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 (6mo-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 6mo-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. These 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.
CPT Codes / HCPCS Codes / ICD-9 Codes
There is no specific CPT code for dendritic cell immunotherapy:
ICD-9 codes not covered for indications listed n the CPB:
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.
Turtle CJ, Hart DN. Dendritic cells in tumor immunology and immunotherapy. Curr Drug Targets. 2004;5(1):17-39.
Santiago-Schwarz F. Dendritic cells: Friend or foe in autoimmunity? Rheum Dis Clin North Am. 2004;30(1):115-134.
Figdor CG, de Vries W, Dendritic cell immunotherapy: Mapping the way. Nature Med. 2004;10:475-480.
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.
Nencioni A, Brossart P. Cellular immunotherapy with dendritic cells in cancer: Current status. Stem Cells. 2004;22(4):501-513.
Dunn G, Oliver KM, Loke D, e al. Dendritic cells and HNSCC: A potential treatment option? (Review). Oncol Rep. 2005;13(1):3-10.
Reichardt VL, Brossart P. Dendritic cells in clinical trials for multiple myeloma. Methods Mol Med. 2005;109:127-136.
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.
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.
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.
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.
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.
Novak N. Targeting dendritic cells in allergen immunotherapy. Immunol Allergy Clin North Am. 2006;26(2):307-319, viii.
Osada T, Clay TM, Woo CY, et al. Dendritic cell-based immunotherapy. Int Rev Immunol. 2006;25(5-6):377-413.
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.
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.
Kawakami Y, Fujita T, Kudo C, et al. Dendritic cell based personalized immunotherapy based on cancer antigen research. Front Biosci. 2008;13:1952-1958.
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.
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.
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.
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.
Kim W, Liau LM. Dendritic cell vaccines for brain tumors. Neurosurg Clin N Am. 2010;21(1):139-157.
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.
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.
Tanyi JL, Chu CS. Dendritic cell-based tumor vaccinations in epithelial ovarian cancer: A systematic review. Immunotherapy. 2012;4(10):995-1009.
Van De Velde AL, Anguille S, Berneman ZN. Immunotherapy in leukaemia. Acta Clin Belg. 2012;67(6):399-402.
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.
Gross CC, Wiendl H. Dendritic cell vaccination in autoimmune disease. Curr Opin Rheumatol. 2013;25(2):268-274.
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.
Thomas R. Dendritic cells as targets or therapeutics in rheumatic autoimmune disease. Curr Opin Rheumatol. 2014;26(2):211-218.
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