Current Status of Immunotherapeutic Strategies for Central Nervous System Tumors

  • Yang, Meng-Yin (UCLA Division of Neurosurgery, UCLA Brain Research Institute, and the Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California at Los Angeles) ;
  • Khan-Farooqi, Haumith (UCLA Division of Neurosurgery, UCLA Brain Research Institute, and the Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California at Los Angeles) ;
  • Prins, Robert M. (UCLA Division of Neurosurgery, UCLA Brain Research Institute, and the Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California at Los Angeles) ;
  • Liau, Linda M. (UCLA Division of Neurosurgery, UCLA Brain Research Institute, and the Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California at Los Angeles)
  • 발행 : 2006.10.30

초록

Malignant gliomas are the most common type of primary brain tumor and are in great need of novel therapeutic approaches. Advances in treatment have been very modest, significant improvement in survival has been lacking for many decades, and prognosis remains dismal. Despite "gross total" surgical resections and currently available radio-chemotherapy, malignant gliomas inevitably recur due to reservoirs of notoriously invasive tumor cells that infiltrate adjacent and non-adjacent areas of normal brain parenchyma. In principle, the immune system is uniquely qualified to recognize and target these infiltrative pockets of tumors cells, which have generally eluded conventional treatment approaches, In the span of the last 10 years, our understanding of the cancer-immune system relationship has increased exponentially; and yet we are only beginning to tease apart the intricacies of the central nervous system and immune cell interactions. This article reviews the complex associations of the immune system with brain tumors. We provide an overview of currently available treatment options for malignant gliomas, existing gaps in our knowledge of brain tumor immunology, and strategies that might be exploited for improved design of "custom immunotherapeutics." We will also examine major new immunotherapy approaches that are being actively investigated to treat patients with malignant glioma, and identify some current and future research priorities in this area.

키워드

참고문헌

  1. American Cancer Society : Cancer Facts and Figures 2005, Atlanta, GA : American Cancer Society, 2005
  2. Adams GP, Weiner LM : Monoclonal antibody therapy of cancer. Nat Biotechnol 23 : 1147-1157, 2005 https://doi.org/10.1038/nbt1137
  3. Aloisi F, Ambrosini E, Columba-Cabezas S, Magliozzi R, Serafini B : Intracerebral regulation of immune responses. Ann Med 33 : 510-515, 2001 https://doi.org/10.3109/07853890108995960
  4. Andersen MH, Pedersen LO, Capeller B, Brocker EB, Becker JC, Straten PT : Spontaneous cytotoxic T-cell responses against survivin-derived MHC class I-restricted T-cell epitopes in situ as well as ex vivo in cancer patients. Cancer Res 61 : 5964-5968, 2001
  5. Badie B, Schartner JM, Paul J, Bartley BA, Vorpahl J, Preston JK : Dexamethasone-induced abolition of the inflammatory response in an experimental glioma model : a flow cytometry study. J Neurosurg 93 : 634-639, 2000 https://doi.org/10.3171/jns.2000.93.4.0634
  6. Bartolomei M, Mazzetta C, Handkiewicz-Junak D, Bodei L, Rocca P, Grana C, et al : Combined treatment of glioblastoma patients with locoregional pre-targeted 90Y-biotin radioimmunotherapy and temozolomide. Q J Nucl Med Mol Imaging 48 : 220-228, 2004
  7. Barton GM, Medzhitov R : Toll-like receptors and their ligands. Curr Top Microbiol Immunol 270 : 81-92, 2002
