Summary
The immunologic treatment of cancer has long been heralded as a targeted molecular therapeutic with the promise of eradicating tumor cells with minimal damage to surrounding normal tissues. However, a demonstrative example of the efficacy of immunotherapy in modulating cancer progression is still lacking for most human cancers. Recent breakthroughs in our understanding of the mechanisms leading to full T-cell activation, and recognition of the importance of overcoming tumor-induced immunosuppressive mechanisms, have shed new light on how to generate effective anti-tumor immune responses in humans, and sparked a renewed and enthusiastic effort to realize the full potential of cancer immunotherapy. The immunologic treatment of invasive malignant brain tumors has not escaped this re-invigorated endeavor, and promising therapies are currently under active investigation in dozens of clinical trials at several institutions worldwide. This review will focus on some of the most important breakthroughs in our understanding of how to generate potent anti-tumor immune responses, and some of the clear challenges that lie ahead in achieving effective immunotherapy for the majority of patients with malignant brain tumors. A review of immunotherapeutic strategies currently under clinical evaluation, as well as an outline of promising novel approaches on the horizon, is included to provide perspective on the active and stalwart progress toward effective immunotherapy for the treatment of malignant brain tumors.
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Kelly PJ. Stereotactic resection and its limitations in glial neoplasms. Stereotact Funct Neurosurg 1992;59: 84–91.
Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352: 987–996.
Walker MD, Green SB, Byar DP, et al. Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med 1980;303: 1323–1329.
Pickard JD, Bailey S, Sanderson H, Rees M, Garfield JS. Steps towards cost-benefit analysis of regional neurosurgical care. Brit Med J 1990;301: 629–635.
Imperato JP, Paleologos NA, Vick NA. Effects of treatment on long-term survivors with malignant astrocytomas. Ann Neurol 1990;28: 818–822.
Hall WA, Fodstad O. Immunotoxins and central nervous system neoplasia. J Neurosurg 1992;76: 1–12.
Shai RM, Reichardt JK, Chen TC. Pharmacogenomics of brain cancer and personalized medicine in malignant gliomas. Future Oncol 2008;4: 525–534.
Owens T, Renno T, Taupin V, Krakowski M. Inflammatory cytokines in the brain: does the CNS shape immune responses? Immunol Today 1994;15: 566–571.
Heimberger AB, Archer GE, Crotty LE, et al. Dendritic cells pulsed with a tumor-specific peptide induce long-lasting immunity and are effective against murine intracerebral melanoma. Neurosurgery 2002;50: 158–164.
Heimberger AB, Crotty LE, Archer GE, et al. Bone marrow-derived dendritic cells pulsed with tumor homogenate induce immunity against syngeneic intracerebral glioma. J Neuroimmunol 2000;103: 16–25.
Porter DL, Antin JH. Donor leukocyte infusions in myeloid malignancies: new strategies. Best Pract Res Clin Haematol 2006;19: 737–755.
Loren AW, Porter DL. Donor leukocyte infusions after unrelated donor hematopoietic stem cell transplantation. Curr Opin Oncol 2006;18: 107–114.
Gilboa E. The promise of cancer vaccines. Nat Rev Canc 2004;4: 401–411.
Gilboa E. The makings of a tumor rejection antigen. Immunity 1999;11: 263–270.
Lennerz V, Fatho M, Gentilini C, et al. The response of autologous T cells to a human melanoma is dominated by mutated neoantigens. Proc Natl Acad Sci U S A 2005;102: 16013–16018.
Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature 1998;396: 643–649.
Loeb LA. A mutator phenotype in cancer. Cancer Res 2001;61: 3230–3239.
Bigner SH, Humphrey PA, Wong AJ, et al. Characterization of the epidermal growth factor receptor in human glioma cell lines and xenografts. Cancer Res 1990;50: 8017–8022.
Libermann TA, Nusbaum HR, Razon N, et al. Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature 1985;313: 144–147.
Chu CT, Everiss KD, Wikstrand CJ, Batra SK, Kung HJ, Bigner DD. Receptor dimerization is not a factor in the signalling activity of a transforming variant epidermal growth factor receptor (EGFRvIII). Biochem J 1997;324: 855–861.
Batra SK, Castelino-Prabhu S, Wikstrand CJ, et al. Epidermal growth factor ligand-independent, unregulated, cell-transforming potential of a naturally occurring human mutant EGFRvIII gene. Cell Growth Differ 1995;6: 1251–1259.
