian cancer patients.  OCDC was administered alone (cohort 1, n = 5), in combination with bevacizumab (cohort 2, n = 10), or bevacizumab plus low-dose intravenous cyclophosphamide (cohort 3, n = 10) until disease progression or vaccine exhaustion.  A total of 392 vaccine doses were administered without serious AEs.  Vaccination induced T cell responses to autologous tumor antigen, which were associated with significantly prolonged survival.  Vaccination also amplified T cell responses against mutated neoepitopes derived from non-synonymous somatic tumor mutations, and this included priming of T cells against previously unrecognized neoepitopes, as well as novel T cell clones of markedly higher avidity against previously recognized neoepitopes.  The authors concluded that the use of oxidized whole-tumor lysate DC vaccine is safe and effective in eliciting a broad anti-tumor immunity, including private neoantigens, and warrants further clinical testing.

Vaccine for Pancreatic Cancer

Yanagisawa and associates (2018) noted that Wilms' tumor 1 (WT1) is a tumor-associated antigen highly expressed in cancer.  These researchers examined the safety of WT1-peptide pulsed DC (WT1-DC) vaccine in combination with chemotherapy in patients with surgically resected pancreatic cancer.  A total of 8 patients with resectable pancreatic cancer undergoing surgery either combined with S-1 or S-1 plus gemcitabine therapy were enrolled.  Immunohistochemical analysis of WT1 was performed in 34 cases of pancreatic cancer.  No serious side-effects were observed, except grade I fever in 5 and grade I reactions at the injection site in all patients.  WT1-specific cytotoxic T-lymphocytes were detected in 7 patients, and WT1 and HLA class I antigens were positive in all 34 cases.  The authors concluded that the findings of this study clarified the safety and potential acquisition of immunity after vaccination targeting WT1.  Moreover, they stated that further efficacy of WT1-DC vaccine to improve prognosis would be determined by a prospective clinical trial for resectable pancreatic cancer.

Vaccine for Gallbladder Cancer

Rojas-Sepulveda and colleagues (2018) stated that immunotherapy based on check-point blockers has proven survival benefits in patients with melanoma and other malignancies.  However, a significant proportion of treated patients remains refractory, suggesting that in combination with active immunizations, such as cancer vaccines, they could be helpful to improve response rates.  During the past 10 years, these researchers have used DC-based vaccines where DCs loaded with an allogeneic heat-conditioned melanoma cell lysate were tested in a series of clinical trials.  In these studies, 60 % of stage IV melanoma DC-treated patients showed immunological responses correlating with improved survival.  Further studies showed that an essential part of the clinical efficacy was associated with the use of conditioned lysates.  Gallbladder cancer (GBC) is a high-incidence malignancy in South America.  In this study, these investigators evaluated the feasibility of producing effective DCs using heat-conditioned cell lysates derived from GBC cell lines (GBCCL).  By characterizing 9 different GBCCLs and several fresh tumor tissues, these researchers found that they expressed some tumor-associated antigens such as CEA, MUC-1, CA19-9, Erb2, Survivin, and several CEAs.  Moreover, heat-shock treatment of GBCCLs induced calreticulin translocation and release of HMGB1 and ATP, both known to act as danger signals.  Monocytes stimulated with combinations of conditioned lysates exhibited a potent increase of DC-maturation markers.  Furthermore, conditioned lysate-matured DCs were capable of strongly inducing CD4+ and CD8+ T cell activation, in both allogeneic and autologous cell co-cultures.  Finally, in-vitro stimulated CD8+ T cells recognized HLA-matched GBCCLs.  The authors concluded that GBC cell lysate-loaded DCs may be considered for future immunotherapy approaches.

Vaccine for Gastric Cancer

In a phase-I/Ib, open-label, single-arm, clinical trial, Sundar and colleagues (2018) evaluated the safety, tolerability and optimal scheduling regimen of OTSGC-A24 cancer vaccine in patients with advanced gastric cancer.  Patients with advanced gastric cancer with HLA-A*24:02 haplotype were included in this study.  OTSGC-A24 was administered at 1 mg in 3-weekly (3w), 2-weekly (2w), and weekly (1w) cohorts to evaluate the safety, immunological response and schedule.  Based on the highest specific cytotoxic T lymphocyte (CTL) induction rate at 4 weeks, using the ELISPOT test, cohorts were expanded to define the optimal dosing schedule for OTSGC-A24.  A total of 24 advanced gastric cancer patients with HLA-A*24:02 haplotype were enrolled and treated in 3 cohorts (3w cohort: n = 3; 2w cohort: n = 11 and 1w cohort: n = 10 patients).  The most common AEs were decreased appetite (29 %), diarrhea (21 %), myalgia (25 %).  The most common treatment-related AE was injection site erythema (25 %).  No dose-limiting toxicities (DLTs) were observed in any cohort and OTSGC-A24 was well-tolerated.  Positive CTL responses after vaccination were observed in 15 patients (75 %) at 4 weeks: 3w cohort (33 %), 2w cohort (88 %), 1w cohort (78 %).  At 12 weeks, 18 patients had responded (90 %); 3w cohort (100 %), 2w cohort (100 %), 1w cohort (78 %).  The best radiological was SD (40 %); median progression free survival (PFS) was 1.7 months (95 % CI: 1.4 to 3.5) and median OS was 5.7 months (95 % CI: 3.8 to 8.6).  The authors concluded that OTSGC-A24 combined peptide cancer vaccine was well-tolerated.  Significant responses in CTL were observed and the recommended phase-II dose is 1 mg OTSGC-A24 sub-cutaneous, every 2 weeks.  Although no radiological response was observed, a respectable OS was achieved, consistent with other immunotherapy agents being investigated in gastric cancer.

