Active immunotherapy for advanced intracranial murine tumors by using dendritic cell-tumor cell fusion vaccines

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Object

Immunotherapy for malignant brain tumors by active immunization or adoptive transfer of tumor antigen-specific T lymphocytes has the potential to make up for some of the limitations of current clinical therapy. In this study, the authors tested whether active immunotherapy is curative in mice bearing advanced, rapidly progressive intracranial tumors.

Methods

Tumor vaccines were created through electrofusion of dendritic cells (DCs) and irradiated tumor cells to form multinucleated heterokaryons that retained the potent antigen processing and costimulatory function of DCs as well as the entire complement of tumor antigens. Murine hosts bearing intracranial GL261 glioma or MCA 205 fibrosarcoma were treated with a combination of local cranial radiotherapy, intrasplenic vaccination with DC/tumor fusion cells, and anti-OX40R (CD134) monoclonal antibody (mAb) 7 days after tumor inoculation.

Whereas control mice had a median survival of approximately 20 days, the treated mice underwent complete tumor regression that was immunologically specific. Seven days after vaccination treated mice demonstrated robust infiltration of CD4+ and CD8+ T cells, which was exclusively confined to the tumor without apparent neurological toxicity. Cured mice survived longer than 120 days with no evidence of tumor recurrence and resisted intracranial tumor challenge.

Conclusions

These data indicate a strategy to achieve an antitumor response against tumors in the central nervous system that is highly focused from both immunological and anatomical perspectives.

Article Information

Address reprint requests to: Gregory Plautz, M.D., Center for Surgery Research, FF5 Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195. email: plautzg@ccf.org.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Results of FACS analysis of DCs and electrofusion product. A: Phenotype of DCs generated from spleens of Flt-3L-treated mice following overnight culture in the presence of GM-CSF and IL-4. Dotted line indicates isotype control antibody staining; solid line antibody staining. B: Results of FACS analysis of nonadherent (N.ad.) cells derived from DC/GL261 electrofusion reaction (upper), adherent (adh.) cells derived from DC/GL261 electrofusion reaction (center), and adherent cells from DC/H12 electrofusion reaction (lower). Each group of cells was stained with the PE-labeled antibody indicated above each column, which was presented as an increased signal on the y axis. The CFSE-labeled tumor cells provide a high signal on the x axis, and fusion heterokaryons are double positive. The percentage of cells residing in each quadrant is indicated in the lower left corner for each sample.

  • View in gallery

    Graphs representing results of active immunotherapy of 7-day-old established intracranial MCA 205 tumor with DC/H12 fusion heterokaryons. A: Local cranial radiation is required for successful therapy. Mice received intracranial injections of 1 × 105 MCA 205 tumor cells on Day 0 and were then pretreated on Day 6 with an 5 Gy radiation dose (IRR) or left untreated, as indicated in the legend. On Day 7, the indicated groups received intrasplenic injection of 6 × 105 DC/H12 fusion cells and all groups received a single intraperitoneal injection of 150 µg anti-OX40R mAb. B: Successful immunotherapy requires the DC component of the vaccine as well as adjuvant mAb. Mice bearing intracranial MCA 205 were pretreated on Day 6 with 5 Gy cranial radiation, then received combinations of H12/H12 tumor fusion cells, the nonadherent fraction of DC/H12 fusion cells, or the adherent fraction of the DC/H12 fusion cells. Adjuvant anti-OX40R mAb was administered to the indicated groups of mice. Rx = no treatment.

  • View in gallery

    Graph demonstrating successful immunotherapy requires formation of electrofusion heterokaryons. Mice were inoculated intracranially with 1 × 105 MCA 205 tumor cells on Day 0 and received 5 Gy local cranial radiation on Day 6. On Day 7, groups were treated with mAb and the H12/H12 tumor-tumor fusion cells, the adherent or nonadherent fractions derived from separate electrofusion of DC and H12 tumor cells with subsequent mixing o/n. Only the nonadherent or adherent fraction derived from the electrofusion reaction, which contains heterokaryons, was effective when combined with mAb.