Nishikawa R, Ji XD, Harmon RC, Lazar CS, Gill GN, Cavenee WK, et al. A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proc Natl Acad Sci U S A 1994;91: 7727–7731.
Huang HS, Nagane M, Klingbeil CK, et al. The enhanced tumorigenic activity of a mutant epidermal growth factor receptor common in human cancers is mediated by threshold levels of constitutive tyrosine phosphorylation and unattenuated signaling. J Biol Chem 1997;272: 2927–2935.
Moscatello DK, Montgomery RB, Sundareshan P, McDanel H, Wong MY, Wong AJ. Transformation and altered signal transduction by a naturally occurring mutant EGF receptor. Oncogene 1996;13: 85–96.
Pedersen MW, Tkach V, Pedersen N, Berezin V, Poulsen HS. Expression of a naturally occurring constitutively active variant of the epidermal growth factor receptor in mouse fibroblasts increases motility. Int J Cancer 2004;108: 643–653.
Boockvar JA, Kapitonov D, Kapoor G, et al. Constitutive EGFR signaling confers a motile phenotype to neural stem cells. Mol Cell Neurosci 2003;24: 1116–1130.
Lammering G, Hewit TH, Holmes M, et al. Inhibition of the type III epidermal growth factor receptor variant mutant receptor by dominant-negative EGFR-CD533 enhances malignant glioma cell radiosensitivity. Clin Canc Res 2004;10: 6732–6743.
Nagane M, Coufal F, Lin H, et al. A common mutant epidermal growth factor receptor confers enhanced tumorigenicity on human glioblastoma cells by increasing proliferation and reducing apoptosis. Cancer Res 1996;56: 5079–5086.
Montgomery RB, Guzman J, O’Rourke DM, Stahl WL. Expression of oncogenic epidermal growth factor receptor family kinases induces paclitaxel resistance and alters beta-tubulin isotype expression. J Biol Chem 2000;275: 17358–17363.
Lammering G, Valerie K, Lin P-S, Hewit TH, Schmidt-Ullrich RK. Radiation-induced activation of a common variant of EGFR confers enhanced radioresistance. Radiother Oncol 2004;72: 267–273.
Li B, Yuan M, Kim I-A, Chang C-M, Bernhard EJ, Shu H-KG. Mutant epidermal growth factor receptor displays increased signaling through the phosphatidylinositol-3 kinase/AKT pathway and promotes radioresistance in cells of astrocytic origin. Oncogene 2004;23: 4594–4602.
Lammering G, Hewit TH, Valerie K, et al. EGFRvIII-mediated radioresistance through a strong cytoprotective response. Oncogene 2003;22: 5545–5553.
Wikstrand CJ, Hale LP, Batra SK, et al. Monoclonal antibodies against EGFRvIII are tumor specific and react with breast and lung carcinomas and malignant gliomas. Cancer Res 1995;55: 3140–3148.
Frederick L, Wang XY, Eley G, James CD. Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. Cancer Res 2000;60: 1383–1387.
Wong AJ, Ruppert JM, Bigner SH, et al. Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci U S A 1992;89: 2965–2969.
Sugawa N, Ekstrand AJ, James CD, Collins VP. Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged genes in human glioblastomas. Proc Natl Acad Sci U S A 1990;87: 8602–8606.
Ekstrand AJ, James CD, Cavenee WK, et al. Genes for epidermal growth factor receptor, transforming growth factor alpha, and epidermal growth factor and their expression in human gliomas in vivo. Cancer Res 1991;51: 2164–2172.
Aldape KD, Ballman K, Furth A, et al. Immunohistochemical detection of EGFRvIII in high malignancy grade astrocytomas and evaluation of prognostic significance. J Neuropathol Exp Neurol 2004;63: 700–707.
Heimberger AB, Hlatky R, Suki D, et al. Prognostic effect of epidermal growth factor receptor and EGFRvIII in glioblastoma multiforme patients. Clin Canc Res 2005;11: 1462–1466.
Cunningham MP, Essapen S, Thomas H, Green M, Lovell DP, Topham C, et al. Coexpression, prognostic significance and predictive value of EGFR, EGFRvIII and phosphorylated EGFR in colorectal cancer. Int J Oncol 2005;27: 317–325.
Garcia de Palazzo IE, Adams GP, Sundareshan P, et al. Expression of mutated epidermal growth factor receptor by non-small cell lung carcinomas. Cancer Res 1993;53: 3217–3220.