  8. Brem H, Gabikian P : Biodegradable polymer implants to treat brain tumors. J Control Release 74 : 63-67, 2001 https://doi.org/10.1016/S0168-3659(01)00311-X
  9. Calzascia T, Di Berardino-Besson W, Wilmotte R, Masson F, de Tribolet N, Dietrich PY, et al : Cutting edge : cross-presentation as a mechanism for efficient recruitment of tumor-specific CTL to the brain. J Immunol 171 : 2187-2191, 2003 https://doi.org/10.4049/jimmunol.171.5.2187
  10. Caruso DA, Orme LM, Neale AM, Radcliff FJ, Amor GM, Maixner W, et al : Results of a phase 1 study utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children and young adults with brain cancer. Neuro-oncol 6 : 236-246, 2004 https://doi.org/10.1215/S1152851703000668
  11. Chabalgoity JA, Dougan G, Mastroeni P, Aspinall RJ : Live bacteria as the basis for immunotherapies against cancer. Expert Rev Vaccines 1 : 495-505, 2002 https://doi.org/10.1586/14760584.1.4.495
  12. Clairmont C, Lee KC, Pike J, Ittensohn M, Low KB, Pawelek J, et al : Biodistribution and genetic stability of the novel antitumor agent VNP 20009, a genetically modified strain of Salmonella typhimurium. J Infect Dis 181 : 1996-2002, 2000 https://doi.org/10.1086/315497
  13. Csatary LK, Gosztonyi G, Szeberenyi J, Fabian Z, Liszka V, Bodey B, et al : MTH-68/H oncolytic viral treatment in human high-grade gliomas. J Neurooncol 67 : 83-93, 2004 https://doi.org/10.1023/B:NEON.0000021735.85511.05
  14. Dillman RO, Duma CM, Schiltz PM, DePriest C, Ellis RA, Okamoto K, et al : Intracavitary placement of autologous lymphokine-activated killer (LAK) cells after resection of recurrent glioblastoma. J Immunother 27 : 398-404, 2004 https://doi.org/10.1097/00002371-200409000-00009
  15. Giezeman-Smits KM, Okada H, Brissette-Storkus CS, Villa LA, Attanucci J, Lotze MT, et al : Cytokine gene therapy of gliomas : induction of reactive CD4+ T cells by interleukin-4-transfected 9L gliosarcoma is essential for protective immunity. Cancer Res 60 : 2449-2457, 2000
  16. Glick RP, Lichtor T, Cohen EP : Cytokine-based immuno-gene therapy for brain tumors, in Liau LM, Becker DP, Cloughesy TF, Bigner DD (eds) : Brain Tumor Immunotherapy, Totowa, New Jersey : Humana Press, 2001, pp 273-288
  17. Gorelik L, Constant S, Flavell RA : Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation. J Exp Med 195 : 1499-1505, 2002 https://doi.org/10.1084/jem.20012076
  18. Gorelik L, Flavell RA : Transforming growth factor-beta in T-cell biology. Nat Rev Immunol 2 : 46-53, 2002 https://doi.org/10.1038/nri704
  19. Hall WA : Targeted toxin therapy for malignant astrocytoma. Neurosurgery 46 : 544-551, 2000 https://doi.org/10.1097/00006123-200003000-00003
  20. Hayes RL, Arbit E, Odaimi M, Pannullo S, Scheff R, Kravchinskiy D, et al : Adoptive cellular immunotherapy for the treatment of malignant gliomas. Crit Rev Oncol Hematol 39 : 31-42, 2001 https://doi.org/10.1016/S1040-8428(01)00122-6
  21. Hickey WF : Basic principles of immunological surveillance of the normal central nervous system. Glia 36 : 118-124, 2001 https://doi.org/10.1002/glia.1101
  22. Hong Y, Rha H, Jung C, Lee S, Jo T, Baik M, et al : Brain tumor immunology -- Part II : Immunotherapy of malignant brain tumors. J Korean Neurosurg Soc 19 : 1389-1396, 1990
  23. Husain SR, Joshi BH, Puri RK : Interleukin-13 receptor as a unique target for anti-glioblastoma therapy. Int J Cancer 92 : 168-175, 2001 https://doi.org/10.1002/1097-0215(200102)9999:9999<::AID-IJC1182>3.0.CO;2-N