Vaccine for Glioma

Platten and associates (2018) reviewed the current state of glioma vaccine development and highlighted the challenges associated with clinical implementation of these approaches.  Vaccination strategies against gliomas have matured considerably during the past years, although proof-of efficacy from controlled clinical trials is still lacking.  Advances in antigen discovery, including the definition of neoepitopes including epidermal growth factor receptor variant III (EGFRvIII), isocitrate dehydrogenase (IDH)1R132H and histone (H)3.3K27M, using multi-omic approaches and computational algorithms allow targeting single antigens, but also implementing truly personalized approaches.  In addition, new concepts of vaccine manufacturing including RNA and DNA vaccines improve immunogenicity and applicability in personalized settings.  The authors concluded that as an increasing amount of clinical data defy the concept of the central nervous system (CNS) as a strictly immuno-privileged site, novel vaccine approaches enter the clinic including critical efforts to identify biomarkers of response and resistance and strategies to overcome the immunosuppressive glioma microenvironment.

Vaccine for Oral Squamous Cell Carcinoma

Dong and co-workers (2018) stated that due to the high-quality immunogenicity of tumor-derived autophagosomes (DRibbles), these researchers examined the anti-tumor ability and mechanism of DRibble-loaded dendritic cells (DRibble-DCs).  DRibbles extracted from the oral squamous cell carcinoma cell line SCC7 express specific LC3-II and ubiquitination marker.  Immunization of mice with the DRibble-DCs vaccine led to the proliferation and differentiation of CD3+CD4+IFN-γ+ and CD3+CD8+IFN-γ+ T cells.  The expression of proteins in endoplasmic reticulum stress (ERS) pathways was determined by Western blot.  Additionally, the functional properties of the DRibble-DCs were examined in mice, and regulatory T cells were measured by flow cytometry.  Excellent biocompatibility was observed in-vitro when DCs were loaded with DRibbles.  T cells of lymph nodes and spleens from mice immunized with DRibble-DCs had cytotoxic effects on SCC7 cells.  DCs homeostasis and ERS-related proteins were affected by DRibbles.  Moreover, the DRibble-DCs vaccine achieved significantly better anti-tumor efficacy than DRibbles and tumor cell lysate-loaded DCs.  The authors concluded that these findings validated the anti-tumor immune responses to the DRibble-DCs vaccine in-vivo and in-vitro; the ERS pathway can be affected by DRibbles.

Vaccine for Breast Cancer

Singer and colleagues (2020) noted that immune-based strategies represent a promising approach in breast cancer (BC) treatment. The glycoprotein mucin-1 (MUC-1) is over-expressed in more than 90 % of BC patients, and is targeted by the cancer vaccine tecemotide.  In a prospective, randomized, neoadjuvant, multi-center phase-II clinical trial, these investigators examined the safety and efficacy of tecemotide when added to neoadjuvant standard-of-care (SOC) treatment in early BC patients.  A total of 400 patients with HER2-early BC were recruited into this 2-arm, phase-II study. Subjects received pre-operative SOC treatment (chemotherapy or endocrine therapy) with or without tecemotide.  Post-menopausal women with estrogen receptor (ER)+++, or ER++ and Ki67 less than 14 %, and G1,2 tumors ('luminal A' tumors) received 6 months of letrozole.  Post-menopausal patients with triple-negative, ER-/+/++ and Ki67 greater than or equal to 14 %, and with G3 tumors, as well as pre-menopausal subjects, received 4 cycles of epirubicin/cyclophosphamide plus 4 cycles of docetaxel.  Primary end-point was residual cancer burden (RCB; 0/I versus II/III) at surgery, and secondary end-points included pathological complete response (pCR), safety, and quality of life (QOL).  These researchers observed no significant difference in RCB 0/I rates between patients with (36.4 %) and without (31.9 %) tecemotide in the overall study population (p = 0.40), nor in endocrine and chemotherapy-treated subgroups (25.0 % versus 13.3 %, p = 0.17; 39.6 % versus 37.8 %, p = 0.75, respectively).  The addition of tecemotide did not affect overall pCR rates (22.5 % versus 17.4 %, p = 0.23), MUC-1 expression, or tumor-infiltrating lymphocytes content.  Tecemotide did not increase toxicity when compared to SOC therapy alone. The authors concluded that neoadjuvant tecemotide was safe, but did not improve RCB or pCR rates in patients receiving standard neoadjuvant therapy.

