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Immunotherapy of Cancer pp 331–353Cite as

Manipulating Immunological Checkpoints to Maximize Antitumor Immunity

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Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Initial clinical trials have demonstrated the safety and bioactivity of cancer vaccines, but vaccine-induced immune responses have seldom translated into clinically meaningful tumor regressions, particularly in advanced disease. It is increasingly clear that tumor-specific immune tolerance represents a layered system of controls that keep the immune system turned off. Immunoregulatory checkpoints map locoregionally to the tumor microenvironment and draining lymph nodes, and arise from the dynamic interactions between the tumor and the immune system. It is now apparent that cancer vaccines will have to be combined with other therapeutics that abrogate immune tolerance, further amplify vaccine-induced T-cell responses, or modify the tumor microenvironment to make it more conducive to the concerted action of innate and antigen-specific immune effector mechanisms. Here, we review the host-tumor dynamic from the perspective of immune tolerance and review current data supporting the integration of cancer vaccines with standard and novel therapeutic agents that can maximize their activity.

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References

  1. Emens LA, Jaffee EM. Cancer vaccines: an old idea comes of age. Cancer Biol Ther 2003; 2(Suppl 1):S161–S168.

    PubMed  Google Scholar 

  2. Walker LS, Abbas AK. The enemy within: keeping self-reactive T cells at bay in the periphery. Nat Rev Immunol 2001; 21:11–19.

    Google Scholar 

  3. Marincola FM, Jaffee EM, Hicklin DJ, Ferrone S. Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv Immunol 2000; 74:181–273.

    PubMed  CAS  Google Scholar 

  4. Spaner DE. Amplifying cancer vaccine responses by modifying pathogenic gene programs in tumor cells. J Leukoc Biol 2004; 76:338–351.

    Article  PubMed  CAS  Google Scholar 

  5. Perez-Diaz A, Spiess PJ, Restifo NP, Matzinger P, Marincola FM. Intensity of the vaccine-elicited immune response determines tumor clearance. J Immunol 2002; 168:338–347.

    Google Scholar 

  6. Emens LA, Machiels J-PH, Reilly RT, Jaffee EM. Chemotherapy: friend or foe to cancer vaccines? Curr Opin Mol Ther 2001; 3:77–82.

    PubMed  CAS  Google Scholar 

  7. Pardoll DM. Spinning molecular immunology into successful immunotherapy. Nat Rev Immunol 2002; 2:227–238.

    Article  PubMed  CAS  Google Scholar 

  8. Carreno BM, Collins M. The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses. Annu Rev Immunol 2002; 20:29–53.

    Article  PubMed  CAS  Google Scholar 

  9. Egen JG, Kuhns MS, Allison JP. CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat Immunol 2002; 3:611–618.

    Article  PubMed  CAS  Google Scholar 

  10. Pentcheva-Hoang T, Egen JG, Wojnoonski K, Allison JP. B7-1 and B7-2 selectively recruit CTLA-4 and CD28 to the immunological synapse. Immunity 2004; 21:401–413.

    Article  PubMed  CAS  Google Scholar 

  11. Khoury SJ, Sayegh MH. The roles of the new negative T cell costimulatory pathways in regulating autoimmunity. Immunity 2004; 20:529–538.

    Article  PubMed  CAS  Google Scholar 

  12. McAdam AJ, Greenwald RJ, Levin MA, et al. ICOS is critical for CD40-mediated antibody class-switching. Nature 2001; 409:102–105.

    Article  PubMed  CAS  Google Scholar 

  13. Wallin JJ, Liang L, Bakardjiev A, Sha W. New regulatory co-receptors: inducible co-stimulator and PD-1. Curr Opin Immunol 2002; 14:779–782.

    Article  Google Scholar 

  14. Chapoval AI, Ni J, Lau JS, et al. B7-H3: a costimulatory molecule for T cell activation and IFN-γ production. Nat Immunol 2001; 2:269–274.

    Article  PubMed  CAS  Google Scholar 

  15. Luo L, Chapoval AI, Flies DB, et al. B7-H3 enhances tumor immunity in vivo by costimulating rapid clonal expansion of antigen-specific CD8+ cytolytic T cells. J Immunol 2004; 173:5445–5450.

    PubMed  CAS  Google Scholar 

  16. Sun X, Vale M, Leung E, Kanwar JR, Gupta R, Krissansen GW. Mouse B7-H3 induces antitumor immunity. Gene Ther 2003; 10:1728–1734.

    Article  PubMed  CAS  Google Scholar 

  17. Suh WK, Gajewska BU, Okada H, et al. The B7 family member B7-H3 preferentially down-regulates T helper type 1-mediated immune responses. Nat Immunol 2003; 4:899–906.

