Dendritic Cell Immunotherapy

Number: 0377


Aetna considers dendritic cell immunotherapy experimental and investigational because the peer-reviewed medical literature does not support its clinical use at this time.

See also CPB 0641 - Adoptive Immunotherapy and Cellular Therapy, and CPB 0802 - Prostate Cancer Vaccine.


Dendritic cells (DCs) are the most potent type of antigen presenting cells and are vital in inducing activation and proliferation of T-lymphocytes.  Their unique property has prompted their recent application to therapeutic cancer vaccines.  Isolated DCs containing tumor antigen ex-vivo and administered as a cellular vaccine, have been found to induce protective and therapeutic anti-tumor immunity in experimental animals.

The clinical evaluation of DC immunotherapy in humans is in its earliest phases for the treatment of malignancies such as leukemia, lymphoma, melanoma, and certain solid tumors.  Specifically, melanoma-associated antigens have been characterized at the molecular level and melanoma vaccine is currently being investigated in clinical trials.  Dendritic cells immunotherapy involves isolating dendritic cells from either circulating blood or bone marrow cells from the patient (or HLA-matched donor) and then exposing them to proteins from the patient's cancer cells in order to activate T-lymphocytes.  These lymphocytes are grown in bioreactors to be infused into the patient when sufficient numbers have been obtained.

Currently, no conclusions regarding the efficacy of DC immunotherapy can be made from the anecdotal reports reported in the published, peer-reviewed medical literature.  Although DC immunotherapy appears to be a promising modality for the treatment of cancer, completion of randomized trials is necessary.  Specifically, the appropriate antigen(s), adjuvant(s), dose, route and schedule need to be established.  In a review of the evidence, Figdor et al (2004) concluded that “[a]lthough early clinical trials indicate that [dendritic cell] vaccines can induce immune responses in some cancer patients, careful study design and use of standardized clinical and immunological criteria are needed”.

Ardon et al (2012) noted that DC-based tumor vaccination has rendered promising results in relapsed high-grade glioma patients.  In the HGG-2006 trial (EudraCT 2006-002881-20), feasibility, toxicity, and clinical efficacy of the full integration of DC-based tumor vaccination into standard post-operative radiochemotherapy were studied in 77 patients with newly diagnosed glioblastoma.  Autologous DC was generated after leukapheresis, which was performed before the start of radiochemotherapy.  Four weekly induction vaccines were administered after the 6-week course of concomitant radiochemotherapy.  During maintenance chemotherapy, 4 boost vaccines are given.  Feasibility and progression-free survival (PFS) at 6 months (6 mo-PFS) were the primary end-points.  Overall survival (OS) and immune profiling, rather than monitoring, as assessed in patients' blood samples, were the secondary end-points.  Analysis has been done on intent-to-treat basis.  The treatment was feasible without major toxicity.  The 6 mo-PFS was 70.1 % from inclusion.  Median OS was 18.3 months.  Outcome improved significantly with lower EORTC RPA classification.  Median OS was 39.7, 18.3, and 10.7 months for RPA classes III, IV, and V, respectively.  Patients with a methylated MGMT promoter had significantly better PFS (p = 0.0027) and OS (p = 0.0082) as compared to patients with an un-methylated status.  Exploratory "immunological profiles" were built to compare to clinical outcome, but no statistical significant evidence was found for these profiles to predict clinical outcome.  The authors concluded that full integration of autologous DC-based tumor vaccination into standard post-operative radiochemotherapy for newly diagnosed glioblastoma seems safe and possibly beneficial.  They stated that these results were used to power the currently running phase IIb randomized clinical trial.

In a systematic review, Tanyi et al (2012) stated that after decades of extensive research, epithelial ovarian cancer still remains a lethal disease.  Multiple new studies have reported that the immune system plays a critical role in the growth and spread of ovarian carcinoma.  These investigators summarized the development of DC vaccinations specific for ovarian cancer.  So far, DC-based vaccines have induced effective anti-tumor responses in animal models, but only limited results from human clinical trials are available.  Although DC-based immunotherapy has proven to be clinically safe and efficient at inducing tumor-specific immune responses, its’ clear role in the therapy of ovarian cancer still needs to be clarified.  The relatively disappointing low-response rates in early clinical trials point to the need for the development of more effective and personalized DC-based anti-cancer vaccines.