  • View in gallery

    Graph demonstrating long-term survival following active immunotherapy of murine glioma. Mice were inoculated intracranialy with 105 GL261 tumor cells on Day 0 and the indicated groups were pretreated with 5 Gy cranial radiation (IRR) followed by intrasplenic injection of the indicated number of adherent or nonadherent DC/GL261 fusion cells on Day 7. All groups received a single intraperitoneal injection 150 µg of anti-OX40R mAb and then were followed up for survival.

  • View in gallery

    Photomicrographs demonstrating that CD4+ and CD8+ T cells infiltrate tumors during successful active immunotherapy. Mice were injected intracranially with 3 × 105 MCA 205 tumor cells on Day 0 and pretreated with 5 Gy cranial irradiation on Day 6 followed by intrasplenic injection of 6 × 105 DC/H12 fusion cells and intraperitoneal injection of 150 µg of anti-OX40R mAb as indicated. On Day 14, mice were killed and brains snap frozen in liquid N2. Tissue sections from throughout the tumors were incubated with anti-CD4 or anti-CD8 mAb, indicated as red cells, and counter-stained with hematoxylin. Cohorts from each group were monitored for survival with effective therapy only in the group treated with adherent fusion cells and mAb. Original magnification × 200.

  • View in gallery

    Graphs depicting specificity of antitumor response induced by active immunotherapy and development of broadened response against shared tumor antigens in cured mice. A: Mice were inoculated intracranially with 1 × 105 MCA 205 or 105 GL261, as indicated. On Day 6, mice were pretreated with 5 Gy cranial radiation and then injected intrasplenically with 0.6 × 106 adherent DC/H12 or DC/GL261 fusion cells as indicated in the legend. All mice received intraperitoneal injection of 150 µg of anti-OX40R mAb. B: Mice with 7-day-old MCA 205 intracranial tumors were cured by active immunotherapy with 5 Gy cranial radiation, adherent DC H12 fusion cells, and anti-OX40R mAb. On Day 60, cured mice or naive controls were challenged with intracranial inoculation of 1 × 105 MCA 205 or 105 GL261 tumor cells and monitored for survival.

References

1.

Akasaki YKikuchi THomma SAbe TKufe DOhno T: Antitumor effect of immunizations with fusions of dendritic and glioma cells in a mouse brain tumor model. J Immunother 24:1061132001Akasaki Y Kikuchi T Homma S Abe T Kufe D Ohno T: Antitumor effect of immunizations with fusions of dendritic and glioma cells in a mouse brain tumor model. J Immunother 24:106–113 2001

2.

Ashley DMFaiola BNair SHale LPBigner DDGilboa E: Bone marrow-generated dendritic cells pulsed with tumor extracts or tumor RNA induce antitumor immunity against central nervous system tumors. J Exp Med 186:117711821997Ashley DM Faiola B Nair S Hale LP Bigner DD Gilboa E: Bone marrow-generated dendritic cells pulsed with tumor extracts or tumor RNA induce antitumor immunity against central nervous system tumors. J Exp Med 186:1177–1182 1997

3.

Ausman JIShapiro WRRall DP: Studies on the chemotherapy of experimental brain tumors: development of an experimental model. Cancer Res 30:239424001970Ausman JI Shapiro WR Rall DP: Studies on the chemotherapy of experimental brain tumors: development of an experimental model. Cancer Res 30:2394–2400 1970

4.

Banchereau JSteinman RM: Dendritic cells and the control of immunity. Nature 392:2452521998Banchereau J Steinman RM: Dendritic cells and the control of immunity. Nature 392:245–252 1998

5.

Basu SBinder RJSuto RAnderson KMSrivastava PK: Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. Int Immunol 12:153915462000Basu S Binder RJ Suto R Anderson KM Srivastava PK: Necrotic but not apoptotic cell death releases heat shock proteins which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. Int Immunol 12:1539–1546 2000

6.