Moscatello DK, Holgado-Madruga M, Godwin AK, et al. Frequent cactivity of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Res 1995;55: 5536–5539.
Luo X, Gong X, Tang CK. Suppression of EGFRvIII-mediated proliferation and tumorigenesis of breast cancer cells by ribozyme. Int J Cancer 2003;104: 716–721.
Ge H, Gong X, Tang CK. Evidence of high incidence of EGFRvIII expression and coexpression with EGFR in human invasive breast cancer by laser capture microdissection and immunohistochemical analysis. Int J Cancer 2002;98: 357–361.
Olapade-Olaopa EO, Moscatello DK, MacKay EH, et al. Evidence for the differential expression of a variant EGF receptor protein in human prostate cancer. Br J Canc 2000;82: 186–194.
Humphrey PA, Wong AJ, Vogelstein B, et al. Anti-synthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastoma. Proc Natl Acad Sci U S A 1990;87: 4207–4211.
Wikstrand CJ, Hale LP, Batra SK, et al. Monoclonal antibodies against EGFRvIII are tumor specific and react with breast and lung carcinomas and malignant gliomas. Cancer Res 1995;55: 3140–3148.
Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Bigner DD. Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with malignant glioma. Semin Immunol 2008: 20: 267–275.
Liao SK, Clarke BJ, Kwong PC, Blickenden A, Gallic BL, Dent PB. Common neuroectodermal antigens on human melanoma, neuroblastoma, retinoblastoma, glioblastoma and fetal brain revealed by hybridoma antibodies raised against melanoma cells. Eur J Immunol 1981;11: 450–454.
Rimoldi D, Romero P, Carrel S. The human melanoma antigenencoding gene, MAGE-1, is expressed by other tumour cells of neuroectodermal origin such as glioblastomas and neuroblastomas. Int J Cancer 1993;54: 527–528.
Sasaki M, Nakahira K, Kawano Y, et al. MAGE-E1, a new member of the melanoma-associated antigen gene family and its expression in human glioma. Cancer Res 2001;61: 4809–4814.
Zhang JG, Eguchi J, Kruse CA, et al. Antigenic profiling of glioma cells to generate allogeneic vaccines or dendritic cell-based therapeutics. Clin Cancer Res 2007;13: 566–575.
Zimmer C, Gottschalk J, Goebel S, Cervos-Navarro J. Melanoma-associated antigens in tumours of the nervous system: an immunohistochemical study with the monoclonal antibody HMB-45. Virchows Arch A Pathol Anat Histopathol 1992;420: 121–126.
Cobbs CS, Harkins L, Samanta M, et al. Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res 2002;62: 3347–3350.
Mitchell DA, Xie W, Schmittling R, et al. Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma. Neuro Oncol 2008;10: 10–18.
Scheurer ME, Bondy ML, Aldape KD, Albrecht T, El-Zein R. Detection of human cytomegalovirus in different histological types of gliomas. Acta Neuropathol 2008;116: 79–86.
Soderberg-Naucler C. HCMV microinfections in inflammatory diseases and cancer. J Clin Virol 2008;41: 218–223.
Prins RM, Cloughesy TF, Liau LM. Cytomegalovirus immunity after vaccination with autologous glioblastoma lysate. N Engl J Med 2008;359: 539–541.
Mintz A, Debinski W. Cancer genetics/epigenetics and the X chromosome: possible new links for malignant glioma pathogenesis and immune-based therapies. Crit Rev Oncog 2000;11: 77–95.
Debinski W. An immune regulatory cytokine receptor and glioblastoma multiforme: an unexpected link. Crit Rev Oncog 1998: 9: 255–268.
Skog J. Glioma-specific antigens for immune tumor therapy. Expert Rev Vaccines 2006;5: 793–802.
Schmittling RJ, Archer GE, Mitchell DA, et al. Detection of humoral response in patients with glioblastoma receiving EGFRvIII-KLH vaccines. J Immunol Methods 2008;339: 74–81.
Izumoto S, Tsuboi A, Oka Y, et al. Phase II clinical trial of Wilms tumor 1 peptide vaccination for patients with recurrent glioblastoma multiforme. J Neurosurg 2008;108: 963–971.
Yajima N, Yamanaka R, Mine T, et al. Immunologic evaluation of personalized peptide vaccination for patients with advanced malignant glioma. Clin Cancer Res 2005;11: 5900–5911.