Bregy et al (2013) stated that glioblastoma multiforme (GBM), the most common malignant brain tumor, still has a dismal prognosis with conventional treatment.  Therefore, it is necessary to explore new and/or adjuvant treatment options to improve patient outcomes.  Active immunotherapy is a new area of research that may be a successful treatment option.  The focus is on vaccines that consist of antigen presenting cells (APCs) loaded with tumor antigen.  hese researchers conducted a systematic review of prospective studies, case reports and clinical trials to examine the safety and effectiveness of active immunotherapy in terms of complications, median OS, PFS and quality of life.  A PubMed search was performed to include all relevant studies that reported the characteristics, outcomes and complications of patients with GBM treated with active immunotherapy using DCs.  Reported parameters were immune response, radiological findings, median PFS and median OS.  Complications were categorized based on association with the craniotomy or with the vaccine itself.  A total of 21 studies with 403 patients were included in this review.  Vaccination with DCs loaded with autologous tumor cells resulted in increased median OS in patients with recurrent GBM (71.6 to 138.0 weeks) as well as those newly diagnosed (65.0 to 230.4 weeks) compared to average survival of 58.4 weeks.  The authors concluded that active immunotherapy, specifically with autologous DCs loaded with autologous tumor cells, seems to have the potential of increasing median OS and prolonged tumor PFS with minimal complications.  Moreover, they stated that larger clinical trials are needed to show the potential benefits of active immunotherapy.

Wang et al (2014) noted 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.

Chen et al (2014) stated that a new strategy of adoptive and passive immunotherapy involves combining dendritic cells (DCs) with a subset of natural killer T lymphocytes termed cytokine-induced killer (CIK) cells.  In a systematic review and meta-analysis, these researchers evaluated the safety and effectiveness of DC-CIK therapy versus placebo, no intervention, conventional treatments, or other complementary and alternative medicines for malignant tumors.  These investigators searched PubMed, Medline, Embase, Cochrane, Wangfang, Weipu, CNKI databases and reference lists of articles.  They selected randomized controlled trials (RCTs) of DC-CIK therapy versus placebo, no intervention, conventional treatments, or other complementary and alternative medicines in patients with all types and stages of malignant tumor.  Primary outcome measures were OS and treatment response.  Secondary outcome measures were health-related quality of life (HRQoL) assessment, PFS, and adverse events.  A total of 6 trials met the inclusion criteria.  There was evidence that chemotherapy + DC-CIK increased the 2-year (RR 2.88, 95 % confidence interval [CI]: 1.38 to 5.99, p = 0.005) and 3-year (RR 11.67, 95 % CI: 2.28 to 59.69, p = 0.003) survival rates and PFS (RR 0.64, 95 % CI: 0.34 to 0.94, p < 0.0001) in patients with non-small cell lung cancer compared to those treated with chemotherapy alone.  DC-CIK therapy appears to be well-tolerated by cancer patients and to improve post-treatment patient health related quality of life.  The authors concluded that DC-CIK immunotherapy is a safe and effective treatment for patients with malignant tumors.  They stated that further clinical trials to provide supportive evidence for the routine use of DC-CIK therapy in clinical practice are needed.

Lombardi et al (2015) stated that plasmacytoid dendritic cells (pDCs) are multi-functional bone marrow-derived immune cells that play a key role in bridging the innate and adaptive immune systems.  Activation of pDCs through toll-like receptor agonists has proven to be an effective treatment for some neoplastic disorders.  These researchers explored the contribution of pDCs to neoplastic pathology and discussed their potential utilization in cancer immunotherapy.  Current research suggests that pDCs have cytotoxic potential and can effectively induce apoptosis of tumor-derived cells lines.  They are also reported to display tolerogenic function with the ability to suppress T-cell proliferation, analogous to regulatory T cells.  In this capacity, they are critical in the suppression of autoimmunity, but can be exploited by tumor cells to circumvent the expansion of tumor-specific T cells, thereby allowing tumors to persist.  The authors concluded that several forms of skin cancer are successfully treated with the topical drug imiquimod, which activates pDCs through toll-like receptor 7.  Furthermore, pDC-based anti-cancer vaccines have shown encouraging results for the treatment of melanoma in early trials.  They stated that future studies regarding the contributions of pDCs to malignancy will likely afford many opportunities for immunotherapy strategies.