    Article  PubMed  CAS  Google Scholar 

  18. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2001; 2:261–268.

    Article  PubMed  CAS  Google Scholar 

  19. Tseng SY, Otsuji M, Gorski K, et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med 2001; 193:839–845.

    Article  PubMed  CAS  Google Scholar 

  20. Shin T, Kennedy G, Gorski K, et al. Cooperative B7-1/2 (CD80/86) and B7-DC costimulation of CD4+ T cells independent of the PD-1 receptor. J Exp Med 2003; 198:31–38.

    Article  PubMed  CAS  Google Scholar 

  21. Liu X, Gao JX, Wen J, et al. B7-DC/PD-L2 promotes tumor immunity by a PD-1-independent mechanism. J Exp Med 2003; 197:1721–1730.

    Article  PubMed  CAS  Google Scholar 

  22. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000; 192:1027–1034.

    Article  PubMed  CAS  Google Scholar 

  23. Sica GL, Choi IH, Zhu G, et al. B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. Immunity 2003; 18:849–861.

    Article  PubMed  CAS  Google Scholar 

  24. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002; 8:793–800.

    PubMed  CAS  Google Scholar 

  25. Croft M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nat Rev Immunol 2003; 3:609–620.

    Article  PubMed  CAS  Google Scholar 

  26. Tong AW, Stone MJ. Prospects for CD-40-directed experimental therapy of human cancer. Cancer Gene Ther 2002; 10:1–13.

    Article  CAS  Google Scholar 

  27. Yu P, Lee Y, Liu W, et al. Priming of naive T cells inside tumors leads to eradication of established tumors. Nat Immunol 2004; 5:141–149.

    Article  PubMed  CAS  Google Scholar 

  28. Bronte V, Serafini P, Mazzoni A, Segal D, Zanovello P. L-Arginine metabolism in myeloid cells controls T-lymphocyte functions. Trends Immunol 2003; 24:301–305.

    Article  CAS  Google Scholar 

  29. Young MR, Lathers DM. Myeloid progenitor cells mediate immune suppression in patients with head and neck cancers. Int J Immunopharmacol 1999; 21:241–252.

    Article  PubMed  CAS  Google Scholar 

  30. O’Garra A, Vierira P. Regulatory T cells and mechanisms of immune system control. Nat Med 2004; 10:801–805.

    Article  PubMed  CAS  Google Scholar 

  31. Pasare C, Medzhitov R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 2004; 299:1033–1036.

    Article  CAS  Google Scholar 

  32. Wang T, Niu G, Kortylewski M, et al. Regulation of the innate and adaptive immune responses by Stat-3-signaling in tumor cells. Nat Med 2004; 10:48–54.

    Article  PubMed  CAS  Google Scholar 

  33. Munn DH, Mellor AL. IDO and tolerance to tumors. Trends Mol Med 2004; 10:15–18.

    Article  PubMed  CAS  Google Scholar 

  34. Mellor AL, Munn DH. Tryptophan catabolism and regulation of adaptive immunity. J Immunol 2003; 170:5809–5813.

    PubMed  CAS  Google Scholar 

  35. Ferrone S, Finerty JF, Jaffee EM, Nabel GJ. How much longer will tumour cells fool the immune system? Immunol Today 2000; 21:70–72.

    Article  PubMed  CAS  Google Scholar 

  36. Hurwitz AA, Yu TF, Leach DR, Allison JP. CTLA-4 blockade synergizes with tumor-derived granulocyte-macrophage colony-stimulating factor for treatment of an experimental mammary carcinoma. Proc Natl Acad Sci USA 1998; 18:10,067–10,071.

    Article  Google Scholar 

  37. van Elsas A, Hurwitz AA, Allison JP. Combination immunotherapy of B16 melanoma using anticytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med 1999; 190:355–366.

    Article  PubMed  Google Scholar 

  38. Hodi FS, Mihm MC, Soiffer RJ, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen-4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci USA 2003; 100:4712–4717.

    Article  PubMed  CAS  Google Scholar 

  39. Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 2003; 100:8372–8377.

    Article  PubMed  CAS  Google Scholar 

  40. Radhakrishnan S, Nguyen LT, Ciric B, et al. Naturally occurring human IgM antibody that binds B7-DC and potentiates T cell stimulation by dendritic cells. J Immunol 2003; 170:1830–1838.