Fakhrai H, Mantil JC, Liu L, et al. Phase I clinical trial of a TGF-beta antisense-modified tumor cell vaccine in patients with advanced glioma. Cancer Gene Ther 2006;13: 1052–1060.
Okada H, Lieberman FS, Walter KA, et al. Autologous glioma cell vaccine admixed with interleukin-4 gene transfected fibro-blasts in the treatment of patients with malignant gliomas. J Transl Med 2007;5: 67.
Okada H, Pollack IF, Lotze MT, et al. Gene therapy of malignant gliomas: a phase I study of IL-4-HSV-TK gene-modified autologous tumor to elicit an immune response. Hum Gene Ther 2000;11: 637–653.
Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998;392: 245–252.
Steinman RM. Dendritic cells and the control of immunity: enhancing the efficiency of antigen presentation. Mt Sinai J Med 2001;68: 106–166.
Fujii S, Shimizu K, Fujimoto K, et al. Analysis of a chronic myelogenous leukemia patient vaccinated with leukemic dendritic cells following autologous peripheral blood stem cell transplantation. Jpn J Cancer Res 1999;90: 1117–1129.
Heiser A, Coleman D, Dannull J, et al. Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate CTL responses against metastatic prostate tumors. J Clin Invest 2002;109: 409–417.
Su Z, Dannull J, Heiser A, et al. Immunological and clinical responses in metastatic renal cancer patients vaccinated with tumor RNA-transfected dendritic cells. Cancer Res 2003;63: 2127–2133.
Holtl L, Rieser C, Papesh C, et al. Cellular and humoral immune responses in patients with metastatic renal cell carcinoma after vaccination with antigen pulsed dendritic cells. J Urol 1999;161: 777–782.
Lodge PA, Jones LA, Bader RA, Murphy GP, Salgaller ML. Dendritic cell-based immunotherapy of prostate cancer: immune monitoring of a phase II clinical trial. Cancer Res 2000;60: 829–833.
Lim SH, Bailey-Wood R. Idiotypic protein-pulsed dendritic cell vaccination in multiple myeloma. Int J Cancer 1999;83: 215–222.
Hsu FJ, Benike C, Fagnoni F, et al. Vaccination of patients with B-cell lympoma using autologous antigen-pulsed dendritic cells. Nat Med 1996;2: 52–58.
Murphy GP, Tjoa BA, Simmons SJ, Rogers MK, Kenny GM, Jarisch J. Higher-dose and less frequent dendritic cell infusions with PSMA peptides in hormone-refractory metastatic prostate cancer patients. Prostate 2000;43: 59–62.
Morse MA, Deng Y, Coleman D, et al. A Phase I study of active immunotherapy with carcinoembryonic antigen peptide (CAP-1)-pulsed, autologous human cultured dendritic cells in patients with metastatic malignancies expressing carcinoembryonic antigen. Clin Cancer Res 1999;5: 1331–1338.
Tjoa BA, Simmons SJ, Bowes VA, et al. Evaluation of phase I/II clinical trials in prostate cancer with dendritic cells and PSMA peptides. Prostate 1998;36: 39–44.
Thurner B, Haendle I, Roder C, et al. Vaccination with mage-3Al peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma. J Exp Med 1999;190: 1669–1678.
Schuler-Thurner B, Dieckmann D, Keikavoussi P, et al. Mage-3 and influenza-matrix peptide-specific cytotoxic T cells are inducible in terminal stage HLA-A2.1 + melanoma patients by mature monocyte-derived dendritic cells. J Immunol 2000;165: 3492–3496.
Salgaller ML, Tjoa BA, Lodge PA, et al. Dendritic cell-based immunotherapy of prostate cancer. Crit Rev Immunol 1998;18: 109–119.
Salgaller ML, Lodge PA, McLean JG, et al. Report of immune monitoring of prostate cancer patients undergoing T-cell therapy using dendritic cells pulsed with HLA-A2-specific peptides from prostate-specific membrane antigen (PSMA). Prostate 1998;35: 144–151.
Rieser C, Ramoner R, Holtl L, et al. Mature dendritic cells induce T-helper type-1-dominant immune responses in patients with metastatic renal cell carcinoma. Urologia Internationalis 2000;63: 151–159.
Nestle FO, Alijagic S, Gilliet M, et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med 1998;4: 328–332.
Murphy G, Tjoa B, Ragde H, Kenny G, Boynton A. Phase I clinical trial: T-cell therapy for prostate cancer using autologous dendritic cells pulsed with HLA-A0201-specific peptides from prostate-specific membrane antigen. Prostate 1996;29: 371–380.