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 :
Dendritic cell immunotherapy:
No specific code
ICD-10 codes not covered for indications listed n the CPB:
C00.0 - C43.9, C44.0 - C75.9,
C76.0 - C86.6, C88.4 - C94.32,
C94.80 - C96.4, C96.6 - C96.9
Malignant neoplasms [leukemia, lymphoma, melanoma, solid tumors]
D03.0 - D03.9 Melanoma in situ

The above policy is based on the following references:
    1. Hemmila MR, Chang AE. Clinical implications of the new biology in the development of melanoma vaccines. J Surg Oncol. 1999;70(4):263-274.
    2. Timmerman JM, Levy R. Dendritic cell vaccines for cancer immunotherapy. Annu Rev Med. 1999;50:507-529.
    3. Burt RK, Link C, Traynor A. Adoptive immunotherapy after hematopoietic stem cell transplantation. Curr Opin Oncol. 1998;10(6):525-532.
    4. Choudhury A, Toubert A, Sutaria S, et al. Human leukemia-derived dendritic cells: Ex-vivo development of specific antileukemic cytotoxicity. Crit Rev Immunol. 1998;18(1-2):121-131.
    5. Esche C, Shurin MR, Lotze MT. The use of dendritic cells for cancer vaccination. Curr Opin Mol Ther. 1999;1(1):72-81.
    6. Gitlitz BJ, Figlin RA, Pantuck AJ, et al. Dendritic cell-based immunotherapy of renal cell carcinoma. Curr Urol Rep. 2001;2(1):46-52.
    7. Freedland SJ, Pantuck AJ, Weider J, et al. Immunotherapy of prostate cancer. Curr Urol Rep. 2001;2(3):242-247.
    8. Ribas A, Butterfield LH, Glaspy JA, et al. Cancer immunotherapy using gene-modified dendritic cells. Curr Gene Ther. 2002;2(1):57-78.
    9. Indar A, Maxwell-Armstrong CA, Durrant LG, et al. Current concepts in immunotherapy for the treatment of colorectal cancer. J R Coll Surg Edinb. 2002;47(2):458-474.
    10. Nishioka Y, Hua W, Nishimura N, et al. Genetic modification of dendritic cells and its application for cancer immunotherapy. J Med Invest. 2002;49(1-2):7-17.
    11. Lopez JA, Hart DN. Current issues in dendritic cell cancer immunotherapy. Curr Opin Mol Ther. 2002;4(1):54-63.
    12. Ravindranath MH, Morton DL. Active specific immunotherapy with vaccines. In: Cancer Medicine. 5th ed. RC Bast, DW Kufe, RE Pollok, et al., eds. Hamilton, ON: BC Decker, Inc.; 2000; Ch 61.
    13. Berger TG, Schultz ES. Dendritic cell-based immunotherapy. Curr Top Microbiol Immunol. 2003;276:163-197.
    14. Yang L, Ng KY, Lillehei KO. Cell-mediated immunotherapy: A new approach to the treatment of malignant glioma. Cancer Control. 2003;10(2):138-147.
    15. Turtle CJ, Hart DN. Dendritic cells in tumor immunology and immunotherapy. Curr Drug Targets. 2004;5(1):17-39.
    16. Santiago-Schwarz F. Dendritic cells: Friend or foe in autoimmunity? Rheum Dis Clin North Am. 2004;30(1):115-134.
    17. Figdor CG, de Vries W, Dendritic cell immunotherapy: Mapping the way. Nature Med. 2004;10:475-480.
    18. Schott M, Scherbaum WA, Seissler J. Dendritic cell-based immunotherapy in thyroid malignancies. Curr Drug Targets Immune Endocr Metabol Disord. 2004;4(3):245-251.
    19. Nencioni A, Brossart P. Cellular immunotherapy with dendritic cells in cancer: Current status. Stem Cells. 2004;22(4):501-513.
    20. Dunn G, Oliver KM, Loke D, e al. Dendritic cells and HNSCC: A potential treatment option? (Review). Oncol Rep. 2005;13(1):3-10.
    21. Reichardt VL, Brossart P. Dendritic cells in clinical trials for multiple myeloma. Methods Mol Med. 2005;109:127-136.
    22. Caruso DA, Orme LM, Amor GM, et al. Results of a Phase I study utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children with Stage 4 neuroblastoma. Cancer. 2005;103(6):1280-1291.
    23. Yamanaka R, Homma J, Yajima N, et al. Clinical evaluation of dendritic cell vaccination for patients with recurrent glioma: Results of a clinical phase I/II trial. Clin Cancer Res. 2005;11(11):4160-4167.
    24. Sheng KC, Pietersz GA, Wright MD, Apostolopoulos V. Dendritic cells: Activation and maturation--applications for cancer immunotherapy. Curr Med Chem. 2005;12(15):1783-1800.
    25. Lee WC, Wang HC, Hung CF, et al. Vaccination of advanced hepatocellular carcinoma patients with tumor lysate-pulsed dendritic cells: A clinical trial. J Immunother. 2005;28(5):496-504.