Bedrosian IMick RXu SNisenbaum HFaries MZhang Pet al: Intranodal administration of peptide-pulsed mature dendritic cell vaccines results in superior CD8+ T-cell function in melanoma patients. J Clin Oncol 21:382638352003Bedrosian I Mick R Xu S Nisenbaum H Faries M Zhang P et al: Intranodal administration of peptide-pulsed mature dendritic cell vaccines results in superior CD8+ T-cell function in melanoma patients. J Clin Oncol 21:3826–3835 2003

7.

Billingham REBrent LMedawar PW: Quantitative studies on tissue transplantation immunity. II, the origin, strength and duration of actively and adoptively acquired immunity. Proc Roy Soc Biol 143:58801954Billingham RE Brent L Medawar PW: Quantitative studies on tissue transplantation immunity. II the origin strength and duration of actively and adoptively acquired immunity. Proc Roy Soc Biol 143:58–80 1954

8.

Calzascia TBerardino-Besson WWilmotte RMasson Fde Tribolet NDietrich PYet al: Cutting edge: cross-presentation as a mechanism for efficient recruitment of tumor-specific CTL to the brain. J Immunol 171:218721912003Calzascia T 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

9.

Chi DDMerchant RERand RConrad AJGarrison DTurner Ret al: Molecular detection of tumor-associated antigens shared by human cutaneous melanomas and gliomas. Am J Pathol 150:214321521997Chi DD Merchant RE Rand R Conrad AJ Garrison D Turner R et al: Molecular detection of tumor-associated antigens shared by human cutaneous melanomas and gliomas. Am J Pathol 150:2143–2152 1997

10.

Conrad CNestle FO: Dendritic cell-based cancer therapy. Curr Opin Mol Ther 5:4054122003Conrad C Nestle FO: Dendritic cell-based cancer therapy. Curr Opin Mol Ther 5:405–412 2003

11.

Engleman EG: Dendritic cell-based cancer immunotherapy. Semin Oncol 30 (Suppl 8):23292003Engleman EG: Dendritic cell-based cancer immunotherapy. Semin Oncol 30 (Suppl 8):23–29 2003

12.

Fecci PEMitchell DAArcher GEMorse MALyerly HKBigner DDet al: The history, evolution, and clinical use of dendritic cell-based immunization strategies in the therapy of brain tumors. J Neurooncol 64:1611762003Fecci PE Mitchell DA Archer GE Morse MA Lyerly HK Bigner DD et al: The history evolution and clinical use of dendritic cell-based immunization strategies in the therapy of brain tumors. J Neurooncol 64:161–176 2003

13.

Fong LEngleman EG: Dendritic cells in cancer immunotherapy. Annu Rev Immunol 18:2452732000Fong L Engleman EG: Dendritic cells in cancer immunotherapy. Annu Rev Immunol 18:245–273 2000

14.

Galetto AButtiglieri SForno SMoro FMussa AMatera L: Drug- and cell-mediated antitumor cytotoxicities modulate crosspresentation of tumor antigens by myeloid dendritic cells. Anti-cancer Drugs 14:8338432003Galetto A Buttiglieri S Forno S Moro F Mussa A Matera L: Drug- and cell-mediated antitumor cytotoxicities modulate crosspresentation of tumor antigens by myeloid dendritic cells. Anti-cancer Drugs 14:833–843 2003

15.

Ganss RRyschich EKlar EArnold BHammerling GJ: Combination of T-cell therapy and trigger of inflammation induces remodeling of the vasculature and tumor eradication. Cancer Res 62:146214702002Ganss R Ryschich E Klar E Arnold B Hammerling GJ: Combination of T-cell therapy and trigger of inflammation induces remodeling of the vasculature and tumor eradication. Cancer Res 62:1462–1470 2002

16.