Brown and associates (2020) stated that AE37 and GP2 are HER2-derived peptide vaccines.  AE37 primarily elicits a CD4+ response while GP2 elicits a CD8+ response against the HER2 antigen.  These peptides were tested in a large randomized trial to examine their ability to prevent recurrence in HER2-expressing BC patients.  The primary analyses found no difference in 5-year overall disease-free survival (DFS) but possible benefit in subgroups.  These researchers presented the final landmark analysis.  In this 4-arm, prospective, randomized, single-blinded, multi-center, phase-II clinical trial, disease-free node positive and high-risk node negative BC patients enrolled after SOC therapy; 6 monthly inoculations of vaccine (VG) versus control (CG) were administered as the primary vaccine series with 4 boosters at 6-month intervals.  Demographic, safety, immunologic, and DFS data were evaluated.  A total of 456 patients were enrolled; 154 patients in the VG and 147 in CG for AE37, 89 patients in the VG and 91 in CG for GP2.  The AE37 arm had no difference in DFS as compared to CG, but pre-specified exploratory subgroup analyses showed a trend towards benefit in advanced stage (p = 0.132, HR 0.573, CI: 0.275 to 1.193), HER2 under-expression (p = 0.181, HR 0.756, CI: 0.499 to 1.145), and triple-negative BC (p = 0.266, HR 0.443, CI: 0.114 to 1.717). In patients with both HER2 under-expression and advanced stage, there was significant benefit in the VG (p = 0.039, HR 0.375, CI: 0.142 to 0.988) as compared to CG.  The GP2 arm had no significant difference in DFS as compared to CG, but on subgroup analysis, HER2-positive patients had no recurrences with a trend toward improved DFS (p = 0.052) in VG as compared to CG.  The authors concluded that the findings of this phase-II clinical trial showed that AE37 and GP2 were safe and possibly associated with improved clinical outcomes of DFS in certain subgroups of BC patients.  These researchers stated that with these findings, further evaluations are needed of AE37 and GP2 vaccines given in combination and/or separately for specific subsets of BC patients based on their disease biology.

Vaccine for Hepatic Cancer

Zhang and colleagues (2020) stated that MAGE family genes have been studied as targets for tumor immunotherapy for a long time.  These researchers combined MAGE1-, MAGE3- and MAGEn-derived peptides as a cancer vaccine and examined if a new combination nano-emulsion-encapsulated vaccine could be used to inhibit the growth of tumor cells in humanized SCID mice.  The nano-emulsion-encapsulated complex protein vaccine (MAGE1, MAGE3, and MAGEn/HSP70 fusion protein; M1M3MnH) was prepared using a magnetic ultrasonic technique.  After screening, human PBMCs were injected into SCID mice to mimic the human immune system.  Then, the humanized SCID mice were challenged with M3-HHCC cells and immunized with nano-emulsion-encapsulated MAGE1-MAGE3-MAGEn/HSP70 [NE(M1M3MnH)] or M1M3MnH.  The cellular immune responses were detected by IFN-γ ELISPOT and cytotoxicity assays.  Therapeutic and tumor challenge experiments were also performed.  The results showed that the immune responses elicited by NE(M1M3MnH) were apparently stronger than those elicited by M1M3MnH, NE(-) or PBS, suggesting that this novel nano-emulsion carrier induced potent anti-tumor immunity against the encapsulated antigens.  The results of the therapeutic and tumor challenge experiments also indicated that the new vaccine had a definite effect on SCID mice bearing human hepatic cancer.  The authors concluded that the findings of this study indicated that the combination of several tumor antigen-derived peptides may be a relatively good strategy for peptide-based cancer immunotherapy.  These researchers stated that these findings suggested that the complex nano-emulsion vaccine could have broader applications for both therapy and prevention mediated by anti-tumor effects in the future.

Dendritic Cell-Based Cancer Vaccines

Chen and colleagues (2020) stated that the success of peptide-based dendritic cell (DC) cancer vaccines mainly depends on the utilized peptides and selection of an appropriate adjuvant.  These researchers evoked a broad immune response against multiple epitopes concurrently in the presence of immunoadjuvant.  Three synthetic HLA-A∗0201-restricted peptides were separately linked with HMGB1-derived peptide (SAFFLFCSE, denoted as HB100-108) as immunoadjuvant via double arginine (RR) linker and loaded onto human monocyte-derived DCs.  Peptide uptake was detected by immunofluorescence microscopy and flow cytometry.  The maturation and activation status of pulsed DCs were monitored by detection of the expression of specific markers and released cytokines.  The ability of peptide-pulsed DCs to activate allogeneic T cells has been evaluated by a degranulation assay and detection of secreted cytokines.  The lytic activity of effector T cells against cancer cells in-vitro was analyzed by a lactate dehydrogenase (LDH) assay.  Results revealed that DCs efficiently take up peptides+HB100-108 and expressed higher levels of surface markers (HLA-ABC, HLA-DR, CD80, CD86, CD83, CD40, and CCR7) and proinflammatory cytokines (IL-6, IFN-γ, TNF-α, and IL-12) than control DCs, free peptide-pulsed DCs, and free HB100-108-pulsed DC groups.  Moreover, peptides+HB100-108/pulsed DCs were capable of activating allogeneic T cells and enhance their lytic activity against a pancreatic cancer cell line (PANC-1) in-vitro.  The authors concluded that these findings suggested that antigenic peptides covalently linked with HB100-108/pulsed DCs could be a promising strategy to improve the current DC-based cancer vaccines.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

