Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

Cancers

Volumn 5, Issue 4, 2013, Pages 1379-1412

  Ahn, Brian J ^a,b   Pollack, Ian F ^a,b   Okada, Hideho ^a,b  

^a UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF PITTSBURGH CANCER INSTITUTE   (United States)

Author keywords

Cancer immunotherapy; Cancer vaccines; Glioma; T cells; Tumor immunity; Tumor microenvironment

Indexed keywords

EID: 84911018402     PISSN: None     EISSN: 20726694     Source Type: Journal    
DOI: 10.3390/cancers5041379     Document Type: Review

References (190)

1. Hodi, F.S.; O’Day, S.J.; McDermott, D.F.; Weber, R.W.; Sosman, J.A.; Haanen, J.B.; Gonzalez, R.; Robert, C.; Schadendorf, D.; Hassel, J.C.; et al. Improved survival with Ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 2010, 363, 711–723.
2. Morgan, R.A.; Chinnasamy, N.; Abate-Daga, D.; Gros, A.; Robbins, P.F.; Zheng, Z.; Dudley, M.E.; Feldman, S.A.; Yang, J.C.; Sherry, R.M.; et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J. Immunother. 2013, 36, 133–151.
3. Kantoff, P.W.; Higano, C.S.; Shore, N.D.; Berger, E.R.; Small, E.J.; Penson, D.F.; Redfern, C.H.; Ferrari, A.C.; Dreicer, R.; Sims, R.B.; et al. Sipuleucel-T immunotherapy for Castration-resistant prostate cancer. N. Engl. J. Med. 2010, 363, 411–422.
4. Okada, H.; Kohanbash, G.; Zhu, X.; Kastenhuber, E.R.; Hoji, A.; Ueda, R.; Fujita, M. Immunotherapeutic approaches for glioma. Crit. Rev. Immunol. 2009, 29, 1–42.
5. Walker, P.R.; Calzascia, T.; de Tribolet, N.; Dietrich, P.Y. T-cell immune responses in the brain and their relevance for cerebral malignancies. Brain Res. Rev. 2003, 42, 97–122.
6. Gorelik, L.; Flavell, R.A. Transforming growth factor-beta in T-cell biology. Nat. Rev. Immunol. 2002, 2, 46–53.
7. Gomez, G.G.; Kruse, C.A. Cellular and functional characterization of immunoresistant human glioma cell clones selected with alloreactive cytotoxic T lymphocytes reveals their up-regulated synthesis of biologically active TGF-beta. J. Immunother. 2007, 30, 261–273.
8. Ueda, R.; Fujita, M.; Zhu, X.; Sasaki, K.; Kastenhuber, E.R.; Kohanbash, G.; McDonald, H.A.; Harper, J.; Lonning, S.; Okada, H. Systemic inhibition of transforming growth factor-beta in glioma-bearing mice improves the therapeutic efficacy of glioma-associated antigen peptide vaccines. Clin. Cancer Res. 2009, 15, 6551–6559.
9. Eisele, G.; Wischhusen, J.; Mittelbronn, M.; Meyermann, R.; Waldhauer, I.; Steinle, A.; Weller, M.; Friese, M.A. TGF-beta and metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells. Brain 2006, 129, 2416–2425.
10. Crane, C.A.; Han, S.J.; Barry, J.J.; Ahn, B.J.; Lanier, L.L.; Parsa, A.T. TGF-beta downregulates the activating receptor NKG2D on NK cells and CD8+ T cells in glioma patients. Neuro-oncology 2010, 12, 7–13.
11. Friese, M.A.; Wischhusen, J.; Wick, W.; Weiler, M.; Eisele, G.; Steinle, A.; Weller, M. RNA interference targeting transforming growth factor-beta enhances NKG2D-mediated antiglioma immune response, inhibits glioma cell migration and invasiveness, and abrogates tumorigenicity in vivo. Cancer Res. 2004, 64, 7596–7603.
12. Naumann, U.; Maass, P.; Gleske, A.K.; Aulwurm, S.; Weller, M.; Eisele, G. Glioma gene therapy with soluble transforming growth factor-beta receptors II and III. Int. J. Oncol. 2008, 33, 759–765.
13. Witham, T.F.; Villa, L.; Yang, T.; Pollack, I.F.; Okada, H.; Robbins, P.D.; Chambers, W.H. Expression of a soluble transforming growth factor-beta (TGFbeta) receptor reduces tumorigenicity by regulating natural killer (NK) cell activity against 9L gliosarcoma in vivo. J. Neurooncol. 2003, 64, 63–69.
14. Liu, Y.; Wang, Q.; Kleinschmidt-DeMasters, B.K.; Franzusoff, A.; Ng, K.Y.; Lillehei, K.O. TGF-beta2 inhibition augments the effect of tumor vaccine and improves the survival of animals with pre-established brain tumors. J. Neurooncol. 2007, 81, 149–162.
15. Anido, J.; Saez-Borderias, A.; Gonzalez-Junca, A.; Rodon, L.; Folch, G.; Carmona, M.A.; Prieto-Sanchez, R.M.; Barba, I.; Martinez-Saez, E.; Prudkin, L.; et al. TGF-beta receptor inhibitors target the CD44(high)/Id1(high) glioma-initiating cell population in human glioblastoma. Cancer Cell 2010, 18, 655–668.
16. Ye, X.Z.; Xu, S.L.; Xin, Y.H.; Yu, S.C.; Ping, Y.F.; Chen, L.; Xiao, H.L.; Wang, B.; Yi, L.; Wang, Q.L.; et al. Tumor-associated microglia/macrophages enhance the invasion of glioma stem-like cells via TGF-beta1 signaling pathway. J. Immunol. 2012, 189, 444–453.
17. Hardee, M.E.; Marciscano, A.E.; Medina-Ramirez, C.M.; Zagzag, D.; Narayana, A.; Lonning, S.M.; Barcellos-Hoff, M.H. Resistance of glioblastoma-initiating cells to radiation mediated by the tumor microenvironment can be abolished by inhibiting transforming growth factor-beta. Cancer Res. 2012, 72, 4119–4129.
18. Penuelas, S.; Anido, J.; Prieto-Sanchez, R.M.; Folch, G.; Barba, I.; Cuartas, I.; Garcia-Dorado, D.; Poca, M.A.; Sahuquillo, J.; Baselga, J.; et al. TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma. Cancer Cell 2009, 15, 315–327.
19. Ikushima, H.; Todo, T.; Ino, Y.; Takahashi, M.; Miyazawa, K.; Miyazono, K. Autocrine TGF-beta signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors. Cell Stem Cell 2009, 5, 504–514.
20. Song, L.; Liu, L.; Wu, Z.; Li, Y.; Ying, Z.; Lin, C.; Wu, J.; Hu, B.; Cheng, S.Y.; Li, M.; et al. TGF-beta induces miR-182 to sustain NF-kappaB activation in glioma subsets. J. Clin. Invest. 2012, 122, 3563–3578.