Hayashi TTanaka HTanaka JWang RAverbook BJCohen PAet al: Immunogenicity and therapeutic efficacy of dendritictumor hybrid cells generated by electrofusion. Clin Immunol 104:14202002Hayashi T Tanaka H Tanaka J Wang R Averbook BJ Cohen PA et al: Immunogenicity and therapeutic efficacy of dendritictumor hybrid cells generated by electrofusion. Clin Immunol 104:14–20 2002

17.

Hobbs SKShi GHomer RHarsh GAtlas SWBednarski MD: Magnetic resonance image-guided proteomics of human glioblastoma multiforme. J Magn Reson Imaging 18:5305362003Hobbs SK Shi G Homer R Harsh G Atlas SW Bednarski MD: Magnetic resonance image-guided proteomics of human glioblastoma multiforme. J Magn Reson Imaging 18:530–536 2003

18.

Huettner CPaulus WRoggendorf W: Messenger RNA expression of the immunosuppressive cytokine Il-10 in human gliomas. Am J Path 146:3173221995Huettner C Paulus W Roggendorf W: Messenger RNA expression of the immunosuppressive cytokine Il-10 in human gliomas. Am J Path 146:317–322 1995

19.

Inoue MPlautz GEShu S: Treatment of intracranial tumors by systemic transfer of superantigen-activated tumor-draining lymph node T cells. Cancer Res 56:470247081996Inoue M Plautz GE Shu S: Treatment of intracranial tumors by systemic transfer of superantigen-activated tumor-draining lymph node T cells. Cancer Res 56:4702–4708 1996

20.

Jelsma RBucy PC: The treatment of glioblastoma multiforme of the brain. J Neurosurg 27:3884001967Jelsma R Bucy PC: The treatment of glioblastoma multiforme of the brain. J Neurosurg 27:388–400 1967

21.

Kikuchi TAkasaki YIrie MHomma SAbe TOhno T: Results of a phase I clinical trial of vaccination of glioma patients with fusions of dendritic and glioma cells. Cancer Immunol Immunother 50:3373442001Kikuchi 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

22.

Kjaergaard JPeng LCohen PADrazba JAWeinbert ADShu S: Augmentation versus inhibition: effects of conjunctional OX-40 receptor monoclonal antibody and IL-2 treatment on adoptive immunotherapy of advanced tumor. J Immunol 167:666966772001Kjaergaard J Peng L Cohen PA Drazba JA Weinbert AD Shu S: Augmentation versus inhibition: effects of conjunctional OX-40 receptor monoclonal antibody and IL-2 treatment on adoptive immunotherapy of advanced tumor. J Immunol 167:6669–6677 2001

23.

Kjaergaard JPeng LCohen PAShu S: Therapeutic efficacy of adoptive immunotherapy is predicated on in vivo antigen-specific proliferation of donor T cells. Clin Immunol 108:8202003Kjaergaard J Peng L Cohen PA Shu S: Therapeutic efficacy of adoptive immunotherapy is predicated on in vivo antigen-specific proliferation of donor T cells. Clin Immunol 108:8–20 2003

24.

Kjaergaard JShimizu KShu S: Electrofusion of syngeneic dendritic cells and tumor generates potent therapeutic vaccine. Cell Immunol 225:65742003Kjaergaard J Shimizu K Shu S: Electrofusion of syngeneic dendritic cells and tumor generates potent therapeutic vaccine. Cell Immunol 225:65–74 2003

25.

Lambert LAGibson GRMaloney MBarth RJ Jr: Equipotent generation of protective antitumor immunity by various methods of dendritic cell loading with whole cell tumor antigens. J Immunother 24:2322362001Lambert LA Gibson GR Maloney M Barth RJ Jr: Equipotent generation of protective antitumor immunity by various methods of dendritic cell loading with whole cell tumor antigens. J Immunother 24:232–236 2001

26.