Ashley 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 1997;186: 1177–1182.
Yu JS, Wheeler CJ, Zeltzer PM, et al. Vaccination of malignant glioma patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T-cell infiltration. Cancer Res 2001;61: 842–847.
Liau L, Black KL, Prins RM, et al. Treatment of intracranial gliomas with bone marrow-derived dendritic cells pulsed with tumor antigens. J Neurosurg 1999;90: 1115–1124.
Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Bigner DD. Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with malignant glioma. Semin Immunol 2008.
Morse MA, Coleman RE, Akabani G, Niehaus N, Coleman D, Lyerly HK. Migration of human dendritic cells after injection in patients with metastatic malignancies. Cancer Res 1999;59: 56–58.
Barratt-Boyes SM, Zimmer MI, Harshyne LA, et al. Maturation and trafficking of monocyte-derived dendritic cells in monkeys: implications for dendritic cell-based vaccines. J Immunol 2000;164: 2487–2495.
Fong L, Brockstedt D, Benike C, Wu L, Engleman EG. Dendritic cells injected via different routes induce immunity in cancer patients. J Immunol 2001;166: 4254–4259.
Kalinski P, Vieira PL, Schuitemaker JH, de Jong EC, Kapsenberg ML. Prostaglandin E(2) is a selective inducer of interleukin-12 p40 (IL-12p40) production and an inhibitor of bioactive IL-12p70 heterodimer. Blood 2001;97: 3466–3469.
Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. N Engl J Med 2005;352: 987–996.
Westphal M, Hilt DC, Bortey E, et al. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro-oncology 2003;5: 79–88.
Parajuli P, Mathupala S, Sloan AE. Systematic comparison of dendritic cell-based immunotherapeutic strategies for malignant gliomas: in vitro induction of cytolytic and natural killer-like T cells. Neurosurgery 2004;55: 1194–1204.
Sloan AE, Parajuli P, Mathupala S. DC-tumor cell fusion for-induction of tumor-specific T-cell response against malignant brain tumors: Comparison with DC pulsed with total tumor RNA or tumor lysate. In: Proceedings of the American Association for Cancer Research; 2002; San Francisco, CA, 2002.
Liau LM, Prins RM, Kiertscher SM, et al. Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin Cancer Res 2005;11: 5515–5525.
De Vleeschouwer S, Fieuws S, Rutkowski S, et al. Postoperative adjuvant dendritic cell-based immunotherapy in patients with relapsed glioblastoma multiforme. Clin Cancer Res 2008;14: 3098–3104.
Wheeler CJ, Black KL, Liu G, et al. Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients. Cancer Res 2008;68: 5955–5964.
Morse MA, Nair SK, Mosca PJ, et al. Immunotherapy with autologous, human dendritic cells transfected with carcinoembryonic antigen mRNA. Cancer Invest 2003;21: 341–349.
Boczkowski D, Nair SK, Snyder D, Gilboa E. Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo. J Exp Med 1996;184: 465–472.
Van Tendeloo VF, Ponsaerts P, Lardon F, et al. Highly efficient gene delivery by mRNA electroporation in human hematopoietic cells: superiority to lipofection and passive pulsing of mRNA and to electroporation of plasmid cDNA for tumor antigen loading of dendritic cells. Blood 2001;98: 49–56.
Strobel I, Berchtold S, Gotze A, Schulze U, Schuler G, Steinkasserer A. Human dendritic cells transfected with either RNA or DNA encoding influenza matrix protein Ml differ in their ability to stimulate cytotoxic T lymphocytes. Gene Ther 2000;7: 2028–2035.
Mitchell DA, Nair SK. RNA-transfected dendritic cells in cancer immunotherapy. J Clin Invest 2000;106: 1065–1069.
Kim JJ, Trivedi NN, Wilson DM, Mahalingam S, et al. Molecular and immunological analysis of genetic prostate specific antigen (PSA) vaccine. Oncogene 1998;17: 3125–3135.
Sercarz EE, Lehmann PV, Ametani A, Benichou G, Miller A, Moudgil K. Dominance and crypticity of T cell antigenic determinants. Ann Rev Immunol 1993;11: 729–766.
Kundig TM, Bachmann MF, Oehen S, et al. On the role of antigen in maintaining cytotoxic T-cell memory. Proc Natl Acad Sci U S A 1996;93: 9716–9723.