21. Joseph, J.V.; Balasubramaniyan, V.; Walenkamp, A.; Kruyt, F.A. TGF-beta as a therapeutic target in high grade gliomas—Promises and challenges. Biochem. Pharmacol. 2013, 85, 478–485.
22. Moore, K.W.; de Waal Malefyt, R.; Coffman, R.L.; O’Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 2001, 19, 683–765.
23. Said, E.A.; Dupuy, F.P.; Trautmann, L.; Zhang, Y.; Shi, Y.; El-Far, M.; Hill, B.J.; Noto, A.; Ancuta, P.; Peretz, Y.; et al. Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nat. Med. 2010, 16, 452–459.
24. Nitta, T.; Hishii, M.; Sato, K.; Okumura, K. Selective expression of interleukin-10 gene within glioblastoma multiforme. Brain Res. 1994, 649, 122–128.
25. Huettner, C.; Czub, S.; Kerkau, S.; Roggendorf, W.; Tonn, J.C. Interleukin 10 is expressed in human gliomas in vivo and increases glioma cell proliferation and motility in vitro. Anticancer Res. 1997, 17, 3217–3224.
26. Oshima, M.; Dinchuk, J.E.; Kargman, S.L.; Oshima, H.; Hancock, B.; Kwong, E.; Trzaskos, J.M.; Evans, J.F.; Taketo, M.M. Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 1996, 87, 803–809.
27. Onguru, O.; Gamsizkan, M.; Ulutin, C.; Gunhan, O. Cyclooxygenase-2 (Cox-2) expression and angiogenesis in glioblastoma. Neuropathology 2008, 28, 29–34.
28. Sharma, S.; Yang, S.C.; Zhu, L.; Reckamp, K.; Gardner, B.; Baratelli, F.; Huang, M.; Batra, R.K.; Dubinett, S.M. Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer. Cancer Res. 2005, 65, 5211–5220.
29. Kalinski, P.; Vieira, P.L.; Schuitemaker, J.H.; de Jong, E.C.; Kapsenberg, M.L. 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.
30. Kalinski, P.; Hilkens, C.M.; Snijders, A.; Snijdewint, F.G.; Kapsenberg, M.L. IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine production in maturing human naive T helper cells. J. Immunol. 1997, 159, 28–35.
31. Kuroda, E.; Sugiura, T.; Okada, K.; Zeki, K.; Yamashita, U. Prostaglandin E2 up-regulates macrophage-derived chemokine production but suppresses IFN-inducible protein-10 production by APC. J. Immunol. 2001, 166, 1650–1658.
32. Lebre, M.C.; Burwell, T.; Vieira, P.L.; Lora, J.; Coyle, A.J.; Kapsenberg, M.L.; Clausen, B.E.; de Jong, E.C. Differential expression of inflammatory chemokines by Th1-and Th2-cell promoting dendritic cells: A role for different mature dendritic cell populations in attracting appropriate effector cells to peripheral sites of inflammation. Immunol. Cell Biol. 2005, 83, 525–535.
33. McIlroy, A.; Caron, G.; Blanchard, S.; Fremaux, I.; Duluc, D.; Delneste, Y.; Chevailler, A.; Jeannin, P. Histamine and prostaglandin E up-regulate the production of Th2-attracting chemokines (CCL17 and CCL22) and down-regulate IFN-gamma-induced CXCL10 production by immature human dendritic cells. Immunology 2006, 117, 507–516.
34. Sinha, P.; Clements, V.K.; Fulton, A.M.; Ostrand-Rosenberg, S. Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res. 2007, 67, 4507–4513.
35. Ochoa, A.C.; Zea, A.H.; Hernandez, C.; Rodriguez, P.C. Arginase, prostaglandins, and myeloid-derived suppressor cells in renal cell carcinoma. Clin. Cancer Res. 2007, 13, 721s–726s.
36. Rodriguez, P.C.; Ochoa, A.C. Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: Mechanisms and therapeutic perspectives. Immunol. Rev. 2008, 222, 180–191.
37. Fujita, M.; Kohanbash, G.; Fellows-Mayle, W.; Hamilton, R.L.; Komohara, Y.; Decker, S.A.; Ohlfest, J.R.; Okada, H. COX-2 blockade suppresses gliomagenesis by inhibiting myeloid-derived suppressor cells. Cancer Res. 2011, 71, 2664–2674.
38. Desbaillets, I.; Tada, M.; de, T.N.; Diserens, A.C.; Hamou, M.F.; van Meir, E.G. Human astrocytomas and glioblastomas express monocyte chemoattractant protein-1 (MCP-1) in vivo and in vitro. Int. J. Cancer 1994, 58, 240–247.
39. Takeshima, H.; Kuratsu, J.; Takeya, M.; Yoshimura, T.; Ushio, Y. Expression and localization of messenger RNA and protein for monocyte chemoattractant protein-1 in human malignant glioma. J. Neurosurg. 1994, 80, 1056–1062.
40. Salcedo, R.; Ponce, M.L.; Young, H.A.; Wasserman, K.; Ward, J.M.; Kleinman, H.K.; Oppenheim, J.J.; Murphy, W.J. Human endothelial cells express CCR2 and respond to MCP-1: Direct role of MCP-1 in angiogenesis and tumor progression. Blood 2000, 96, 34–40.
41. Huang, B.; Lei, Z.; Zhao, J.; Gong, W.; Liu, J.; Chen, Z.; Liu, Y.; Li, D.; Yuan, Y.; Zhang, G.M.; Feng, Z.H. CCL2/CCR2 pathway mediates recruitment of myeloid suppressor cells to cancers. Cancer Lett. 2007, 252, 86–92.
42. Jordan, J.T.; Sun, W.; Hussain, S.F.; Deangulo, G.; Prabhu, S.S.; Heimberger, A.B. Preferential migration of regulatory T cells mediated by glioma-secreted chemokines can be blocked with chemotherapy. Cancer Immunol. Immunother. 2008, 57, 123–131.
43. Fujita, M.; Scheurer, M.E.; Decker, S.A.; McDonald, H.A.; Kohanbash, G.; Kastenhuber, E.R.; Kato, H.; Bondy, M.L.; Ohlfest, J.R.; Okada, H. Role of type 1 IFNs in antiglioma immunosurveillance―Using mouse studies to guide examination of novel prognostic markers in humans. Clin. Cancer Res. 2010, 16, 3409–3419.
44. Zhu, X.; Fujita, M.; Snyder, L.A.; Okada, H. Systemic delivery of neutralizing antibody targeting CCL2 for glioma therapy. J. Neurooncol. 2011, 104, 83–92.
45. Kagi, D.; Vignaux, F.; Ledermann, B.; Burki, K.; Depraetere, V.; Nagata, S.; Hengartner, H.; Golstein, P. Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity. Science 1994, 265, 528–530.
46. Saas, P.; Walker, P.R.; Hahne, M.; Quiquerez, A.L.; Schnuriger, V.; Perrin, G.; French, L.; van Meir, E.G.; de Tribolet, N.; Tschopp, J.; et al. Fas ligand expression by astrocytoma in vivo: Maintaining immune privilege in the brain? J. Clin. Invest. 1997, 99, 1173–1178.