Lambert LAGibson GRMaloney MDurell BNoelle RJBarth RJ Jr: Intranodal immunization with tumor lysate-pulsed dendritic cells enhances protective antitumor immunity. Cancer Res 61:6416462001Lambert LA Gibson GR Maloney M Durell B Noelle RJ Barth RJ Jr: Intranodal immunization with tumor lysate-pulsed dendritic cells enhances protective antitumor immunity. Cancer Res 61:641–646 2001

27.

Liau LMBlack KLPrins RMSykes SNDiPatra PLCloughesy TFet al: Treatment of intracranial gliomas with bone marrow-derived dendritic cells pulsed with tumor antigens. J Neurosurg 90:111511241999Liau LM Black KL Prins RM Sykes SN DiPatra 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

28.

Maxwell MGalanpoulos TNeville-Golden JAntoniades HN: Effect of the expression of transforming growth factor-β2 in primary human glioblastomas on immunosuppression and loss of immune surveillance. J Neurosurg 76:7998041992Maxwell M Galanpoulos T Neville-Golden J Antoniades HN: Effect of the expression of transforming growth factor-β2 in primary human glioblastomas on immunosuppression and loss of immune surveillance. J Neurosurg 76:799–804 1992

29.

Medzhitov RJaneway CA Jr: Innate immunity: the virtues of a nonclonal system of recognition. Cell 91:2952981997Medzhitov R Janeway CA Jr: Innate immunity: the virtues of a nonclonal system of recognition. Cell 91:295–298 1997

30.

Mukai SKjaergaard JShu SPlautz GE: Infiltration of tumors by systemically transferred tumor-reactive T lymphocytes is required for antitumor efficacy. Cancer Res 59:524552491999Mukai S Kjaergaard J Shu S Plautz GE: Infiltration of tumors by systemically transferred tumor-reactive T lymphocytes is required for antitumor efficacy. Cancer Res 59:5245–5249 1999

31.

Neil GAZimmermann U: Electrofusion. Methods Enzymol 220:1741961993Neil GA Zimmermann U: Electrofusion. Methods Enzymol 220:174–196 1993

32.

Nestle FOAlijagic SGilliet MSun YGrabbe SDummer Ret al: Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med 4:3283321998Nestle FO Alijagic S Gilliet M Sun Y Grabbe S Dummer R et al: Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med 4:328–332 1998

33.

North RJ: Gamma-radiation facilitates the expression of adoptive immunity against established tumors by eliminating suppressor T cells. Cancer Immunol Immunother 16:1751811984North RJ: Gamma-radiation facilitates the expression of adoptive immunity against established tumors by eliminating suppressor T cells. Cancer Immunol Immunother 16:175–181 1984

34.

Okada HTahara HShurin MRAttanucci JGiezeman-Smits KMFellows WKet al: Bone marrow-derived dendritic cells pulsed with a tumor-specific peptide elicit effective anti-tumor immunity against intracranial neoplasms. Int J Cancer 78:1962011998Okada H Tahara H Shurin MR Attanucci J Giezeman-Smits KM Fellows WK et al: Bone marrow-derived dendritic cells pulsed with a tumor-specific peptide elicit effective anti-tumor immunity against intracranial neoplasms. Int J Cancer 78:196–201 1998

35.

Okano FStorkus WJChambers WHPollac IFOkada H: Identification of a novel HLA-A*0201-restricted, cytotoxic T lymphocyte epitope in a human glioma-associated antigen, interleukin 13 receptor alpha2 chain. Clin Cancer Res 8:285128552002Okano F Storkus WJ Chambers WH Pollac IF Okada H: Identification of a novel HLA-A*0201-restricted cytotoxic T lymphocyte epitope in a human glioma-associated antigen interleukin 13 receptor alpha2 chain. Clin Cancer Res 8:2851–2855 2002

36.