Boczkowski D, Nair SK, Nam JH, Lyerly HK, Gilboa E. Induction of tumor immunity and cytotoxic T lymphocyte responses using dendritic cells transfected with messenger RNA amplified from tumor cells. Cancer Res 2000;60: 1028–1034.
Caruso DA, Orme LM, Neale AM, 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. Neurooncol 2004;6: 236–246.
Van Tendeloo VF, Ponsaerts P, Lardon F, et al. Highly efficient gene delivery by mRNA electroporation in human hematopoietic cells: superiority to lipofection and passive pulsing of mRNA and to electroporation of plasmid cDNA for tumor antigen loading of dendritic cells. Blood 2001;98: 49–56.
Mackensen A, Herbst B, Chen JL, et al. Phase I study in melanoma patients of a vaccine with peptide-pulsed dendritic cells generated in vitro from CD34(+) hematopoietic progenitor cells. Int J Cancer 2000;86: 385–392.
Heimberger AB, Archer GE, Crotty LE, et al. Dendritic cells pulsed with a tumor-specific peptide induce long-lasting immunity and are effective against murine intracerebral melanoma. Neurosurgery 2002;50: 158–166.
Ochsenbein AF, Klenerman P, Karrer U, et al. Immune surveillance against a solid tumor fails because of immunological ignorance. Proc Natl Acad Sci U S A 1999;96: 2233–2238.
Ludewig B, Ochsenbein AF, Odermatt B, Paulin D, Hengartner H, Zinkemagel RM. Immunotherapy with dendritic cells directed against tumor antigens shared with normal host cells results in severe autoimmune disease. J Exp Med 2000;191: 795–804.
Steinbok P, Thomas JP, Grossman L, Dolman CL. Intratumoral autologous mononuclear cells in the treatment of recurrent glioblastoma multiforme. A phase 1 (toxicity) study. J Neurooncol 1984;2: 147–151.
Young H, Kaplan A, Regelson W. Immunotherapy with autologous white cell infusions (“lymphocytes”) in the treatment of recurrrent glioblastoma multiforme: a preliminary report. Cancer 1977;40: 1037–1044.
Hayes RL, Koslow M, Hiesiger EM, et al. Improved long term survival after intracavitary interleukin-2 and lymphokine-activated killer cells for adults with recurrent malignant glioma. Cancer 1995;76: 840–852.
Blancher A, Roubinet F, Grancher AS, et al. Local immunotherapy of recurrent glioblastoma multiforme by intracerebral perfusion of interleukin-2 and LAK cells. Eur Cytokine Netw 1993;4: 331–341.
Jacobs SK, Wilson DJ, Kornblith PL, Grimm EA. Interleukin-2 or autologous lymphokine-activated killer cell treatment of malignant glioma: phase I trial. Cancer Res 1986;46: 2101–2104.
Jeffes EW, 3rd, Beamer YB, Jacques S, et al. Therapy of recurrent high grade gliomas with surgery, and autologous mitogen activated IL-2 stimulated killer (MAK) lymphocytes: I. Enhancement of MAK lytic activity and cytokine production by PHA and clinical use of PHA. J Neuro-Oncol 1993;15: 141–155.
Ingram M, Buckwalter JG, Jacques DB, et al. Immunotherapy for recurrent malignant glioma: an interim report on survival. Neurol Res 1990;12: 265–273.
Quattrocchi KB, Miller CH, Cush S, et al. Pilot study of local autologous tumor infiltrating lymphocytes for the treatment of recurrent malignant gliomas. J Neuro-Oncol 1999;45: 141–157.
Tsurushima H, Liu SQ, Tuboi K, et al. Reduction of end-stage malignant glioma by injection with autologous cytotoxic T lymphocytes. Jpn J Cancer Res 1999;90: 536–545.
Kitahara T, Watanabe O, Yamaura A, et al. Establishment of interleukin 2 dependent cytotoxic T lymphocyte cell line specific for autologous brain tumor and its intracranial administration for therapy of the tumor. J Neurooncol 1987;4: 329–336.
Yaghoubi SS, Jensen MC, Satyamurthy N, et al. Noninvasive detection of therapeutic cytolytic T cells with 18F-FHBG PET in a patient with glioma. Nat Clin Pract Oncol 2009;6: 53–58.
Dudley ME, Yang JC, Sherry R, et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol 2008.
Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer 2008;8: 299–308.