47. Walker, P.R.; Saas, P.; Dietrich, P.Y. Role of Fas ligand (CD95L) in immune escape: The tumor cell strikes back. J. Immunol. 1997, 158, 4521–4524.
48. Shinohara, H.; Yagita, H.; Ikawa, Y.; Oyaizu, N. Fas drives cell cycle progression in glioma cells via extracellular signal-regulated kinase activation. Cancer Res. 2000, 60, 1766–1772.
49. Poulaki, V.; Mitsiades, C.S.; Mitsiades, N. The role of Fas and FasL as mediators of anticancer chemotherapy. Drug Resist. Updat. 2001, 4, 233–242.
50. Xia, S.; Rosen, E.M.; Laterra, J. Sensitization of glioma cells to Fas-dependent apoptosis by chemotherapy-induced oxidative stress. Cancer Res. 2005, 65, 5248–5255.
51. Giraud, S.; Bessette, B.; Boda, C.; Lalloue, F.; Petit, D.; Mathonnet, M.; Jauberteau, M.O. In vitro apoptotic induction of human glioblastoma cells by Fas ligand plus etoposide and in vivo antitumour activity of combined drugs in xenografted nude rats. Int. J. Oncol. 2007, 30, 273–281.
52. Jansen, T.; Tyler, B.; Mankowski, J.L.; Recinos, V.R.; Pradilla, G.; Legnani, F.; Laterra, J.; Olivi, A. FasL gene knock-down therapy enhances the antiglioma immune response. Neuro-oncology 2010, 12, 482–489.
53. Ho, I.A.; Ng, W.H.; Lam, P.Y. FasL and FADD delivery by a glioma-specific and cell cycle-dependent HSV-1 amplicon virus enhanced apoptosis in primary human brain tumors. Mol. Cancer 2010, 9, e270.
54. McCoy, K.D.; Le Gros, G. The role of CTLA-4 in the regulation of T cell immune responses. Immunol. Cell Biol. 1999, 77, 1–10.
55. Friedline, R.H.; Brown, D.S.; Nguyen, H.; Kornfeld, H.; Lee, J.; Zhang, Y.; Appleby, M.; Der, S.D.; Kang, J.; Chambers, C.A. CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance. J. Exp. Med. 2009, 206, 421–434.
56. Fecci, P.E.; Ochiai, H.; Mitchell, D.A.; Grossi, P.M.; Sweeney, A.E.; Archer, G.E.; Cummings, T.; Allison, J.P.; Bigner, D.D.; Sampson, J.H. Systemic CTLA-4 blockade ameliorates glioma-induced changes to the CD4+ T cell compartment without affecting regulatory T-cell function. Clin. Cancer Res. 2007, 13, 2158–2167.
57. Agarwalla, P.; Barnard, Z.; Fecci, P.; Dranoff, G.; Curry, W.T., Jr. Sequential immunotherapy by vaccination with GM-CSF-expressing glioma cells and CTLA-4 blockade effectively treats established murine intracranial tumors. J. Immunother. 2012, 35, 385–389.
58. Chen, L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat. Rev. Immunol. 2004, 4, 336–347.
59. Wintterle, S.; Schreiner, B.; Mitsdoerffer, M.; Schneider, D.; Chen, L.; Meyermann, R.; Weller, M.; Wiendl, H. Expression of the B7-related molecule B7-H1 by glioma cells: A potential mechanism of immune paralysis. Cancer Res. 2003, 63, 7462–7467.
60. Parsa, A.T.; Waldron, J.S.; Panner, A.; Crane, C.A.; Parney, I.F.; Barry, J.J.; Cachola, K.E.; Murray, J.C.; Tihan, T.; Jensen, M.C.; et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat. Med. 2007, 13, 84–88.
61. Han, S.J.; Ahn, B.J.; Waldron, J.S.; Yang, I.; Fang, S.; Crane, C.A.; Pieper, R.O.; Parsa, A.T. Gamma interferon-mediated superinduction of B7-H1 in PTEN-deficient glioblastoma: A paradoxical mechanism of immune evasion. Neuro. Rep. 2009, 20, 1597–1602.
62. Crane, C.; Panner, A.; Pieper, R.O.; Arbiser, J.; Parsa, A.T. Honokiol-mediated inhibition of PI3K/mTOR pathway: A potential strategy to overcome immunoresistance in glioma, breast, and prostate carcinoma without impacting T cell function. J. Immunother. 2009, 32, 585–592.
63. Zeng, J.; See, A.P.; Phallen, J.; Jackson, C.M.; Belcaid, Z.; Ruzevick, J.; Durham, N.; Meyer, C.; Harris, T.J.; Albesiano, E.; et al. Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int. J. Radiat. Oncol. Biol. Phys. 2013, 86, 343–349.
64. Topalian, S.L.; Hodi, F.S.; Brahmer, J.R.; Gettinger, S.N.; Smith, D.C.; McDermott, D.F.; Powderly, J.D.; Carvajal, R.D.; Sosman, J.A.; Atkins, M.B.; et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 2012, 366, 2443–2454.
65. Brahmer, J.R.; Tykodi, S.S.; Chow, L.Q.; Hwu, W.J.; Topalian, S.L.; Hwu, P.; Drake, C.G.; Camacho, L.H.; Kauh, J.; Odunsi, K.; et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 2012, 366, 2455–2465.
66. Gabrilovich, D.I.; Ostrand-Rosenberg, S.; Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 2012, 12, 253–268.
67. Sica, A.; Schioppa, T.; Mantovani, A.; Allavena, P. Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: Potential targets of anti-cancer therapy. Eur. J. Cancer 2006, 42, 717–727.
68. Ohkura, N.; Kitagawa, Y.; Sakaguchi, S. Development and maintenance of regulatory T cells. Immunity 2013, 38, 414–423.
69. Condamine, T.; Gabrilovich, D.I. Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol. 2011, 32, 19–25.
70. Gabrilovich, D.I.; Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 2009, 9, 162–174.
71. Liu, C.Y.; Wang, Y.M.; Wang, C.L.; Feng, P.H.; Ko, H.W.; Liu, Y.H.; Wu, Y.C.; Chu, Y.; Chung, F.T.; Kuo, C.H.; et al. Population alterations of L-arginase-and inducible nitric oxide synthase-expressed CD11b+/CD14-/CD15+/CD33+ myeloid-derived suppressor cells and CD8+ T lymphocytes in patients with advanced-stage non-small cell lung cancer. J. Cancer Res. Clin. Oncol. 2010, 136, 35–45.
72. Schmielau, J.; Finn, O.J. Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of T-cell function in advanced cancer patients. Cancer Res. 2001, 61, 4756–4760.
73. Srivastava, M.K.; Sinha, P.; Clements, V.K.; Rodriguez, P.; Ostrand-Rosenberg, S. Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res. 2010, 70, 68–77.
74. Youn, J.I.; Gabrilovich, D.I. The biology of myeloid-derived suppressor cells: The blessing and the curse of morphological and functional heterogeneity. Eur. J. Immunol. 2010, 40, 2969–2975.