Parkhurst MRDePan CRiley JPRosenberg SAShu S: Hybrids of dendritic cells and tumor cells generated by electrofusion simultaneously present immunodominant epitopes from multiple human tumor-associated antigens in the context of MHC class I and class II molecules. J Immunol 170:531753252003Parkhurst MR DePan C Riley JP Rosenberg SA Shu S: Hybrids of dendritic cells and tumor cells generated by electrofusion simultaneously present immunodominant epitopes from multiple human tumor-associated antigens in the context of MHC class I and class II molecules. J Immunol 170:5317–5325 2003

37.

Perrin GSchnuriger VQuiquerez ALSaas PPannetier Cde Tribolet Net al: Astrocytoma infiltrating lymphocytes include major T cell clonal expansions confined to the CD8 subset. Int Immunol 11:133713501999Perrin G Schnuriger V Quiquerez AL Saas P Pannetier C de Tribolet N et al: Astrocytoma infiltrating lymphocytes include major T cell clonal expansions confined to the CD8 subset. Int Immunol 11:1337–1350 1999

38.

Plautz GEBarnett GHMiller DWCohen BHPrayson RAKrauss JCet al: Systemic T cell adoptive immunotherapy of malignant gliomas. J Neurosurg 89:42511998Plautz GE Barnett GH Miller DW Cohen BH Prayson RA Krauss JC et al: Systemic T cell adoptive immunotherapy of malignant gliomas. J Neurosurg 89:42–51 1998

39.

Plautz GEInoue MShu S: Defining the synergistic effects of radiation and T-cell immunotherapy for murine intracranial tumors. Cell Immunol 171:2772841996Plautz GE Inoue M Shu S: Defining the synergistic effects of radiation and T-cell immunotherapy for murine intracranial tumors. Cell Immunol 171:277–284 1996

40.

Plautz GEMiller DWBarnett GHStevens GHMaffett SKim Jet al: T cell adoptive immunotherapy of newly diagnosed gliomas. Clin Cancer Res 6:220922182000Plautz 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

41.

Plautz GEMukai SCohen PAShu S: Cross-presentation of tumor antigens to effector T cells is sufficient to mediate effective immunotherapy of established intracranial tumors. J Immunol 165:365636622000Plautz 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

42.

Plautz GETouhalisky JEShu S: Treatment of murine gliomas by adoptive transfer of ex vivo activated tumor-draining lymph node cells. Cell Immunol 178:1011071997Plautz GE Touhalisky JE Shu S: Treatment of murine gliomas by adoptive transfer of ex vivo activated tumor-draining lymph node cells. Cell Immunol 178:101–107 1997

43.

Prins RMGraf MRMerchant REBlack KLWheeler CJ: Thymic function and output of recent thymic emigrant T cells during intracranial glioma progression. J Neurooncol 64:45542003Prins RM Graf MR Merchant RE Black KL Wheeler CJ: Thymic function and output of recent thymic emigrant T cells during intracranial glioma progression. J Neurooncol 64:45–54 2003

44.

Prins RMOdesa SKLiau LM: Immunotherapeutic targeting of shared melanoma-associated antigens in a murine glioma model. Cancer Res 63:848784912003Prins RM Odesa SK Liau LM: Immunotherapeutic targeting of shared melanoma-associated antigens in a murine glioma model. Cancer Res 63:8487–8491 2003

45.

Scarcella DLChow CWGonzales MFEconomou CBrasseur FAshley DM: Expression of MAGE and GAGE in high-grade brain tumors: a potential target for specific immunotherapy and diagnostic markers. Clin Cancer Res 5:3353411999Scarcella DL Chow CW Gonzales MF Economou C Brasseur F Ashley DM: Expression of MAGE and GAGE in high-grade brain tumors: a potential target for specific immunotherapy and diagnostic markers. Clin Cancer Res 5:335–341 1999

46.

Schuler GSchuler-Thurner BSteinman RM: The use of dendritic cells in cancer immunotherapy. Curr Opin Immunol 15:1381472003Schuler G Schuler-Thurner B Steinman RM: The use of dendritic cells in cancer immunotherapy. Curr Opin Immunol 15:138–147 2003

47.