  24. Husain SR, Puri RK : Interleukin-13 receptor-directed cytotoxin for malignant glioma therapy : from bench to bedside. J Neurooncol 65 : 37-48, 2003 https://doi.org/10.1023/A:1026242432647
  25. Ishikawa E, Tsuboi K, Saijo K, Harada H, Takano S, Nose T, et al : Autologous natural killer cell therapy for human recurrent malignant glioma. Anticancer Res 24 : 1861-1871, 2004
  26. Kikuchi T, Akasaki Y, Abe T, Fukuda T, Saotome H, Ryan JL, et al : Vaccination of glioma patients with fusions of dendritic and glioma cells and recombinant human interleukin 12. J Immunother 27 : 452- 459, 2004 https://doi.org/10.1097/00002371-200411000-00005
  27. Kikuchi T, Akasaki Y, Irie M, Homma S, Abe T, Ohno T : Results of a phase I clinical trial of vaccination of glioma patients with fusions of dendritic and glioma cells. Cancer Immunol Immunother 50 : 337-344, 2001 https://doi.org/10.1007/s002620100205
  28. Kruse CA, Cepeda L, Owens B, Johnson SD, Stears J, Lillehei KO : Treatment of recurrent glioma with intracavitary alloreactive cytotoxic T lymphocytes and interleukin-2. Cancer Immunol Immunother. 45 : 77-87, 1997 https://doi.org/10.1007/s002620050405
  29. Kunwar S : Convection-enhanced delivery of IL13-PE38QQR for treatment of recurrent malignant glioma : presentation of interim findings from ongoing Phase I studies. Acta Neurochir Suppl 88 : 105-111, 2003
  30. Kunwar S, Chang SM, Prados MD, Berger MS, Sampson JH, Croteau D, et al : Safety of intraparenchymal convection-enhanced delivery of cintredekin besudotox in early-phase studies. Neurosurg Focus 20 : E15, 2006
  31. Lesniak MS, Gabikian P, Tyler BM, Pardoll DM, Brem H : Dexamethasone mediated inhibition of local IL-2 immunotherapy is dose dependent in experimental brain tumors. J Neurooncol 70 : 23-28, 2004 https://doi.org/10.1023/B:NEON.0000040821.50347.c5
  32. Liau LM, Black KL, Prins RM, Sykes SN, DiPatre PL, Cloughesy TF, et al : Treatment of intracranial gliomas with bone marrow-derived dendritic cells pulsed with tumor antigens. J Neurosurg 90 : 1115-1124, 1999 https://doi.org/10.3171/jns.1999.90.6.1115
  33. Liau LM, Jensen ER, Kremen TJ, Odesa SK, Sykes SN, Soung MC, et al : Tumor immunity within the central nervous system stimulated by recombinant Listeria monocytogenes vaccination. Cancer Res 62 : 2287-2293, 2002
  34. Liau LM, Prins RM, Kiertscher SM, Odesa SK, Kremen TJ, Giovannone AJ, et al : Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local CNS tumor microenvironment. Clin Cancer Res 11 : 5515-5525, 2005 https://doi.org/10.1158/1078-0432.CCR-05-0464
  35. Matzinger P : The danger model : a renewed sense of self. Science 296 : 301-305, 2002 https://doi.org/10.1126/science.1071059
  36. Merchant RE, Baldwin NG, Rice CD, Bear HD : Adoptive immunotherapy of malignant glioma using tumor-sensitized T lymphocytes. Neurol Res 19 : 145-152, 1997 https://doi.org/10.1080/01616412.1997.11740788
  37. Merchant RE, Grant AJ, Merchant LH, Young HF : Adoptive immunotherapy for recurrent glioblastoma multiforme using lymphokine activated killer cells and recombinant interleukin-2. Cancer 62 : 665-671, 1988 https://doi.org/10.1002/1097-0142(19880815)62:4<665::AID-CNCR2820620403>3.0.CO;2-O
  38. Mitchell DA, Fecci PE, Sampson JH : Adoptive immunotherapy for malignant glioma. Cancer J 9 : 157-166, 2003 https://doi.org/10.1097/00130404-200305000-00004
  39. Ochsenbein AF, Sierro S, Odermatt B, Pericin M, Karrer U, Hermans J, et al : Roles of tumour localization, second signals and cross priming in cytotoxic T-cell induction. Nature 411 : 1058-1064, 2001 https://doi.org/10.1038/35082583