75. Walter, S.; Weinschenk, T.; Stenzl, A.; Zdrojowy, R.; Pluzanska, A.; Szczylik, C.; Staehler, M.; Brugger, W.; Dietrich, P.-Y.; Mendrzyk, R.; et al. Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat. Med. 2012, 18, 1254–1261.
76. Fecci, P.E.; Sweeney, A.E.; Grossi, P.M.; Nair, S.K.; Learn, C.A.; Mitchell, D.A.; Cui, X.; Cummings, T.J.; Bigner, D.D.; Gilboa, E.; 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.
77. Grauer, O.M.; Nierkens, S.; Bennink, E.; Toonen, L.W.; Boon, L.; Wesseling, P.; Sutmuller, R.P.; Adema, G.J. CD4+FoxP3+ regulatory T cells gradually accumulate in gliomas during tumor growth and efficiently suppress antiglioma immune responses in vivo. Int. J. Cancer 2007, 121, 95–105.
78. Maes, W.; Rosas, G.G.; Verbinnen, B.; Boon, L.; de Vleeschouwer, S.; Ceuppens, J.L.; van Gool, S.W. DC vaccination with anti-CD25 treatment leads to long-term immunity against experimental glioma. Neuro-oncology 2009, 11, 529–542.
79. Sampson, J.H.; Schmittling, R.J.; Archer, G.E.; Congdon, K.L.; Nair, S.K.; Reap, E.A.; Desjardins, A.; Friedman, A.H.; Friedman, H.S.; Herndon, J.E., 2nd; et al. A pilot study of IL-2Ralpha blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma. PLoS One 2012, 7, e31046.
80. Banissi, C.; Ghiringhelli, F.; Chen, L.; Carpentier, A.F. Treg depletion with a low-dose metronomic temozolomide regimen in a rat glioma model. Cancer Immunol. Immunother. 2009, 58, 1627–1634.
81. Czabanka, M.; Bruenner, J.; Parmaksiz, G.; Broggini, T.; Topalovic, M.; Bayerl, S.H.; Auf, G.; Kremenetskaia, I.; Nieminen, M.; Jabouille, A.; et al. Combined temozolomide and sunitinib treatment leads to better tumour control but increased vascular resistance in O-methylguanine methyltransferase-methylated gliomas. Eur. J. Cancer 2013, 49, 2243–2252.
82. D’Amico, R.; Lei, L.; Kennedy, B.C.; Sisti, J.; Ebiana, V.; Crisman, C.; Christensen, J.G.; Gil, O.; Rosenfeld, S.S.; Canoll, P.; et al. The addition of Sunitinib to radiation delays tumor growth in a murine model of glioblastoma. Neurol. Res. 2012, 34, 252–261.
83. Joshi, A.D.; Loilome, W.; Siu, I.M.; Tyler, B.; Gallia, G.L.; Riggins, G.J. Evaluation of tyrosine kinase inhibitor combinations for glioblastoma therapy. PLoS One 2012, 7, e44372.
84. Neyns, B.; Sadones, J.; Chaskis, C.; Dujardin, M.; Everaert, H.; Lv, S.; Duerinck, J.; Tynninen, O.; Nupponen, N.; Michotte, A.; et al. Phase II study of sunitinib malate in patients with recurrent high-grade glioma. J. Neurooncol. 2011, 103, 491–501.
85. Pan, E.; Yu, D.; Yue, B.; Potthast, L.; Chowdhary, S.; Smith, P.; Chamberlain, M. A prospective phase II single-institution trial of sunitinib for recurrent malignant glioma. J. Neurooncol. 2012, 110, 111–118.
86. Kreisl, T.N.; Smith, P.; Sul, J.; Salgado, C.; Iwamoto, F.M.; Shih, J.H.; Fine, H.A. Continuous daily sunitinib for recurrent glioblastoma. J. Neurooncol. 2013, 111, 41–48.
87. Niu, C.S.; Li, M.W.; Ni, Y.F.; Chen, J.M.; Mei, J.M.; Li, J.; Fu, X.M. Effect of all-trans retinoic acid on the proliferation and differentiation of brain tumor stem cells. J. Exp. Clin. Cancer Res. 2010, 29, e113.
88. Karsy, M.; Albert, L.; Tobias, M.E.; Murali, R.; Jhanwar-Uniyal, M. All-trans retinoic acid modulates cancer stem cells of glioblastoma multiforme in an MAPK-dependent manner. Anticancer Res. 2010, 30, 4915–4920.
89. Black, K.L.; Yin, D.; Ong, J.M.; Hu, J.; Konda, B.M.; Wang, X.; Ko, M.K.; Bayan, J.A.; Sacapano, M.R.; Espinoza, A.; et al. PDE5 inhibitors enhance tumor permeability and efficacy of chemotherapy in a rat brain tumor model. Brain Res. 2008, 1230, 290–302.
90. Raychaudhuri, B.; Rayman, P.; Ireland, J.; Ko, J.; Rini, B.; Borden, E.C.; Garcia, J.; Vogelbaum, M.A.; Finke, J. Myeloid-derived suppressor cell accumulation and function in patients with newly diagnosed glioblastoma. Neuro-oncology 2011, 13, 591–599.
91. Najjar, Y.G.; Finke, J.H. Clinical perspectives on targeting of myeloid derived suppressor cells in the treatment of cancer. Front. Oncol. 2013, 3, e49.
92. Nefedova, Y.; Fishman, M.; Sherman, S.; Wang, X.; Beg, A.A.; Gabrilovich, D.I. Mechanism of all-trans retinoic acid effect on tumor-associated myeloid-derived suppressor cells. Cancer Res. 2007, 67, 11021–11028.
93. Iclozan, C.; Antonia, S.; Chiappori, A.; Chen, D.T.; Gabrilovich, D. Therapeutic regulation of myeloid-derived suppressor cells and immune response to cancer vaccine in patients with extensive stage small cell lung cancer. Cancer Immunol. Immunother. 2013, 62, 909–918.
94. Mirza, N.; Fishman, M.; Fricke, I.; Dunn, M.; Neuger, A.M.; Frost, T.J.; Lush, R.M.; Antonia, S.; Gabrilovich, D.I. All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Res. 2006, 66, 9299–9307.
95. Lathers, D.M.; Clark, J.I.; Achille, N.J.; Young, M.R. Phase 1B study to improve immune responses in head and neck cancer patients using escalating doses of 25-hydroxyvitamin D3. Cancer Immunol. Immunother. 2004, 53, 422–430.
96. Hartmann, J.T.; Kanz, L. Sunitinib and periodic hair depigmentation due to temporary c-KIT inhibition. Arch. Dermatol. 2008, 144, 1525–1526.
97. Wood, L. Sunitinib malate for the treatment of renal cell carcinoma. Expert Opin. Pharmacother. 2012, 13, 1323–1336.
98. Van Cruijsen, H.; van der Veldt, A.A.; Vroling, L.; Oosterhoff, D.; Broxterman, H.J.; Scheper, R.J.; Giaccone, G.; Haanen, J.B.; van den Eertwegh, A.J.; Boven, E.; et al. Sunitinib-induced myeloid lineage redistribution in renal cell cancer patients: CD1c+ dendritic cell frequency predicts progression-free survival. Clin. Cancer Res. 2008, 14, 5884–5892.