    PubMed  CAS  Google Scholar 

  41. Radhakrishnan S, Nguyen LT, Ciric B, et al. Immunotherapeutic potential of B7-DC (PD-L2) crosslinking antibody in conferring antitumor immunity. Cancer Res 2004; 64:4965–4972.

    Article  PubMed  CAS  Google Scholar 

  42. Curiel TJ, Wei S, Dong H, et al. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med 2003; 9:562–567.

    Article  PubMed  CAS  Google Scholar 

  43. Strome SE, Dong H, Tamura H, et al. B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res 2003; 63:6501–6505.

    PubMed  CAS  Google Scholar 

  44. Diehl L, den Boer AT, van der Voort EI, Melief CJ, Offringa R, Toes RE. The role of CD40 in peripheral T cell tolerance and immunity. J Mol Med 2000; 78:363–371.

    Article  PubMed  CAS  Google Scholar 

  45. Sotomayor EM, Borrello I, Tubb E, et al. Conversion of tumor-specific CD4+ T-cell tolerance to T-cell priming through in vivo ligation of CD40. Nat Med 1999; 5:780–787.

    Article  PubMed  CAS  Google Scholar 

  46. Sugamura K, Ishii N, Weinberg AD. Therapeutic targeting of the effector T-cell co-stimulatory molecule OX40. Nat Rev Immunol 2004; 4:420–431.

    Article  PubMed  CAS  Google Scholar 

  47. Bansal-Pakala P, Jember A-H, Croft M. Signaling through OX40 (CD134) breaks peripheral T-cell tolerance. Nat Med 2001; 7:907–902.

    Article  PubMed  CAS  Google Scholar 

  48. Maxwell JR, Weinberg A, Prell RA, Vella AT. Danger and OX40 receptor signaling synergize to enhance memory T cell survival by inhibiting peripheral deletion. J Immunol 2000; 164:107–112.

    PubMed  CAS  Google Scholar 

  49. Takeda I, Ine S, Killeen N, et al. Distinct roles for the OX40-OX40 ligand interaction in regulatory and nonregulatory T cells. J Immunol 2004; 172:3580–3589.

    PubMed  CAS  Google Scholar 

  50. Pan PY, Zang Y, Weber K, Meseck ML, Chen SH. OX40 ligation enhances primary and memory cytotoxic T lymphocyte responses in an immunotherapy for hepatic colon metastases. Mol Ther 2002; 6:528–536.

    Article  PubMed  CAS  Google Scholar 

  51. Gri G, Gallo E, Di Carlo E, Musiani P, Colombo MP. OX40 ligand-transduced tumor cell vaccine synergizes with GM-CSF and requires CD40-APC signaling to boost the host T cell antitumor response. J Immunol 2003; 170:99–106.

    PubMed  CAS  Google Scholar 

  52. Melero I, Shuford WW, Newby SA, et al. Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nat Med 1997; 3:682–685.

    Article  PubMed  CAS  Google Scholar 

  53. May KJ, Chen L, Zheng P, Liu Y. Anti-4-1BB monoclonal antibody enhances rejection of large tumor burden by promoting survival but not clonal expansion of tumor-specific CD8+ T cells. Cancer Res 2002; 62:3459–465.

    PubMed  CAS  Google Scholar 

  54. Wilcox RA, Flies DB, Zhu G, et al. Provision of antigen and CD137 signaling breaks immunological ignorance, promoting regression of poorly immunogenic tumors. J Clin Invest 2002; 109:651–659.

    Article  PubMed  CAS  Google Scholar 

  55. Hong HJ, Lee JW, Park SS, et al. A humanized anti-4-1BB monoclonal antibody suppresses antigeninduced humoral immune responses in nonhuman primates. J Immunother 2000; 23:613–621.

    Article  PubMed  CAS  Google Scholar 

  56. Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 1999; 59:3128–3133.

    PubMed  CAS  Google Scholar 

  57. Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S. Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 2002; 3:135–142.

    Article  PubMed  CAS  Google Scholar 

  58. Sutmuller RP, van Duivenvoorde LM, van Elsas A, et al. Synergism of cytotoxic T lymphocyte-associated antigen-4 blockade and depletion of CD25+ regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 2001; 194:824–832.

    Article  Google Scholar 

  59. Vieweg J, Su Z, Dannull J. Enhancement of antitumor immunity following depletion of CD4+CD25+ regulatory T cells. Proc Am Soc Clin Oncol 2004; Abstract no. 23:164.

    Google Scholar 

  60. Dyall R, Vasovic LV, Clynes RA, Nikolic-Zugic J. Cellular requirements for the monoclonal antibody-mediated eradication of an established solid tumor. Eur J Immunol 1999; 29:30–37.