Shai RShi TKremen TJHorvath SLiau LMCloughesy TFet al: Gene expression profiling identifies molecular subtypes of gliomas. Oncogene 22:491849232003Shai R Shi T Kremen TJ Horvath S Liau LM Cloughesy TF et al: Gene expression profiling identifies molecular subtypes of gliomas. Oncogene 22:4918–4923 2003

48.

Shimizu KKuriyama HKjaergaard JLee WTanaka HShu S: Comparative analysis of antigen loading strategies of dendritic cells for tumor immunotherapy. J Immunother 27:2652722004Shimizu K Kuriyama H Kjaergaard J Lee W Tanaka H Shu S: Comparative analysis of antigen loading strategies of dendritic cells for tumor immunotherapy. J Immunother 27:265–272 2004

49.

Stewart LA: Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359:101110182002Stewart 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

50.

Struss AKRomeike BFMunnia ANastainczyk WSteudel WIKonig Jet al: PHF3-specific antibody responses in over 60% of patients with glioblastoma multiforme. Oncogene 20:410741142001Struss AK Romeike BF Munnia A Nastainczyk W Steudel WI Konig J et al: PHF3-specific antibody responses in over 60% of patients with glioblastoma multiforme. Oncogene 20:4107–4114 2001

51.

Tanaka HShimizu KHayashi TShu S: Therapeutic immune response induced by electrofusion of dendritic and tumor cells. Cell Immunol 220:1122002Tanaka H Shimizu K Hayashi T Shu S: Therapeutic immune response induced by electrofusion of dendritic and tumor cells. Cell Immunol 220:1–12 2002

52.

Walker MDAlexander E JrHunt WEMacCarty CSMahaley MS JrMealey J Jret al: Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg 49:3333431978Walker MD Alexander E Jr Hunt WE MacCarty CS Mahaley MS Jr Mealey J Jr et al: Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg 49:333–343 1978

53.

Walker MDGreen SBByar DPAlexander E JrBatzdorf UBrooks WHet al: Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant gliomas after surgery. N Engl J Med 303:132313291980Walker MD Green SB Byar DP Alexander E Jr Batzdorf U Brooks WH et al: Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant gliomas after surgery. N Engl J Med 303:1323–1329 1980

54.

Wang LXKjaergaard JCohen PAShu SPlautz GE: Memory T cells originate from adoptively transferred effectors and reconstituting host cells after sequential lymphodepletion and adoptive immunotherapy. J Immunol 172:346234682004Wang LX Kjaergaard J Cohen PA Shu S Plautz GE: Memory T cells originate from adoptively transferred effectors and reconstituting host cells after sequential lymphodepletion and adoptive immunotherapy. J Immunol 172:3462–3468 2004

55.

Wheeler CJBlack KLLiu GYing HYu JSZhang Wet al: Thymic CD8+ T cell production strongly influences tumor antigen recognition and age-dependent glioma mortality. J Immunol 171:492749332003Wheeler CJ Black KL Liu G Ying H Yu JS Zhang W et al: Thymic CD8+ T cell production strongly influences tumor antigen recognition and age-dependent glioma mortality. J Immunol 171:4927–4933 2003

56.

Yoshizawa HChang AEShu S: Specific adoptive immunotherapy mediated by tumor-draining lymph node cells sequentially activated with anti-CD3 and IL-2. J Immunol 147:7297371991Yoshizawa H Chang AE Shu S: Specific adoptive immunotherapy mediated by tumor-draining lymph node cells sequentially activated with anti-CD3 and IL-2. J Immunol 147:729–737 1991

57.

Yu JSWheeler CJZeltzer PMYing HFinger DNLee PKet al: Vaccination of malignant glioma patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T-cell infiltration. Cancer Res 61:8428472001Yu 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

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