99. Finke, J.H.; Rini, B.; Ireland, J.; Rayman, P.; Richmond, A.; Golshayan, A.; Wood, L.; Elson, P.; Garcia, J.; Dreicer, R.; et al. Sunitinib reverses type-1 immune suppression and decreases T-regulatory cells in renal cell carcinoma patients. Clin. Cancer Res. 2008, 14, 6674–6682.
100. Ozao-Choy, J.; Ma, G.; Kao, J.; Wang, G.X.; Meseck, M.; Sung, M.; Schwartz, M.; Divino, C.M.; Pan, P.Y.; Chen, S.H. The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res. 2009, 69, 2514–2522.
101. Ko, J.S.; Rayman, P.; Ireland, J.; Swaidani, S.; Li, G.; Bunting, K.D.; Rini, B.; Finke, J.H.; Cohen, P.A. Direct and differential suppression of myeloid-derived suppressor cell subsets by sunitinib is compartmentally constrained. Cancer Res. 2010, 70, 3526–3536.
102. Bose, A.; Taylor, J.L.; Alber, S.; Watkins, S.C.; Garcia, J.A.; Rini, B.I.; Ko, J.S.; Cohen, P.A.; Finke, J.H.; Storkus, W.J. Sunitinib facilitates the activation and recruitment of therapeutic anti-tumor immunity in concert with specific vaccination. Int. J. Cancer 2011, 129, 2158–2170.
103. Kujawski, M.; Zhang, C.; Herrmann, A.; Reckamp, K.; Scuto, A.; Jensen, M.; Deng, J.; Forman, S.; Figlin, R.; Yu, H. Targeting STAT3 in adoptively transferred T cells promotes their in vivo expansion and antitumor effects. Cancer Res. 2010, 70, 9599–9610.
104. Suzuki, E.; Kapoor, V.; Jassar, A.S.; Kaiser, L.R.; Albelda, S.M. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin. Cancer Res. 2005, 11, 6713–6721.
105. Vincent, J.; Mignot, G.; Chalmin, F.; Ladoire, S.; Bruchard, M.; Chevriaux, A.; Martin, F.; Apetoh, L.; Rebe, C.; Ghiringhelli, F. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res. 2010, 70, 3052–3061.
106. Rodriguez, P.C.; Hernandez, C.P.; Quiceno, D.; Dubinett, S.M.; Zabaleta, J.; Ochoa, J.B.; Gilbert, J.; Ochoa, A.C. Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma. J. Exp. Med. 2005, 202, 931–939.
107. Obermajer, N.; Muthuswamy, R.; Odunsi, K.; Edwards, R.P.; Kalinski, P. PGE2-induced CXCL12 production and CXCR4 expression controls the accumulation of human MDSCs in ovarian cancer environment. Cancer Res. 2011, 71, 7463–7470.
108. Serafini, P.; Meckel, K.; Kelso, M.; Noonan, K.; Califano, J.; Koch, W.; Dolcetti, L.; Bronte, V.; Borrello, I. Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J. Exp. Med. 2006, 203, 2691–2702.
109. Umansky, V.; Sevko, A. Overcoming immunosuppression in the melanoma microenvironment induced by chronic inflammation. Cancer Immunol. Immunother. 2012, 61, 275–282.
110. Giometto, B.; Bozza, F.; Faresin, F.; Alessio, L.; Mingrino, S.; Tavolato, B. Immune infiltrates and cytokines in gliomas. Acta Neurochir. 1996, 138, 50–56.
111. Komohara, Y.; Ohnishi, K.; Kuratsu, J.; Takeya, M. Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas. J. Pathol. 2008, 216, 15–24.
112. Alterman, R.L.; Stanley, E.R. Colony stimulating factor-1 expression in human glioma. Mol. Chem. Neuropathol. 1994, 21, 177–188.
113. Coniglio, S.J.; Eugenin, E.; Dobrenis, K.; Stanley, E.R.; West, B.L.; Symons, M.H.; Segall, J.E. Microglial stimulation of glioblastoma invasion involves epidermal growth factor receptor (EGFR) and colony stimulating factor 1 receptor (CSF-1R) signaling. Mol. Med. 2012, 18, 519–527.
114. Wang, S.C.; Hong, J.H.; Hsueh, C.; Chiang, C.S. Tumor-secreted SDF-1 promotes glioma invasiveness and TAM tropism toward hypoxia in a murine astrocytoma model. Lab. Invest. 2012, 92, 151–162.
115. Wang, H.; Zhang, L.; Zhang, I.Y.; Chen, X.; da Fonseca, A.; Wu, S.; Ren, H.; Badie, S.; Sadeghi, S.; Ouyang, M.; et al. S100B promotes glioma growth through chemoattraction of myeloid-derived macrophages. Clin. Cancer Res. 2013, 19, 3764–3775.
116. Pyonteck, S.M.; Akkari, L.; Schuhmacher, A.J.; Bowman, R.L.; Sevenich, L.; Quail, D.F.; Olson, O.C.; Quick, M.L.; Huse, J.T.; Teijeiro, V.; et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat. Med. 2013, 19, 1264–1272.
117. Bettinger, I.; Thanos, S.; Paulus, W. Microglia promote glioma migration. Acta Neuropathol. 2002, 103, 351–355.
118. Markovic, D.S.; Glass, R.; Synowitz, M.; Rooijen, N.; Kettenmann, H. Microglia stimulate the invasiveness of glioma cells by increasing the activity of metalloprotease-2. J. Neuropathol. Exp. Neurol. 2005, 64, 754–762.
119. Rao, J.S. Molecular mechanisms of glioma invasiveness: The role of proteases. Nat. Rev. Cancer 2003, 3, 489–501.
120. Ginhoux, F.; Greter, M.; Leboeuf, M.; Nandi, S.; See, P.; Gokhan, S.; Mehler, M.F.; Conway, S.J.; Ng, L.G.; Stanley, E.R.; et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 2010, 330, 841–845.
121. Ford, A.L.; Goodsall, A.L.; Hickey, W.F.; Sedgwick, J.D. Normal adult ramified microglia separated from other central nervous system macrophages by flow cytometric sorting. Phenotypic differences defined and direct ex vivo antigen presentation to myelin basic protein-reactive CD4+ T cells compared. J. Immunol. 1995, 154, 4309–4321.
122. Zou, J.P.; Morford, L.A.; Chougnet, C.; Dix, A.R.; Brooks, A.G.; Torres, N.; Shuman, J.D.; Coligan, J.E.; Brooks, W.H.; Roszman, T.L.; et al. Human glioma-induced immunosuppression involves soluble factor(s) that alters monocyte cytokine profile and surface markers. J. Immunol. 1999, 162, 4882–4892.