There is no specific CPT code for melanoma vaccine (e.g., Theraccine vaccine or Oncophage vaccine, cancer vaccine therapy, helper multi-peptide (6MHP) vaccine, or vaccine therapy including tumor-associated antigenic peptide-based vaccines):

CPT codes not covered for indications listed in the CPB:

HLA-A-24-binding peptide vaccines, p16(INK4a)-based peptide vaccine, p62 DNA vaccine (Elenagen) - no specific code:

ICD-10 codes not covered for indications listed in the CPB:

Melanoma of ovary or kidney - no specific code :
C00.0 - C14.8 Malignant neoplasm of lip, oral cavity and pharynx
C16.0 - C16.9 Malignant neoplasm of stomach
C18.0 - C21.8 Malignant neoplasm of colon, rectum, rectosigmoid junction, and anus
C22.0 - C22.9 Malignant neoplasm of liver and intrahepatic bile ducts
C23 Malignant neoplasm of gallbladder
C25.0 - C25.9 Malignant neoplasm of pancreas
C34.00 - C34.92 Malignant neoplasm of bronchus and lung
C43.0 - C44.99 Malignant melanoma of skin
C50.011 - C50.929 Malignant neoplasm of breast
C51.0 - C51.9 Malignant neoplasm of vulva
C52 Malignant neoplasm of vagina
C53.0 - C53.9 Malignant neoplasm of cervix uteri
C56.1 - C56.9 Malignant neoplasm of ovary
C60.0 - C60.9 Malignant neoplasm of penis
C64.1 - C64.9 Malignant neoplasm of kidney, except renal pelvis
C70.0 - C70.9, C72.0 - C72.9 Malignant neoplasm of meninges, spinal cord, cranial nerves and other parts of central nervous system
C71.0 - C71.9 Malignant neoplasm of brain [glioma]
C76.0 Malignant neoplasm of head, face, and neck
C79.81 Secondary malignant neoplasm of breast
D03.52 Melanoma in situ of breast (skin) (soft tissue)
D03.59 Melanoma in situ of other part of trunk
Z23 Encounter for immunization

The above policy is based on the following references:

Melanoma Vaccine

  1. Abdel-Wahab Z, Weltz C, Hester D, et al. A Phase I clinical trial of immunotherapy with interferon-gamma gene-modified autologous melanoma cells: Monitoring the humoral immune response. Cancer. 1997;80(3):401-412.
  2. Adler A, Schachter J, Barenholz Y, et al. Allogeneic human liposomal melanoma vaccine with or without IL-2 in metastatic melanoma patients: Clinical and immunobiological effects. Cancer Biother. 1995;10(4):293-306.
  3. Agarwala SS. Intermediate- and high-risk melanoma. Curr Treat Options Oncol. 2002;3(3):205-217.
  4. Belli F, Arienti F, Sule-Suso J, et al. Active immunization of metastatic melanoma patients with interleukin-2-transduced allogeneic melanoma cells: Evaluation of efficacy and tolerability. Cancer Immunol Immunother. 1997;44(4):197-203.
  5. Berd D, Maguire HC Jr, Schuchter LM, et al. Autologous hapten-modified melanoma vaccine as postsurgical adjuvant treatment after resection of nodal metastases. J Clin Oncol. 1997;15(6):2359-2370.
  6. Berd D, Maguire HC, Mastrangelo MJ. Treatment of human melanoma with a hapten-modified autologous vaccine. Ann NY Acad Sci. 1993;690:147-152.
  7. BlueCross BlueShield Association (BCBSA), Technology Evaluation Center (TEC). Special Report: Vaccines for the treatment of malignant melanoma. TEC Assessment Program. Chicago, IL: BCBSA; May 2001:16(4).
  8. Bystryn JC, Reynolds SR. Melanoma vaccines: What we know so far. Oncology (Williston Park). 2005;19(1):97-108; discussion 108, 111-112, 115.
  9. Bystryn JC. Vaccines for melanoma. Dermatol Clin. 2002;20(4):717-725.
  10. Canadian Coordinating Office for Health Technology Assessment (CCOHTA). Metastatic melanoma vaccines. Emerging Drug List Issue 69. Ottawa, ON: CCOHTA; 2006.
  11. Chang AE, Aruga A, Cameron MJ, et al. Adoptive immunotherapy with vaccine-primed lymph node cells secondarily activated with anti-CD3 and interleukin-2. J Clin Oncol. 1997;15(2):796-807.
  12. Chapman PB. Melanoma vaccines. Semin Oncol. 2007;34(6):516-523.
  13. Dangoor A, Lorigan P, Keilholz U, et al. Clinical and immunological responses in metastatic melanoma patients vaccinated with a high-dose poly-epitope vaccine. Cancer Immunol Immunother. 2010;59(6):863-873.
  14. Elliott B, Dalgleish A. Melanoma vaccines. Hosp Med. 2004;65(11):668-673.
  15. Faries MB, Hsueh EC, Ye X, et al. Effect of granulocyte/macrophage colony-stimulating factor on vaccination with an allogeneic whole-cell melanoma vaccine. Clin Cancer Res. 2009;15(22):7029-7035.
  16. Hansson J. Systemic therapy of malignant melanoma. Med Oncol. 1997;14(2):73-81.
  17. Helling F, Zhang S, Shang A, et al. GM2-KLH conjugate vaccine: Increased immunogenicity in melanoma patients after administration with immunological adjuvant QS-21. Cancer Res. 1995;55(13):2783-2788.
  18. Hemmila MR, Chang AE. Clinical implications of the new biology in the development of melanoma vaccines. J Surg Oncol. 1999;70(4):263-274.
  19. Ho RC. Medical management of stage IV malignant melanoma: Medical Issues. Cancer. 1995;75(2 Suppl):735-741.
  20. Hsueh EC, Gupta RK, Qi K, et al. TA90 immune complex predicts survival following surgery and adjuvant vaccine immunotherapy for stage IV melanoma. Cancer J Sci Am. 1997;3(6):364-370.
  21. Hsueh EC. Tumour cell-based vaccines for the treatment of melanoma. BioDrugs. 2001;15(11):713-720.
  22. Itoh K, Yamada A, Mine T, Noguchi M. Recent advances in cancer vaccines: An overview. Jpn J Clin Oncol. 2009;39(2):73-80.
  23. Kaufman HL. Vaccines for melanoma and renal cell carcinoma. Semin Oncol. 2012;39(3):263-275.
  24. Kuhn CA, Hanke CW. Current status of melanoma vaccines. Dermatol Surg. 1997;23(8):649-654; discussion 654-655.
  25. Lai YH, Wang C. Delivery strategies of melanoma vaccines: An overview. Expert Opin Drug Deliv. 2008;5(9):979-1001.
  26. Lawson DH. Update on the systemic treatment of malignant melanoma. Semin Oncol. 2004;31(2 Suppl 4):33-37.
  27. Lens M. The role of vaccine therapy in the treatment of melanoma. Expert Opin Biol Ther. 2008;8(3):315-323.
  28. Lesterhuis WJ, Aarntzen EH, De Vries IJ, et al. Dendritic cell vaccines in melanoma: From promise to proof? Crit Rev Oncol Hematol. 2008;66(2):118-134.
  29. Livingston PO, Wong GYC, Adluri S, et al. Improved survival in stage III melanoma patients with GM2 antibodies: A randomized trial of adjuvant vaccination with GM2 ganglioside. J Clin Oncol. 1994;12:1036-1044.
  30. Mackensen A, Veelken H, Lahn M, et al. Induction of tumor-specific cytotoxic T lymphocytes by immunization with autologous tumor cells and interleukin-2 gene transfected fibroblasts. J Mol Med. 1997;75(4):290-296.
  31. Miller K, Abeles G, Oratz R, et al. Improved survival of patients with melanoma with an antibody response to immunization to a polyvalent melanoma vaccine. Cancer. 1995;75(2):495-502.
  32. Mitchell MS, Harel W, Kan-Mitchell J, et al. Active specific immunotherapy of melanoma with allogeneic cell lysates. Ann NY Acad Sci. 1993;690:153-166.
  33. Morton DL, Foshag LJ, Hoon DSB, et al. Prolongation of survival in metastatic melanoma after active specific immunotherapy with a new polyvalent melanoma vaccine. Ann Surg. 1992;216(4):463-482.
  34. Morton DL, Foshag LJ, Nizze JA, et al. Active specific immunotherapy in malignant melanoma. Semin Surg Oncol. 1989;5:420-425.
  35. Morton DL, Hoon DSB, Nizze JA, et al. Polyvalent melanoma vaccine improves survival of patients with metastatic melanoma. Ann NY Acad Sci. 1993;690:120-134.
  36. National Institute for Health and Clinical Excellence (NICE). Improving outcomes for people with skin tumours including melanoma: The manual. Guidance on Cancer Services. London, UK: NICE; 2006.