    26. Banchereau J, Ueno H, Dhodapkar M, et al. Immune and clinical outcomes in patients with stage IV melanoma vaccinated with peptide-pulsed dendritic cells derived from CD34+ progenitors and activated with type I interferon. J Immunother. 2005;28(5):505-516.
    27. Novak N. Targeting dendritic cells in allergen immunotherapy. Immunol Allergy Clin North Am. 2006;26(2):307-319, viii.
    28. Osada T, Clay TM, Woo CY, et al. Dendritic cell-based immunotherapy. Int Rev Immunol. 2006;25(5-6):377-413.
    29. Parajuli P, Mathupala S, Mittal S, Sloan AE. Dendritic cell-based active specific immunotherapy for malignant glioma. Expert Opin Biol Ther. 2007;7(4):439-448.
    30. Tuettenberg A, Schmitt E, Knop J, Jonuleit H. Dendritic cell-based immunotherapy of malignant melanoma: Success and limitations. J Dtsch Dermatol Ges. 2007;5(3):190-196.
    31. Kawakami Y, Fujita T, Kudo C, et al. Dendritic cell based personalized immunotherapy based on cancer antigen research. Front Biosci. 2008;13:1952-1958.  
    32. Sbiera S, Wortmann S, Fassnacht M. Dendritic cell based immunotherapy -- a promising therapeutic approach for endocrine malignancies. Horm Metab Res. 2008;40(2):89-98.
    33. Nencioni A, Grünebach F, Schmidt SM, et al. The use of dendritic cells in cancer immunotherapy. Crit Rev Oncol Hematol. 2008;65(3):191-199.
    34. van de Loosdrecht AA, van den Ancker W, Houtenbos I, et al. Dendritic cell-based immunotherapy in myeloid leukaemia: Translating fundamental mechanisms into clinical applications. Handb Exp Pharmacol. 2009;(188):319-348.
    35. Tyagi RK, Mangal S, Garg N, Sharma PK. RNA-based immunotherapy of cancer: Role and therapeutic implications of dendritic cells. Expert Rev Anticancer Ther. 2009;9(1):97-114.
    36. Kim W, Liau LM. Dendritic cell vaccines for brain tumors. Neurosurg Clin N Am. 2010;21(1):139-157.
    37. Palucka K, Ueno H, Zurawski G, et al. Building on dendritic cell subsets to improve cancer vaccines. Curr Opin Immunol. 2010;22(2):258-263.
    38. Ardon H, Van Gool SW, Verschuere T, et al. Integration of autologous dendritic cell-based immunotherapy in the standard of care treatment for patients with newly diagnosed glioblastoma: Results of the HGG-2006 phase I/II trial. Cancer Immunol Immunother. 2012;61(11):2033-2044.
    39. Tanyi JL, Chu CS. Dendritic cell-based tumor vaccinations in epithelial ovarian cancer: A systematic review. Immunotherapy. 2012;4(10):995-1009.
    40. Van De Velde AL, Anguille S, Berneman ZN. Immunotherapy in leukaemia. Acta Clin Belg. 2012;67(6):399-402.
    41. Bregy A, Wong TM, Shah AH, et al. Active immunotherapy using dendritic cells in the treatment of glioblastoma multiforme. Cancer Treat Rev. 2013;39(8):891-907.
    42. Gross CC, Wiendl H. Dendritic cell vaccination in autoimmune disease. Curr Opin Rheumatol. 2013;25(2):268-274.
    43. Van Brussel I, Lee WP, Rombouts M, et al. Tolerogenic dendritic cell vaccines to treat autoimmune diseases: Can the unattainable dream turn into reality? Autoimmun Rev. 2014;13(2):138-150.
    44. Thomas R. Dendritic cells as targets or therapeutics in rheumatic autoimmune disease. Curr Opin Rheumatol. 2014;26(2):211-218.
    45. 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.
    46. Chen R, Deng X, Wu H, et al. Combined immunotherapy with dendritic cells and cytokine-induced killer cells for malignant tumors: A systematic review and meta-analysis. Int Immunopharmacol. 2014;22(2):451-464.
    47. Lombardi VC, Khaiboullina SF, Rizvanov AA. Plasmacytoid dendritic cells, a role in neoplastic prevention and progression. Eur J Clin Invest. 2015;45 Suppl 1:1-8.

You are now leaving the Aetna website.

Links to various non-Aetna sites are provided for your convenience only. Aetna Inc. and its subsidiary companies are not responsible or liable for the content, accuracy, or privacy practices of linked sites, or for products or services described on these sites.

Continue >