123. Okada, M.; Saio, M.; Kito, Y.; Ohe, N.; Yano, H.; Yoshimura, S.; Iwama, T.; Takami, T. Tumor-associated macrophage/microglia infiltration in human gliomas is correlated with MCP-3, but not MCP-1. Int. J. Oncol. 2009, 34, 1621–1627.
124. Nishie, A.; Ono, M.; Shono, T.; Fukushi, J.; Otsubo, M.; Onoue, H.; Ito, Y.; Inamura, T.; Ikezaki, K.; Fukui, M.; et al. Macrophage infiltration and heme oxygenase-1 expression correlate with angiogenesis in human gliomas. Clin. Cancer Res. 1999, 5, 1107–1113.
125. Zhai, H.; Heppner, F.L.; Tsirka, S.E. Microglia/macrophages promote glioma progression. Glia 2011, 59, 472–485.
126. Wei, J.; Gabrusiewicz, K.; Heimberger, A. The controversial role of microglia in malignant gliomas. Clin. Dev. Immunol. 2013, 2013, e285246.
127. Fecci, P.E.; Mitchell, D.A.; Whitesides, J.F.; Xie, W.; Friedman, A.H.; Archer, G.E.; Herndon, J.E.; Bigner, D.D.; Dranoff, G.; Sampson, J.H. 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.
128. Crane, C.A.; Ahn, B.J.; Han, S.J.; Parsa, A.T. Soluble factors secreted by glioblastoma cell lines facilitate recruitment, survival, and expansion of regulatory T cells: Implications for immunotherapy. Neuro-oncology 2012, 14, 584–595.
129. Wei, J.; Barr, J.; Kong, L.Y.; Wang, Y.; Wu, A.; Sharma, A.K.; Gumin, J.; Henry, V.; Colman, H.; Priebe, W.; et al. Glioblastoma cancer-initiating cells inhibit T-cell proliferation and effector responses by the signal transducers and activators of transcription 3 pathway. Mol. Cancer Ther. 2010, 9, 67–78.
130. Wei, J.; Wu, A.; Kong, L.Y.; Wang, Y.; Fuller, G.; Fokt, I.; Melillo, G.; Priebe, W.; Heimberger, A.B. Hypoxia potentiates glioma-mediated immunosuppression. PLoS One 2011, 6, e16195.
131. Wainwright, D.A.; Sengupta, S.; Han, Y.; Lesniak, M.S. Thymus-derived rather than tumor-induced regulatory T cells predominate in brain tumors. Neuro-oncology 2011, 13, 1308–1323.
132. Wainwright, D.A.; Balyasnikova, I.V.; Chang, A.L.; Ahmed, A.U.; Moon, K.S.; Auffinger, B.; Tobias, A.L.; Han, Y.; Lesniak, M.S. IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival. Clin. Cancer Res. 2012, 18, 6110–6121.
133. Fong, B.; Jin, R.; Wang, X.; Safaee, M.; Lisiero, D.N.; Yang, I.; Li, G.; Liau, L.M.; Prins, R.M. Monitoring of regulatory T cell frequencies and expression of CTLA-4 on T cells, before and after DC vaccination, can predict survival in GBM patients. PLoS One 2012, 7, e32614.
134. Grauer, O.M.; Sutmuller, R.P.; van Maren, W.; Jacobs, J.F.; Bennink, E.; Toonen, L.W.; Nierkens, S.; Adema, G.J. Elimination of regulatory T cells is essential for an effective vaccination with tumor lysate-pulsed dendritic cells in a murine glioma model. Int. J. Cancer 2008, 122, 1794–1802.
135. Maes, W.; Verschuere, T.; van Hoylandt, A.; Boon, L.; van Gool, S. Depletion of regulatory T cells in a mouse experimental glioma model through anti-CD25 treatment results in the infiltration of non-immunosuppressive myeloid cells in the brain. Clin. Dev. Immunol. 2013, 2013, e952469.
136. Lutsiak, M.E.; Semnani, R.T.; de Pascalis, R.; Kashmiri, S.V.; Schlom, J.; Sabzevari, H. Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 2005, 105, 2862–2868.
137. Dannull, J.; Su, Z.; Rizzieri, D.; Yang, B.K.; Coleman, D.; Yancey, D.; Zhang, A.; Dahm, P.; Chao, N.; Gilboa, E.; et al. Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J. Clin. Invest. 2005, 115, 3623–3633.
138. Morse, M.A.; Hobeika, A.C.; Osada, T.; Serra, D.; Niedzwiecki, D.; Lyerly, H.K.; Clay, T.M. Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines. Blood 2008, 112, 610–618.
139. Attia, P.; Powell, D.J., Jr.; Maker, A.V.; Kreitman, R.J.; Pastan, I.; Rosenberg, S.A. Selective elimination of human regulatory T lymphocytes in vitro with the recombinant immunotoxin LMB-2. J. Immunother. 2006, 29, 208–214.
140. De Rezende, L.C.; Silva, I.V.; Rangel, L.B.; Guimaraes, M.C. Regulatory T cell as a target for cancer therapy. Arch. Immunol. Ther. Exp. (Warsz.) 2010, 58, 179–190.
141. Bovenberg, M.S.; Degeling, M.H.; Tannous, B.A. Cell-based immunotherapy against gliomas: From bench to bedside. Mol. Ther. 2013, 21, 1297–1305.
142. Chow, K.H.; Gottschalk, S. Cellular immunotherapy for high-grade glioma. Immunotherapy 2011, 3, 423–434.
143. Schwartzentruber, D.J.; Lawson, D.H.; Richards, J.M.; Conry, R.M.; Miller, D.M.; Treisman, J.; Gailani, F.; Riley, L.; Conlon, K.; Pockaj, B.; et al. gp100 Peptide vaccine and interleukin-2 in patients with advanced melanoma. N. Engl. J. Med. 2011, 364, 2119–2127.
144. Wikstrand, C.J.; Bigner, D.D. Immunobiologic aspects of the brain and human gliomas. A review. Am. J. Pathol. 1980, 98, 517–568.
145. Neller, M.A.; López, J.A.; Schmidt, C.W. Antigens for cancer immunotherapy. Semin. Immunol. 2008, 20, 286–295.
146. Prins, R.M.; Wang, X.; Soto, H.; Young, E.; Lisiero, D.N.; Fong, B.; Everson, R.; Yong, W.H.; Lai, A.; Li, G.; et al. Comparison of glioma-associated antigen peptide-loaded versus autologous tumor lysate-loaded dendritic cell vaccination in malignant glioma patients. J. Immunother. 2013, 36, 152–157.
147. Zhang, J.G.; Eguchi, J.; Kruse, C.A.; Gomez, G.G.; Fakhrai, H.; Schroter, S.; Ma, W.; Hoa, N.; Minev, B.; Delgado, C.; et al. Antigenic profiling of glioma cells to generate allogeneic vaccines or dendritic cell-based therapeutics. Clin. Cancer Res. 2007, 13, 566–575.