Muranski P, Boni A, Wrzesinski C, et al. Increased intensity lymphodepletion and adoptive immunotherapy—how far can we go? Nat Clin Pract Oncol 2006;3: 668–681.
Wrzesinski C, Paulos CM, Gattinoni L, et al. Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8 T cells. J Clin Invest 2007;117: 492–501.
Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002;298: 850–854.
Tanchot C, Rosado MM, Agenes F, Freitas AA, Rocha B. Lymphocyte homeostasis. Semin Immunol 1997;9: 331–337.
Grossman Z, Paul WE. Self-tolerance: context dependent tuning of T cell antigen recognition. Semin Immunol 2000;12: 197–203.
Cho BK, Rao VP, Ge Q, Eisen HN, Chen J. Homeostasis-stimulated proliferation drives naive T cells to differentiate directly into memory T cells. J Exp Med 2000;192: 549–556.
Dummer W, Niethammer AG, Baccala R, et al. T cell homeostatic proliferation elicits effective antitumor autoimmunity. J Clin Invest 2002;110: 185–192.
Asavaroengchai W, Kotera Y, Mule JJ. Tumor lysate-pulsed dendritic cells can elicit an effective antitumor immune response during early lymphoid recovery. Proc Natl Acad Sci U S A 2002;99: 931–936.
Rapoport AP, Stadtmauer EA, Aqui N, et al. Restoration of immunity in lymphopenic individuals with cancer by vaccination and adoptive T-cell transfer. Nat Med 2005;11: 1230–1237.
Hu HM, Poehlein CH, Urba WJ, Fox BA. Development of anti-tumor immune responses in reconstituted lymphopenic hosts. Cancer Res 2002;62: 3914–3919.
Khoruts A, Fraser JM, Khoruts A, Fraser JM. A causal link between lymphopenia and autoimmunity. Immunol Lett 2005;98: 23–31.
Krupica T, Jr., Fry TJ, Mackall CL, Krupica T, Jr., Fry TJ, Mackall CL. Autoimmunity during lymphopenia: a two-hit model. Clin Immunol 2006;120: 121–128.
Lizee G, Radvanyi LG, Overwijk WW, Hwu P. Immunosuppression in melanoma immunotherapy: potential opportunities for intervention. Clin Cancer Res 2006;12: 2359s-2365s.
Klebanoff CA, Khong HT, Antony PA, Palmer DC, Restifo NP. Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends Immunol 2005;26: 111–117.
Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 2005;23: 2346–2357.
Robbins PF, Dudley ME, Wunderlich J, et al. Cutting edge: persistence of transferred lymphocyte clonotypes correlates with cancer regression in patients receiving cell transfer therapy. J Immunol 2004;173: 7125–7130.
Rosenberg SA. Development of effective immunotherapy for the treatment of patients with cancer. Journal of the Am Coll Surg 2004;198: 685–696.
Rosenberg SA, Rosenberg SA. Cancer immunotherapy comes of age. Nat Clin Pract Oncol 2005;2: 115.
Zhou J, Dudley ME, Rosenberg SA, Robbins PF. Persistence of multiple tumor-specific T-cell clones is associated with complete tumor regression in a melanoma patient receiving adoptive cell transfer therapy. J Immunother Emphasis Tumor Immunol 2005;28: 53–62.
Zhou J, Shen X, Huang J, Hodes RJ, Rosenberg SA, Robbins PF. Telomere length of transferred lymphocytes correlates with in vivo persistence and tumor regression in melanoma patients receiving cell transfer therapy. J Immunol 2005;175: 7046–7052.
Dudley ME, Rosenberg SA. Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nat Rev Cancer 2003;3: 666–675.
Restifo NP, Rosenberg SA, Restifo NP, Rosenberg SA. Use of standard criteria for assessment of cancer vaccines. Lancet Oncol 2005;6: 3–4.
Wrzesinski C, Paulos CM, Gattinoni L, et al. Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8 T cells. J Clin Invest 2007;117: 492–501.
Fecci PE, Mitchell DA, Whitesides JF, et al. Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res 2006;66: 3294–3302.
Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995;155: 1151–1164.
Thornton AM, Shevach EM. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 1998;188: 287–296.
Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH. Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood. J Exp Med 2001;193: 1285–1294.
Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler G. Ex vivo isolation and characterization of CD4(+)CD25(+) T cells with regulatory properties from human blood. J Exp Med 2001;193: 1303–1310.
Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003;4: 330–336.
Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 2003;4: 337–342.
Green DR, Webb DR. Saying the “S” word in public. Immunol Today 1993;14: 523–525.