  37. Palmer K, Moore J, Everard M, et al. Gene therapy with autologous, interleukin 2-secreting tumor cells in patients with malignant melanoma. Hum Gene Ther. 1999;10(8):1261-1268.
  38. Pilla L, Patuzzo R, Rivoltini L, et al. A phase II trial of vaccination with autologous, tumor-derived heat-shock protein peptide complexes Gp96, in combination with GM-CSF and interferon-alpha in metastatic melanoma patients. Cancer Immunol Immunother. 2006;55(8):958-968.  
  39. Pilla L, Valenti R, Marrari A, et al. Vaccination: Role in metastatic melanoma. Expert Rev Anticancer Ther. 2006;6(8):1305-1318.
  40. Quan WD Jr, Dean GE, Spears CP, et al. Active specific immunotherapy of metastatic melanoma with an antiidiotype vaccine: A phase I/II trial of I-Mel-2 plus SAF-m. J Clin Oncol. 1997;15(5):2103-2110.
  41. Rass K, Diefenbacher M, Tilgen W. Experimental treatment of malignant melanoma and its rationale. Hautarzt. 2008;59(6):475-483.
  42. Restifo NP, Rosenberg SA. Developing recombinant and synthetic vaccines for the treatment of melanoma. Curr Opin Oncol. 1999;11(1):50-57.
  43. Reynolds SR, Oratz R, Shapiro RL, et al. Stimulation of CD8+T cell responses to MAGE-3 and Melan A/MART-1 by immunization to a polyvalent melanoma vaccine. Int J Cancer. 1997;72(6):972-976.
  44. Sabel MS, Sondak VK. Tumor vaccines: A role in preventing recurrence in melanoma? Am J Clin Dermatol. 2002;3(9):609-616.
  45. Sasse AD, Sasse EC, Clark LGO, et al. Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma. Cochrane Database Syst Rev. 2007;(1):CD005413.
  46. Savage P. Malignant melanoma (non-metastatic). In: BMJ Clinical Evidence. London, UK: BMJ Publishing Group; October 2006.  
  47. Schreiber S, Kampgen E, Wagner E, et al. Immunotherapy of metastatic malignant melanoma by a vaccine consisting of autologous interleukin 2-transfected cancer cells: Outcome of a phase I study. Hum Gene Ther. 1999;10(6):983-993.
  48. Schultz N, Oratz R, Chen D, et al. Effect of DETOX as an adjuvant for melanoma vaccine. Vaccine. 1995;13(5):503-508.
  49. Schwartzentruber DJ, Lawson DH, et al. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med. 2011;364(22):2119-2127.
  50. Slingluff CL Jr, Petroni GR, Olson WC, et al. Effect of granulocyte/macrophage colony-stimulating factor on circulating CD8+ and CD4+ T-cell responses to a multipeptide melanoma vaccine: Outcome of a multicenter randomized trial. Clin Cancer Res. 2009;15(22):7036-7044.
  51. Sondak VK, Sabel MS, Mule JJ. et al. Allogeneic and autologous melanoma vaccines: Where have we been and where are we going? Clin Cancer Res. 2006;12(7 Pt 2):2337s-2341s.
  52. Sondak VK, Wolfe JA. Adjuvant therapy for melanoma. Curr Opin Oncol. 1997;9(2):175-177.
  53. Stein JA, Brownell I. Treatment approaches for advanced cutaneous melanoma. J Drugs Dermatol. 2008;7(2):175-179.
  54. Stingel G, Brocker EB, Merelsmann R, et al. Phase I study to the immunotherapy of metastatic malignant melanoma by a cancer vaccine consisting of autologous cancer cells transfected with the human IL-2 gene. Hum Gene Ther. 1996;7(4):551-563.
  55. Swedish Council on Technology Assessment in Health Care (SBU). Tumor vaccination- early assessment briefs (Alert). Stockholm, Sweden; SBU; 2003.
  56. Tosti G, di Pietro A, Ferrucci PF, Testori A. HSPPC-96 vaccine in metastatic melanoma patients: From the state of the art to a possible future. Expert Rev Vaccines. 2009;8(11):1513-1526.
  57. Trepiakas R, Berntsen A, Hadrup SR, et al. Vaccination with autologous dendritic cells pulsed with multiple tumor antigens for treatment of patients with malignant melanoma: Results from a phase I/II trial. Cytotherapy. 2010;12(6):721-734.
  58. U.S. Grants orphan drug status to melanoma vaccine. Reuters Health, July 24, 2002.
  59. United States Pharmacopeial Convention, Inc. USP DI: Oncology Drug Information 1997-1998. 1st ed. Rockville, MD: Association of Community Cancer Centers; 1997:435.
  60. Veelken H, Mackensen A, Lahn M, et al. A phase-I clinical study of autologous tumor cells plus interleukin-2-gene-transferred allogeneic fibroblasts as a vaccine in patients with cancer. Int J Cancer. 1997;70(3):269-277.
  61. Verma S, Quirt I, McCready D, et al. Systematic review of systemic adjuvant therapy for patients at high risk for recurrent melanoma. Cancer. 2006;106(7):1431-1442.
  62. Wallack MK, Sivanandham M, Balch CM, et al. A phase III randomized, double-blind multiinstitutional trial of vaccinia melanoma oncolysate-active specific immunotherapy for patients with stage II melanoma. Cancer. 1995;75(1):34-42.
  63. Wallack MK, Sivanandham M, Ditaranto K, et al. Increased survival of patients treated with a vaccinia melanoma oncolysate vaccine: Second interim analysis of data from a phase III, multi-institutional trial. Ann Surg. 1997;226(2):198-206.
  64. Wallack MK, Sivanandham M, Whooley B, et al. Favorable clinical responses in subsets of patients from a randomized, multi-institutional melanoma vaccine trial. Ann Surg Oncol. 1996;3(2):110-117.
  65. Weston A, Standfield L, Hillman A. M-VAX(TM) - a treatment for patients with advanced stage III melanoma. MSAC Application 1049. Canberra, ACT: Medical Services Advisory Committee (MSAC); 2002.
  66. Wolchok JD, Livingston PO. Vaccines for melanoma: Translating basic immunology into new therapies. Lancet Oncol. 2001;2(4):205-211.
  67. Wood CG, Mulders P. Vitespen: A preclinical and clinical review. Future Oncol. 2009;5(6):763-774.
  68. Zarour HM, Kirkwood JM. Melanoma vaccines: Early progress and future promises. Semin Cutan Med Surg. 2003;22(1):68-75.

