Cancer Vaccines

Number: 0557


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 vaccine therapy in the treatment of central nervous system cancers (e.g., glioblastoma and neuroblastoma), colorectal cancer, lung cancer, ovarian cancer and pancreatic cancer 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.


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: (i) whole-cell vaccines, (ii) dendritic cell vaccines, (iii) peptide vaccines, (iv) ganglioside vaccines, (v) DNA vaccines and (vi) 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 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 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.

Vacines 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.

CPT Codes / HCPCS Codes / ICD-9 Codes
There is no specific CPT code for melanoma vaccine (e.g., Theraccine vaccine or Oncophage vaccine) or cancer vaccine therapy:
ICD-9 codes not covered for indications listed in the CPB:
153.0 - 154.9 Malignant neoplasm of colon, rectum, rectosigmoid junction and anus
157.0 - 157.9 Malignant neoplasm of pancreas
162.3 - 162.9 Malignant neoplasm of lung
172.0 - 172.9 Malignant melanoma of skin
183.0 Malignant neoplasm of ovary
191.0 - 191.9 Malignant neoplasm of brain
192.0 - 192.9 Malignant neoplasm of other and unspecified parts of nervous system
V05.8 Need for other prophylactic vaccination and inoculation against other specified disease
CPT Codes / HCPCS Codes / ICD-10 Codes
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
ICD-10 codes will become effective as of October 1, 2015:
There is no specific CPT code for melanoma vaccine (e.g., Theraccine vaccine or Oncophage vaccine) or cancer vaccine therapy:
ICD-10 codes not covered for indications listed in the CPB:
C18.0 - C21.8 Malignant neoplasm of colon, rectum, rectosigmoid junction, and anus
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
C56.1 - C56.9 Malignant neoplasm of ovary
C70.0 - C70.9, C72.0 - C72.9 Malignant neoplasm of meninges, spinal cord, cranial nerves and other parts of central nerous system
C71.0 - C71.9 Malignant neoplasm of brain
Z23 Encounter for immunization

The above policy is based on the following references:

    Melanoma Vaccine

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    52. Pilla L, Valenti R, Marrari A, et al. Vaccination: Role in metastatic melanoma. Expert Rev Anticancer Ther. 2006;6(8):1305-1318.
    53. 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.
    54. Sasse AD, Sasse EC, Clark LGO, et al. Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma. Cochrane Database Syst Rev. 2007;(1):CD005413.
    55. Chapman PB. Melanoma vaccines. Semin Oncol. 2007;34(6):516-523.
    56. 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.
    57. Lens M. The role of vaccine therapy in the treatment of melanoma. Expert Opin Biol Ther. 2008;8(3):315-323.
    58. Stein JA, Brownell I. Treatment approaches for advanced cutaneous melanoma. J Drugs Dermatol. 2008;7(2):175-179.
    59. Lai YH, Wang C. Delivery strategies of melanoma vaccines: An overview. Expert Opin Drug Deliv. 2008;5(9):979-1001.
    60. Rass K, Diefenbacher M, Tilgen W. Experimental treatment of malignant melanoma and its rationale. Hautarzt. 2008;59(6):475-483.
    61. Itoh K, Yamada A, Mine T, Noguchi M. Recent advances in cancer vaccines: An overview. Jpn J Clin Oncol. 2009;39(2):73-80.
    62. Wood CG, Mulders P. Vitespen: A preclinical and clinical review. Future Oncol. 2009;5(6):763-774.
    63. 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.
    64. 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.
    65. 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.
    66. 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.
    67. 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.
    68. 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.
    69. Kaufman HL. Vaccines for melanoma and renal cell carcinoma. Semin Oncol. 2012;39(3):263-275.

    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 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.
    13. Sabbatini P, Odunsi K. Immunologic approaches to ovarian cancer treatment. J Clin Oncol. 2007;25(20):2884-2893.
    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. U.S. Food and Drug Administration.
    16. 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. Krishnadas DK, Shapiro T, Lucas K. Complete remission following decitabine/dendritic cell vaccine for relapsed neuroblastoma. Pediatrics. 2013;131(1):e336-e341.
    2. 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.
    3. Shohet JM, Nuchtern JG. Treatment and prognosis of neuroblastoma. UpToDate Inc., Waltham, MA. Last reviewed April 2014.
    4. Gettinger S. Immunotherapy for non-small cell lung cancer. UpToDate Inc., Waltham, MA. Last reviewed April 2014.
    5. National Comprehensive Cancer Network. Clinical practice guideline: Central nervous system cancers. Version 1.2014. NCCN: Fort Washington, PA.
    6. National Comprehensive Cancer Network. Clinical practice guideline: Non-small cell lung cancer. Version 3.2014. NCCN: Fort Washington, PA.
    7. 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.
    8. Ding M, Yang J. Therapeutic vaccination for non-small-cell lung cancer: A meta-analysis. Med Oncol. 2014;31(4):928.
    9. 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.
    10. 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.

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