148. Sloan, A.E.; Dansey, R.; Zamorano, L.; Barger, G.; Hamm, C.; Diaz, F.; Baynes, R.; Wood, G. Adoptive immunotherapy in patients with recurrent malignant glioma: Preliminary results of using autologous whole-tumor vaccine plus granulocyte-macrophage colony-stimulating factor and adoptive transfer of anti-CD3-activated lymphocytes. Neurosurg. Focus 2000, 9, e9.
149. Schneider, T.; Gerhards, R.; Kirches, E.; Firsching, R. Preliminary results of active specific immunization with modified tumor cell vaccine in glioblastoma multiforme. J. Neurooncol. 2001, 53, 39–46.
150. Steiner, H.H.; Bonsanto, M.M.; Beckhove, P.; Brysch, M.; Geletneky, K.; Ahmadi, R.; Schuele-Freyer, R.; Kremer, P.; Ranaie, G.; Matejic, D.; et al. Antitumor vaccination of patients with glioblastoma multiforme: A pilot study to assess feasibility, safety, and clinical benefit. J. Clin. Oncol. 2004, 22, 4272–4281.
151. Ishikawa, E.; Tsuboi, K.; Yamamoto, T.; Muroi, A.; Takano, S.; Enomoto, T.; Matsumura, A.; Ohno, T. Clinical trial of autologous formalin-fixed tumor vaccine for glioblastoma multiforme patients. Cancer Sci. 2007, 98, 1226–1233.
152. Banchereau, J.; Briere, F.; Caux, C.; Davoust, J.; Lebecque, S.; Liu, Y.J.; Pulendran, B.; Palucka, K. Immunobiology of dendritic cells. Annu. Rev. Immunol. 2000, 18, 767–811.
153. Yu, J.S.; Wheeler, C.J.; Zeltzer, P.M.; Ying, H.; Finger, D.N.; Lee, P.K.; Yong, W.H.; Incardona, F.; Thompson, R.C.; Riedinger, M.S.; 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.
154. Liau, L.M.; Prins, R.M.; Kiertscher, S.M.; Odesa, S.K.; Kremen, T.J.; Giovannone, A.J.; Lin, J.W.; Chute, D.J.; Mischel, P.S.; Cloughesy, T.F.; 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.
155. Yamanaka, R.; Abe, T.; Yajima, N.; Tsuchiya, N.; Homma, J.; Kobayashi, T.; Narita, M.; Takahashi, M.; Tanaka, R. 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 2003, 89, 1172–1179.
156. Yamanaka, R.; Homma, J.; Yajima, N.; Tsuchiya, N.; Sano, M.; Kobayashi, T.; Yoshida, S.; Abe, T.; Narita, M.; Takahashi, M.; 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, 4160–4167.
157. Wheeler, C.J.; Black, K.L.; Liu, G.; Mazer, M.; Zhang, X.X.; Pepkowitz, S.; Goldfinger, D.; Ng, H.; Irvin, D.; Yu, J.S. Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients. Cancer Res. 2008, 68, 5955–5964.
158. De Vleeschouwer, S.; Fieuws, S.; Rutkowski, S.; Van, C.F.; Van, L.J.; Goffin, J.; Sciot, R.; Wilms, G.; Demaerel, P.; Warmuth-Metz, M.; et al. Postoperative adjuvant dendritic cell-based immunotherapy in patients with relapsed glioblastoma multiforme. Clin. Cancer Res. 2008, 14, 3098–3104.
159. Ardon, H.; van Gool, S.; Lopes, I.S.; Maes, W.; Sciot, R.; Wilms, G.; Demaerel, P.; Bijttebier, P.; Claes, L.; Goffin, J.; et al. Integration of autologous dendritic cell-based immunotherapy in the primary treatment for patients with newly diagnosed glioblastoma multiforme: A pilot study. J. Neurooncol. 2010, 99, 261–272.
160. Prins, R.M.; Soto, H.; Konkankit, V.; Odesa, S.K.; Eskin, A.; Yong, W.H.; Nelson, S.F.; Liau, L.M. Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clin. Cancer Res. 2011, 17, 1603–1615.
161. Fadul, C.E.; Fisher, J.L.; Hampton, T.H.; Lallana, E.C.; Li, Z.; Gui, J.; Szczepiorkowski, Z.M.; Tosteson, T.D.; Rhodes, C.H.; Wishart, H.A.; et al. Immune response in patients with newly diagnosed glioblastoma multiforme treated with intranodal autologous tumor lysate-dendritic cell vaccination after radiation chemotherapy. J. Immunother. 2011, 34, 382–389.
162. Cho, D.Y.; Yang, W.K.; Lee, H.C.; Hsu, D.M.; Lin, H.L.; Lin, S.Z.; Chen, C.C.; Harn, H.J.; Liu, C.L.; Lee, W.Y.; et al. Adjuvant immunotherapy with whole-cell lysate dendritic cells vaccine for glioblastoma multiforme: A phase II clinical trial. World Neurosurg. 2012, 77, 736–744.
163. Izumoto, S.; Tsuboi, A.; Oka, Y.; Suzuki, T.; Hashiba, T.; Kagawa, N.; Hashimoto, N.; Maruno, M.; Elisseeva, O.A.; Shirakata, T.; et al. Phase II clinical trial of Wilms tumor 1 peptide vaccination for patients with recurrent glioblastoma multiforme. J. Neurosurg. 2008, 108, 963–971.
164. Otto, K.; Andersen, M.H.; Eggert, A.; Keikavoussi, P.; Pedersen, L.O.; Rath, J.C.; Bock, M.; Brocker, E.B.; Straten, P.T.; Kampgen, E.; et al. Lack of toxicity of therapy-induced T cell responses against the universal tumour antigen survivin. Vaccine 2005, 23, 884–889.
165. Uematsu, M.; Ohsawa, I.; Aokage, T.; Nishimaki, K.; Matsumoto, K.; Takahashi, H.; Asoh, S.; Teramoto, A.; Ohta, S. Prognostic significance of the immunohistochemical index of survivin in glioma: A comparative study with the MIB-1 index. J. Neurooncol. 2005, 72, 231–238.
166. Ciesielski, M.; Ahluwalia, M.; Munich, S.; Orton, M.; Barone, T.; Chanan-Khan, A.; Fenstermaker, R. Antitumor cytotoxic T-cell response induced by a survivin peptide mimic. Cancer Immunol. Immunother. 2010, 59, 1211–1221.
167. Hatanpaa, K.J.; Burma, S.; Zhao, D.; Habib, A.A. Epidermal growth factor receptor in glioma: Signal transduction, neuropathology, imaging, and radioresistance. Neoplasia 2010, 12, 675–684.
168. Gupta, P.; Han, S.-Y.; Holgado-Madruga, M.; Mitra, S.; Li, G.; Nitta, R.; Wong, A. Development of an EGFRvIII specific recombinant antibody. BMC Biotechnol. 2010, 10, e72.
169. Wong, A.; Bigner, S.; Bigner, D.; Kinzler, K.; Hamilton, S.; Vogelstein, B. Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc. Natl. Acad. Sci. USA 1987, 84, 6899–6903.