Ovarian Cancer Vaccine

  1. Berd D. Autologous, hapten-modified vaccine as a treatment for human cancers. Semin Oncol. 1998;25(6):646-653.
  2. Chianese-Bullock KA, Irvin WP Jr, Petroni GR, et al.  A multipeptide vaccine is safe and elicits T-cell responses in participants with advanced stage ovarian cancer. J Immunother. 2008;31(4):420-430.
  3. Gardner CJ, Jewell EL. Current and future directions of clinical trials for ovarian cancer. Cancer Control. 2011;18(1):44-51.
  4. Gurski KJ, Steller MA. Progress and prospects in vaccine therapy for gynecologic cancers. Oncology (Huntingt). 1997;11(11):1727-1734.
  5. Hodge JW, Tsang KY, Poole DJ, Schlom J. General keynote: Vaccine strategies for the therapy of ovarian cancer. Gynecol Oncol. 2003;88(1 Pt 2):S97-S104; discussion S110-S113.
  6. Hwu P, Freedman RS. The immunotherapy of patients with ovarian cancer. J Immunotherapy. 2002;25(3):189-201.
  7. Leffers N, Daemen T, Helfrich W, et al. Antigen-specific active immunotherapy for ovarian cancer. Cochrane Database Syst Rev. 2010;(1):CD007287.
  8. Leffers N, Lambeck AJ, Gooden MJ, et al. Immunization with a P53 synthetic long peptide vaccine induces P53-specific immune responses in ovarian cancer patients, a phase II trial. Int J Cancer. 2009;125(9):2104-2113.
  9. Linehan DC, Goedegebuure PS, Eberlein TJ. Vaccine therapy for cancer. Ann Surg Oncol. 1996;3(2):219-228.
  10. National Cancer Institute. Ovarian Epithelial Cancer PDQ. October 1999. March 2003. February 2004. July 2008. May 2010. August 2011.
  11. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Ovarian Cancer. V.1.2008. V.2.2010. V.2.2011. V.3.2012.
  12. Sabbatini P, Odunsi K. Immunologic approaches to ovarian cancer treatment. J Clin Oncol. 2007;25(20):2884-2893.
  13. Sabbatini PJ, Ragupathi G, Hood C, et al. Pilot study of a heptavalent vaccine-keyhole limpet hemocyanin conjugate plus QS21 in patients with epithelial ovarian, fallopian tube, or peritoneal cancer. Clin Cancer Res. 2007;13(14):4170-4177.
  14. Tsuda N, Mochizuki K, Harada M, et al. Vaccination with predesignated or evidence-based peptides for patients with recurrent gynecologic cancers. J Immunother. 2004;27(1):60-72.
  15. Wang B, Kaumaya PT, Cohn DE. Immunization with synthetic VEGF peptides in ovarian cancer. Gynecol Oncol. 2010;119(3):564-570.