  40. Okada H, Lieberman FS, Edington HD, Witham TF, Wargo MJ, Cai Q, et al : Autologous glioma cell vaccine admixed with interleukin-4 gene transfected fibroblasts in the treatment of recurrent glioblastoma : preliminary observations in a patient with a favorable response to therapy. J Neurooncol 64 : 13-20, 2003
  41. Okada H, Pollack IF : Cytokine gene therapy for malignant glioma. Expert Opin Biol Ther 4 : 1609-1620, 2004 https://doi.org/10.1517/14712598.4.10.1609
  42. Paganelli G, Bartolomei M, Ferrari M, Cremonesi M, Broggi G, Maira G, et al : Pre-targeted locoregional radioimmunotherapy with 90Y-biotin in glioma patients : phase I study and preliminary therapeutic results. Cancer Biother Radiopharm 16 : 227-235, 2001
  43. Parney IF, Kunwar S, McDermott M, Berger MS, Prados M, Cha S, et al : Neuroradiographic changes following convection-enhanced delivery of the recombinant cytotoxin interleukin 13-PE38QQR for recurrent malignant glioma. J Neurosurg 102 : 267-275, 2005 https://doi.org/10.3171/jns.2005.102.2.0267
  44. Plautz GE, Miller DW, Barnett GH, Stevens GH, Maffett S, Kim J, et al : T cell adoptive immunotherapy of newly diagnosed gliomas. Clin. Cancer Res 6 : 2209-2218, 2000
  45. Plautz GE, Mukai S, Cohen PA, Shu S : Cross-presentation of tumor antigens to effector T cells is sufficient to mediate effective immunotherapy of established intracranial tumors. J Immunol 165 : 3656-3662, 2000 https://doi.org/10.4049/jimmunol.165.7.3656
  46. Preston-Martin S, Davis F, McKean-Cowdin R : Epidemiology of primary brain tumors, in Liau LM, Becker DP, Cloughesy TF, Bigner DD (eds) : Brain Tumor Immunotherapy, Totowa, New Jersey : Humana Press, 2001, pp 47-71
  47. Prins RM, Liau LM : Immunology and immunotherapy in neurosurgical disease. Neurosurgery 53 : 144-152, 2003 https://doi.org/10.1227/01.NEU.0000068865.34216.3A
  48. Quang TS, Brady LW : Radioimmunotherapy as a novel treatment regimen : 125I-labeled monoclonal antibody 425 in the treatment of highgrade brain gliomas. Int J Radiat Oncol Biol Phys 58 : 972-975, 2004 https://doi.org/10.1016/j.ijrobp.2003.09.096
  49. Quattrocchi KB, Miller CH, Cush S, Bernard SA, Dull ST, Smith M, et al : Pilot study of local autologous tumor infiltrating lymphocytes for the treatment of recurrent malignant gliomas. J Neurooncol 45 : 141-157, 1999 https://doi.org/10.1023/A:1006293606710
  50. Rand RW, Kreitman RJ, Patronas N, Varricchio F, Pastan I, Puri RK : Intratumoral administration of recombinant circularly permuted inter-leukin-4-Pseudomonas exotoxin in patients with high-grade glioma. Clin Cancer Res 6 : 2157-2165, 2000
  51. Read SB, Kulprathipanja NV, Gomez GG, Paul DB, Winston KR, Robbins JM, et al : Human alloreactive CTL interactions with gliomas and with those having upregulated HLA expression from exogenous IFN-gamma or IFN-gamma gene modification. J Interferon Cytokine Res 23 : 379-393, 2003 https://doi.org/10.1089/107999003322226032
  52. Reardon DA, Akabani G, Coleman RE, Friedman AH, Friedman HS, Herndon JE, et al : Phase II trial of murine (131)I-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas. J Clin Oncol 20 : 1389-1397, 2002 https://doi.org/10.1200/JCO.20.5.1389
  53. Ren H, Boulikas T, Lundstrom K, Soling A, Warnke PC, Rainov NG : Immunogene therapy of recurrent glioblastoma multiforme with a liposomally encapsulated replication-incompetent Semliki forest virus vector carrying the human interleukin-12 gene--a phase I/II clinical protocol. J Neurooncol 64 : 147-154, 2003 https://doi.org/10.1023/A:1024979103780