Asano M, Toda M, Sakaguchi N, Sakaguchi S. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med 1996;184: 387–396.
Salomon B, Lenschow DJ, Rhee L, et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 2000;12: 431–440.
Stephens LA, Mason D. CD25 is a marker for CD4+ thymocytes that prevent autoimmune diabetes in rats, but peripheral T cells with this function are found in both CD25+ and CD25− sub-populations. J Immunol 2000;165: 3105–3110.
Taguchi O, Nishizuka Y. Self tolerance and localized autoimmunity. Mouse models of autoimmune disease that suggest tissue-specific suppressor T cells are involved in self tolerance. J Exp Med 1987;165: 146–156.
Taguchi O, Kontani K, Ikeda H, Kezuka T, Takeuchi M, Takahashi T. Tissue-specific suppressor T cells involved in self-tolerance are activated extrathymically by self-antigens. Immunology 1994;82: 365–369.
Seddon B, Mason D. Regulatory T cells in the control of autoimmunity: the essential role of transforming growth factor beta and interleukin 4 in the prevention of autoimmune thyroiditis in rats by peripheral CD4(+)CD45RC-cells and CD4(+)CD8(−) thymocytes. J Exp Med 1999;189: 279–288.
Seddon B, Mason D. Peripheral autoantigen induces regulatory T cells that prevent autoimmunity. J Exp Med 1999;189: 877–882.
Bagavant H, Thompson C, Ohno K, Setiady Y, Tung KSK. Differential effect of neonatal thymectomy on systemic and organ-specific autoimmune disease. Intl Immunol 2002;14: 1397–1406.
Somasundaram R, Jacob L, Swoboda R, et al. Inhibition of cytolytic T lymphocyte proliferation by autologous CD4+/CD25 + regulatory T cells in a colorectal carcinoma patient is mediated by transforming growth factor-beta. Cancer Res 2002;62: 5267–5272.
Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004;10: 942–949.
Liyanage UK, Moore TT, Joo HG, et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironmet of patients with pancreas or breast adenocarcinoma. J Immunol 2002;169: 2756–2761.
Wolf AM, Wolf D, Steurer M, Gastl G, Gunsilius E, Grubeck-Loebenstein B. Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res 2003;9: 606–612.
Ichihara F, Kono K, Takahashi A, Kawaida H, Sugai H, Fujii H. Increased populations of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patients with gastric and esophageal cancers. Clin Cancer Res 2003;9: 4404–4408.
Woo EY, Chu CS, Goletz TJ, et al. Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res 2001;61: 4766–4772.
Heimberger AB, Abou-Ghazal M, Reina-Ortiz C, et al. Incidence and prognostic impact of FoxP3+ regulatory T cells in human gliomas. Clin Cancer Res 2008;14: 5166–5172.
Chen A, Liu S, Park D, Kang Y, Zheng G. Depleting intratumoral CD4+CD25+ regulatory T cells via FasL protein transfer enhances the therapeutic efficacy of adoptive T cell transfer. Cancer Res 2007;67: 1291–1298.
Quezada SA, Peggs KS, Simpson TR, Shen Y, Littman DR, Allison JP. Limited tumor infiltration by activated T effector cells restricts the therapeutic activity of regulatory T cell depletion against established melanoma. J Exp Med 2008;205: 2125–2138.
Yu P, Lee Y, Liu W, Krausz T, Chong A, Schreiber H, et al. Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J Exp Med 2005;201: 779–791.
Kong L-Y, Abou-Ghazal MK, Wei J, et al. A novel inhibitor of signal transducers and activators of transcription 3 activation is efficacious against established central nervous system melanoma and inhibits regulatory T cells. Clin Cancer Res %R 10.1158/1078-0432.CCR-08-0377 2008;14: 5759–5768.
Fecci PE, Sweeney AE, Grossi PM, et al. Systemic anti-CD25 monoclonal antibody administration safely enhances immunity in murine glioma without eliminating regulatory T cells. Clin Cancer Res 2006;12: 4294–4305.
Morse MA, Hobeika AC, Osada T, et al. Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines. Blood 2008;112: 610–618.
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Mitchell, D.A., Sampson, J.H. Toward effective immunotherapy for the treatment of malignant brain tumors. Neurotherapeutics 6, 527–538 (2009). https://doi.org/10.1016/j.nurt.2009.04.003
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DOI: https://doi.org/10.1016/j.nurt.2009.04.003