Vaccines for Selected Types of Cancer

  1. Brown TA 2nd, Mittendorf EA, Hale DF, et al. Prospective, randomized, single-blinded, multi-center phase II trial of two HER2 peptide vaccines, GP2 and AE37, in breast cancer patients to prevent recurrence. Breast Cancer Res Treat. 2020 Apr 22 [Online ahead of print].
  2. Chamani R, Ranji P, Hadji M, et al. Application of E75 peptide vaccine in breast cancer patients: A systematic review and meta-analysis. Eur J Pharmacol. 2018;831:87-93.
  3. Chen C, Aldarouish M, Li Q, et al. Triggered immune response induced by antigenic epitopes covalently linked with immunoadjuvant-pulsed dendritic cells as a promising cancer vaccine. J Immunol Res. 2020;2020:3965061.
  4. Ding M, Yang J. Therapeutic vaccination for non-small-cell lung cancer: A meta-analysis. Med Oncol. 2014;31(4):928.
  5. Dong H, Su H, Chen L, et al. Immunocompetence and mechanism of the DRibble-DCs vaccine for oral squamous cell carcinoma. Cancer Manag Res. 2018;10:493-501.
  6. Elicin O, Cihoric N, Vlaskou Badra E, Ozsahin M. Emerging patient-specific treatment modalities in head and neck cancer - a systematic review. Expert Opin Investig Drugs. 2019;28(4):365-376. 
  7. Fujiwara Y, Okada K, Omori T, et al. Multiple therapeutic peptide vaccines for patients with advanced gastric cancer. Int J Oncol. 2017;50(5):1655-1662.
  8. Gettinger S. Immunotherapy for non-small cell lung cancer. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed April 2014.
  9. Hall RD, Gray JE, Chiappori AA. Beyond the standard of care: A review of novel immunotherapy trials for the treatment of lung cancer. Cancer Control. 2013;20(1):22-31.
  10. Hu Y, Kim H, Blackwell CM, Slingluff CL Jr. Long-term outcomes of helper peptide vaccination for metastatic melanoma. Ann Surg. 2015;262(3):456-464; discussion 462-464.
  11. Kajihara M, Takakura K, Kanai T, et al. Advances in inducing adaptive immunity using cell-based cancer vaccines: Clinical applications in pancreatic cancer. World J Gastroenterol. 2016;22(18):4446-4458.
  12. Kobayashi M, Shimodaira S, Nagai K, et al; DC Vaccine Study Group at the Japan Society of Innovative Cell Therapy (J-SICT). Prognostic factors related to add-on dendritic cell vaccines on patients with inoperable pancreatic cancer receiving chemotherapy: A multicenter analysis. Cancer Immunol Immunother. 2014;63(8):797-806.
  13. Krishnadas DK, Shapiro T, Lucas K. Complete remission following decitabine/dendritic cell vaccine for relapsed neuroblastoma. Pediatrics. 2013;131(1):e336-e341.
  14. Mohammadzadeh M, Shirmohammadi M, Ghojazadeh M, et al. Dendritic cells pulsed with prostate-specific membrane antigen in metastatic castration-resistant prostate cancer patients: A systematic review and meta-analysis. Prostate Int. 2018;6(4):119-125.
  15. Morse MA, Niedzwiecki D, Marshall JL, et al. A randomized phase II study of immunization with dendritic cells modified with poxvectors encoding CEA and MUC1 compared with the same poxvectors plus GM-CSF for resected metastatic colorectal cancer. Ann Surg. 2013;258(6):879-886.
  16. National Comprehensive Cancer Network (NCCN). Central nervous system cancers. NCCN Clinical Practice Guidelines in Oncology, Version 1.2014. Fort Washington, PA: NCCN; 2014.
  17. National Comprehensive Cancer Network (NCCN). Non-small cell lung cancer. NCCN Clinical Practice Guidelines in Oncology, Version 3.2014. Fort Washington, PA: NCCN: 2014.
  18. Nishimura Y, Tomita Y, Yuno A, et al. Cancer immunotherapy using novel tumor-associated antigenic peptides identified by genome-wide cDNA microarray analyses. Cancer Sci. 2015;106(5):505-511
  19. Peres Lde P, da Luz FA, Pultz Bdos A, et al. Peptide vaccines in breast cancer: The immunological basis for clinical response. Biotechnol Adv. 2015;33(8):1868-1877.
  20. Platten M, Bunse L, Riehl D, et al. Vaccine strategies in gliomas. Curr Treat Options Neurol. 2018;20(5):11.
  21. Ponomarenko DM, Klimova ID, Chapygina YA, et al. Safety and efficacy of p62 DNA vaccine ELENAGEN in a first-in-human trial in patients with advanced solid tumors. Oncotarget. 2017;8(32):53730-53739.
  22. Reuschenbach M, Pauligk C, Karbach J, et al. A phase 1/2a study to test the safety and immunogenicity of a p16(INK4a) peptide vaccine in patients with advanced human papillomavirus-associated cancers. Cancer. 2016;122(9):1425-1433.
  23. Rojas-Sepulveda D, Tittarelli A, Gleisner MA, et al. Tumor lysate-based vaccines: On the road to immunotherapy for gallbladder cancer. Cancer Immunol Immunother. 2018;67(12):1897-1910.
  24. Shohet JM, Nuchtern JG. Treatment and prognosis of neuroblastoma. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed April 2014.
  25. Singer CF, Pfeiler G, Hubalek M, et al; Austrian Breast & Colorectal Cancer Study Group. Efficacy and safety of the therapeutic cancer vaccine tecemotide (L-BLP25) in early breast cancer: Results from a prospective, randomised, neoadjuvant phase II study (ABCSG 34). Eur J Cancer. 2020;132:43-52.
  26. Sundar R, Rha SY, Yamaue H, et al. A phase I/Ib study of OTSGC-A24 combined peptide vaccine in advanced gastric cancer. BMC Cancer. 2018;18(1):332.
  27. Tanyi JL, Bobisse S, Ophir E, et al. Personalized cancer vaccine effectively mobilizes antitumor T cell immunity in ovarian cancer. Sci Transl Med. 2018;10(436).
  28. Wang X, Zhao HY, Zhang FC, et al. Dendritic cell-based vaccine for the treatment of malignant glioma: A systematic review. Cancer Invest. 2014;32(9):451-457.
  29. Whiteside TL, Demaria S, Rodriguez-Ruiz ME, et al. Emerging opportunities and challenges in cancer immunotherapy. Clin Cancer Res. 2016;22(8):1845-1855.
  30. Yanagisawa R, Koizumi T, Koya T, et al. WT1-pulsed dendritic cell vaccine combined with chemotherapy for resected pancreatic cancer in a phase I study. Anticancer Res. 2018;38(4):2217-2225.
  31. Zhang X, Huang Y, Li X, et al. Preparation of a new combination nanoemulsion-encapsulated MAGE1-MAGE3-MAGEn/HSP70 vaccine and study of its immunotherapeutic effect.  Pathol Res Pract. 2020 Apr 17 [Online ahead of print].