  54. Riva P, Franceschi G, Frattarelli M, Lazzari S, Riva N, Giuliani G, et al : Loco-regional radioimmunotherapy of high-grade malignant gliomas using specific monoclonal antibodies labeled with 90Y : a phase I study. Clin Cancer Res 5 : 3275s-3280s, 1999
  55. Rosenberg SA, Spiess PJ, Kleiner DE : Antitumor effects in mice of the intravenous injection of attenuated Salmonella typhimurium. J Immunother 25 : 218-225, 2002 https://doi.org/10.1097/00002371-200205000-00004
  56. Ryu J, Kim C, Cheong J, Bak K, Kim J, Oh S : Co-expression of survivin and Bcl-2 in primary brain tumors : their potential effect on anti-apoptosis. J Korean Neurosurg Soc 40 : 1-5, 2006
  57. Saas P, Walker PR, Quiquerez AL, Chalmers DE, Arrighi JF, Lienard A, et al : A self-defence mechanism of astrocytes against Fas-mediated death involving interleukin-8 and CXCR2. Neuroreport 13 : 1921-1924, 2002 https://doi.org/10.1097/00001756-200210280-00018
  58. Salgaller ML : American Association for Cancer Research : dendritic cells : strategies and vaccines. April 1-5, 2000, San Francisco, CA, USA. Expert Opin Investig Drugs 9 : 1407-1412, 2000 https://doi.org/10.1517/13543784.9.6.1407
  59. Salgaller ML, Liau LM : Current status of clinical trials for glioblastoma. Reviews on Recent Clinical Trials 1 : in press, 2006
  60. Sampson JH, Akabani G, Archer GE, Bigner DD, Berger MS, Friedman AH, et al : Progress report of a Phase I study of the intracerebral microinfusion of a recombinant chimeric protein composed of transforming growth factor(TGF)-alpha and a mutated form of the Pseudomonas exotoxin termed PE-38 (TP-38) for the treatment of malignant brain tumors. J Neurooncol 65 : 27-35, 2003 https://doi.org/10.1023/A:1026290315809
  61. Sampson JH, Crotty LE, Lee S, Archer GE, Ashley DM, Wikstrand CJ, et al : Unarmed, tumor-specific monoclonal antibody effectively treats brain tumors. Proc Natl Acad Sci USA 97 : 7503-7508, 2000
  62. Schneider T, Gerhards R, Kirches E, Firsching R : Preliminary results of active specific immunization with modified tumor cell vaccine in glioblastoma multiforme. J Neurooncol 53 : 39-46, 2001 https://doi.org/10.1023/A:1011856406683
  63. Sehati N, Liau LM : Adjuvant treatment for gliomas. Contemporary Neurosurgery 25 : 1-9, 2003
  64. Shimamura T, Husain SR, Puri RK : The IL-4 and IL-13 pseudomonas exotoxins : new hope for brain tumor therapy. Neurosurg Focus 20 : E11, 2006 https://doi.org/10.3171/foc.2006.20.4.6
  65. Smits HA, van Beelen AJ, de Vos NM, Rijsmus A, van der Bruggen T, Verhoef J, et al : Activation of human macrophages by amyloid-beta is attenuated by astrocytes. J Immunol 166 : 6869-6876, 2001 https://doi.org/10.4049/jimmunol.166.11.6869
  66. Steiner HH, Bonsanto MM, Beckhove P, Brysch M, Geletneky K, Ahmadi R, et al : Antitumor vaccination of patients with glioblastoma multiforme : a pilot study to assess feasibility, safety, and clinical benefit. J Clin Oncol 22 : 4272-4281, 2004 https://doi.org/10.1200/JCO.2004.09.038
  67. Stewart LA : Chemotherapy in adult high-grade glioma : a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359 : 1011-1018, 2002 https://doi.org/10.1016/S0140-6736(02)08091-1
  68. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al : Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352 : 987-996, 2005 https://doi.org/10.1056/NEJMoa043330
  69. Takagi Y, Kikuchi T, Niimura M, Ohno T : Effects of glucocorticoids on antitumor effects of immunizations with fusions of dendritic and tumor cells. Anticancer Res 23 : 2553-2558, 2003