170. Friguet, B.; Chaffotte, A.; Djavadi-Ohaniance, L.; Goldberg, M. Measurements of the true affinity constant in solution of antigen-antibody complexes by enzyme-linked immunosorbent assay. J. Immunol. Methods 1985, 77, 305–319.
171. Mukasa, A.; Wykosky, J.; Ligon, K.; Chin, L.; Cavenee, W.; Furnari, F. Mutant EGFR is required for maintainenece of glioma growth in vivo, and its ablation leads to escape from receptor dependence. Proc. Natl. Acad. Sci. USA 2010, 107, 2616–2621.
172. Heimberger, A.B.; Suki, D.; Yang, D.; Shi, W.; Aldape, K. The natural history of EGFR and EGFRvIII in glioblastoma patients. J. Transl. Med. 2005, 3, e38.
173. Heimberger, A.B.; Hlatky, R.; Suki, D.; Yang, D.; Weinberg, J.; Gilbert, M.; Sawaya, R.; Aldape, K. Prognostic effect of epidermal growth factor receptor and EGFRvIII in glioblastoma multiforme patients. Clin. Cancer Res. 2005, 11, 1462–1466.
174. Sampson, J.H.; Heimberger, A.B.; Archer, G.E.; Aldape, K.D.; Friedman, A.H.; Friedman, H.S.; Gilbert, M.R.; Herndon, J.E.; McLendon, R.E.; Mitchell, D.A.; et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J. Clin. Oncol. 2010, 28, 4722–4729.
175. Vanderlugt, C.L.; Miller, S.D. Epitope spreading in immune-mediated diseases: Implications for immunotherapy. Nat. Rev. Immunol. 2002, 2, 85–95.
176. Yajima, N.; Yamanaka, R.; Mine, T.; Tsuchiya, N.; Homma, J.; Sano, M.; Kuramoto, T.; Obata, Y.; Komatsu, N.; Arima, Y.; et al. Immunologic evaluation of personalized peptide vaccination for patients with advanced malignant glioma. Clin. Cancer Res. 2005, 11, 5900–5911.
177. Terasaki, M.; Shibui, S.; Narita, Y.; Fujimaki, T.; Aoki, T.; Kajiwara, K.; Sawamura, Y.; Kurisu, K.; Mineta, T.; Yamada, A.; et al. Phase I trial of a personalized peptide vaccine for patients positive for human leukocyte antigen-A24 with recurrent or progressive glioblastoma multiforme. J. Clin. Oncol. 2011, 29, 337–344.
178. Phuphanich, S.; Wheeler, C.J.; Rudnick, J.D.; Mazer, M.; Wang, H.; Nuno, M.A.; Richardson, J.E.; Fan, X.; Ji, J.; Chu, R.M.; et al. Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunol. Immunother. 2012, 62, 125–135.
179. Nishimura, F.; Dusak, J.E.; Eguchi, J.; Zhu, X.; Gambotto, A.; Storkus, W.J.; Okada, H. Adoptive transfer of Type 1 CTL mediates effective anti-central nervous system tumor response: Critical roles of IFN-inducible protein-10. Cancer Res. 2006, 66, 4478–4487.
180. Fujita, M.; Zhu, X.; Sasaki, K.; Ueda, R.; Low, K.L.; Pollack, I.F.; Okada, H. Inhibition of STAT3 promotes the efficacy of adoptive transfer therapy using type-1 CTLs by modulation of the immunological microenvironment in a murine intracranial glioma. J. Immunol. 2008, 180, 2089–2098.
181. Zhu, X.; Fallert-Junecko, B.; Fujita, M.; Ueda, R.; Kohanbash, G.; Kastenhuber, E.; McDonald, H.; Liu, Y.; Kalinski, P.; Reinhart, T.; et al. Poly-ICLC promotes the infiltration of effector T cells into intracranial gliomas via induction of CXCL10 in IFN-α and IFN-γ dependent manners. Cancer Immunol. Immunother. 2010, 59, 1401–1409.
182. Zhu, X.; Nishimura, F.; Sasaki, K.; Fujita, M.; Dusak, J.E.; Eguchi, J.; Fellows-Mayle, W.; Storkus, W.J.; Walker, P.R.; Salazar, A.M.; et al. Toll like receptor-3 ligand poly-ICLC promotes the efficacy of peripheral vaccinations with tumor antigen-derived peptide epitopes in murine CNS tumor models. J. Transl. Med. 2007, 5, e10.
183. Okada, H.; Kalinski, P.; Ueda, R.; Hoji, A.; Kohanbash, G.; Donegan, T.E.; Mintz, A.H.; Engh, J.A.; Bartlett, D.L.; Brown, C.K.; et al. Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with {alpha}-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma. J. Clin. Oncol. 2011, 29, 330–336.
184. Iwami, K.; Shimato, S.; Ohno, M.; Okada, H.; Nakahara, N.; Sato, Y.; Yoshida, J.; Suzuki, S.; Nishikawa, H.; Shiku, H.; et al. Peptide-pulsed dendritic cell vaccination targeting interleukin-13 receptor alpha2 chain in recurrent malignant glioma patients with HLA-A*24/A*02 allele. Cytotherapy 2012, 14, 733–742.
185. Dutoit, V.; Herold-Mende, C.; Hilf, N.; Schoor, O.; Beckhove, P.; Bucher, J.; Dorsch, K.; Flohr, S.; Fritsche, J.; Lewandrowski, P.; et al. Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy. Brain 2012, 135, 1042–1054.
186. Ardon, H.; de Vleeschouwer, S.; van Calenbergh, F.; Claes, L.; Kramm, C.M.; Rutkowski, S.; Wolff, J.E.; van Gool, S.W. Adjuvant dendritic cell-based tumour vaccination for children with malignant brain tumours. Pediatr. Blood Cancer 2010, 54, 519–525.
187. Caruso, D.A.; Orme, L.M.; Neale, A.M.; Radcliff, F.J.; Amor, G.M.; Maixner, W.; Downie, P.; Hassall, T.E.; Tang, M.L.; Ashley, D.M. Results of a phase 1 study utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children and young adults with brain cancer. Neuro-oncology 2004, 6, 236–246.
188. Pollack, I.F.; Jakacki, R.I.; Butterfield, L.H.; Okada, H. Results of a pilot study to evaluate the effects of vaccinations with HLA-A2 restricted glioma antigen-peptides in combination with poly-ICLC for children with newly diagnosed malignant brainstem gliomas, non-brainstem high-grade gliomas, or recurrent unresectable gliomas. Neuro-oncology 2011, 13, 34–40.
189. Pollack, I.F.; Jakacki, R.I.; Butterfield, L.H.; Okada, H. Peptide vaccine therapy for childhood gliomas. J. Neurosurg. 2012, 60, 113–119.
190. Prins, R.M.; Craft, N.; Bruhn, K.W.; Khan-Farooqi, H.; Koya, R.C.; Stripecke, R.; Miller, J.F.; Liau, L.M. The TLR-7 agonist, imiquimod, enhances dendritic cell survival and promotes tumor antigen-specific T cell priming: Relation to central nervous system antitumor immunity. J. Immunol. 2006, 176, 157–164.