  70. Taniguchi Y, Ono K, Yoshida S, Tanaka R : Antigen-presenting capability of glial cells under glioma-harboring conditions and the effect of gliomaderived factors on antigen presentation. J Neuroimmunol 111 : 177-185, 2000 https://doi.org/10.1016/S0165-5728(00)00361-1
  71. Toso JF, Gill VJ, Hwu P, Marincola FM, Restifo NP, Schwartzentruber DJ, et al : Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma. J Clin Oncol 20 : 142-152, 2002 https://doi.org/10.1200/JCO.20.1.142
  72. Ulevitch RJ : Therapeutics targeting the innate immune system. Nat Rev Immunol 4 : 512-520, 2004 https://doi.org/10.1038/nri1396
  73. Walker PR, Calzascia T, Dietrich PY : All in the head: obstacles for immune rejection of brain tumours. Immunology 107 : 28-38, 2002 https://doi.org/10.1046/j.1365-2567.2002.01507.x
  74. Walker PR, Calzascia T, Schnuriger V, Scamuffa N, Saas P, de Tribolet N, et al : The brain parenchyma is permissive for full antitumor CTL effector function, even in the absence of CD4 T cells. J Immunol 165 : 3128-3135, 2000 https://doi.org/10.4049/jimmunol.165.6.3128
  75. Wang LX, Huang WX, Graor H, Cohen PA, Kim JA, Shu S, et al : Adoptive immunotherapy of cancer with polyclonal, 108-fold hyperexpanded, CD4+ and CD8+ T cells. J Transl Med 2 : 41, 2004 https://doi.org/10.1186/1479-5876-2-41
  76. Wiendl H, Mitsdoerffer M, Weller M : Hide-and-seek in the brain : a role for HLA-G mediating immune privilege for glioma cells. Semin Cancer Biol 13 : 343-351, 2003
  77. Wikstrand CJ, Cole VR, Crotty LE, Sampson JH, Bigner DD : Generation of anti-idiotypic reagents in the EGFRvIII tumor-associated antigen system. Cancer Immunol Immunother 50 : 639-652, 2002 https://doi.org/10.1007/s00262-001-0243-5
  78. Wikstrand CJ, Zalutsky MR, Bigner DD : Radiolabeled antibodies for therapy of brain tumors, in Liau LM, Becker DP, Cloughesy TF, Bigner DD (eds) : Brain Tumor Immunotherapy, Totowa : Humana Press, 2001, pp 205-229
  79. Wischhusen J, Schneider D, Mittelbronn M, Meyermann R, Engelmann H, Jung G, et al : Death receptor-mediated apoptosis in human malignant glioma cells: modulation by the CD40/CD40L system. J Neuroimmunol 162 : 28-42, 2005 https://doi.org/10.1016/j.jneuroim.2005.01.005
  80. Wood GW, Holladay FP, Turner T, Wang YY, Chiga M : A pilot study of autologous cancer cell vaccination and cellular immunotherapy using anti-CD3 stimulated lymphocytes in patients with recurrent grade III/IV astrocytoma. J Neurooncol 48 : 113-120, 2000 https://doi.org/10.1023/A:1006456421177
  81. Yamanaka R, Abe T, Yajima N, Tsuchiya N, Homma J, Kobayashi T, et al : Vaccination of recurrent glioma patients with tumour lysate-pulsed dendritic cells elicits immune responses : results of a clinical phase I/II trial. Br J Cancer 89 : 1172-1179, 2003 https://doi.org/10.1038/sj.bjc.6601268
  82. Yamanaka R, Homma J, Yajima N, Tsuchiya N, Sano M, Kobayashi T, et al : Clinical Evaluation of Dendritic Cell Vaccination for Patients with Recurrent Glioma : Results of a Clinical Phase I/II Trial. Clin Cancer Res 11 : 4160-4167, 2005 https://doi.org/10.1158/1078-0432.CCR-05-0120
  83. Yamanaka R, Yajima N, Abe T, Tsuchiya N, Homma J, Narita M, et al : Dendritic cell-based glioma immunotherapy (review). Int J Oncol 23 : 5-15, 2003
  84. Yu JS, Liu G, Ying H, Yong WH, Black KL, Wheeler CJ : Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. Cancer Res 64 : 4973-4979, 2004 https://doi.org/10.1158/0008-5472.CAN-03-3505
  85. Yu JS, Wheeler CJ, Zeltzer PM, Ying H, Finger DN, Lee PK, et al : Vaccination of malignant glioma patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T-cell infiltration. Cancer Res 61 : 842-847, 2001