    Article  PubMed  CAS  Google Scholar 

  61. Reilly RT, Machiels J-PH, Emens LA, et al. The collaboration of both humoral and cellular HER-2-targeted immune responses is required for the complete eradication of HER-2/neu-expressing tumors. Cancer Res 2001; 61:880–883.

    PubMed  CAS  Google Scholar 

  62. Reilly RT, Emens LA, Jaffee EM. Humoral and cellular immune responses: independent forces or collaborators in the fight against cancer? Curr Opin Invest Drugs 2001; 2:133–135.

    CAS  Google Scholar 

  63. Vasovic LV, Dyall R, Clynes RA, Ravetch JV, Nicolic-Zugic J. Synergy between an antibody and CD8+ cells in eliminating an established tumor. Eur J Immunol 1997; 27:374–382.

    Article  PubMed  CAS  Google Scholar 

  64. Wu CJ, Yang XF, McLaughlin S, et al. Detection of a potent humoral response associated with immuneinduced remission of chronic myelogenous leukemia. J Clin Invest 2000; 106:705–714.

    PubMed  CAS  Google Scholar 

  65. Yang XF, Wu CJ, McLaughlin S, et al. CML66, a broadly immunogenic tumor antigen, elicits a humoral immune response associated with remission of chronic myelogenous leukemia. Proc Natl Acad Sci USA 2001; 98:7492–7497.

    Article  PubMed  CAS  Google Scholar 

  66. Emens LA, Davidson NE. Trastuzumab in breast cancer. Oncology 2004; 18:1117–1128.

    PubMed  Google Scholar 

  67. Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med 2000; 6:443–446.

    Article  PubMed  CAS  Google Scholar 

  68. Gennari R, Menard S, Fagnoni F, et al. Pilot study of the mechanism of action of preoperative Trastuzumab in patients with primary operable breast tumors overexpressing HER2. Clin Cancer Res 2004; 10:5650–5645.

    Article  PubMed  CAS  Google Scholar 

  69. zum Buschenfelde CM, Hermann C, Schmidt B, Peschel C, Bernhard H. Antihuman epidermal growth factor receptor 2 (HER2) monoclonal antibody Trastuzumab enhances cytolytic activity of Class Irestricted HER2-specific T lymphocytes against HER2-overexpressing tumor cells. Cancer Res 2002; 62:2244–2247.

    Google Scholar 

  70. Castilleja A, Ward NE, O’Brian CA, et al. Accelerated HER-2 degradation enhances ovarian tumor recognition by CTL. Implications for tumor immunogenicity. Mol Cell Biochem 2001; 217:21–33.

    Article  PubMed  CAS  Google Scholar 

  71. Klapper LN, Waterman H, Sela M, Yarden Y. Tumor-inhibitory antibodies to HER-2/ErbB-2 may act by recruiting c-Cbl and enhancing ubiquitination of HER-2. Cancer Res 2000; 60:3384–3348.

    PubMed  CAS  Google Scholar 

  72. Wolpoe ME, Lutz ER, Ercolini AM, et al. HER-2/neu-specific monoclonal antibodies collaborate with HER-2-targeted granulocyte macrophage colony-stimulating factor secreting whole cell vaccination to augment CD8+ T cell effector function and tumor-free survival in HER-2/neu transgenic mice. J Immunol 2003; 15:2161–2169.

    Google Scholar 

  73. Jasinska J, Wagner S, Radauer C, et al. Inhibition of tumor cell growth by antibodies induced after vaccination with peptides derived from the extracellular domain of HER-2/neu. Int J Cancer 2003; 107:976–983.

    Article  PubMed  CAS  Google Scholar 

  74. Olszewski AJ, Grossbard ML. Empowering targeted therapy: lessons from Rituximab. Science STKE 2004; 241:pe30.

    Article  Google Scholar 

  75. Vega MI, Huerta-Yepaz S, Garban H, Jazirehi C, Emmanouilides C, Bonavida B. Rituximab inhibits p38 MAPK activity in 2F7 B NHL and decreases IL-10 transcription: pivotal role of p38 MAPK in drug resistance. Oncogene 2004; 23:3530–3540.

    Article  PubMed  CAS  Google Scholar 

  76. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004; 351:337–345.

    Article  PubMed  CAS  Google Scholar 

  77. Almand B, Resser JR, Lindman B, et al. Clinical significance of defective dendritic cell differentiation in cancer. Clin Cancer Res 2000; 6:1755–1766.

    PubMed  CAS  Google Scholar 

  78. Gabrilovich DI, Ishida T, Nadaf S, Ohm JE, Carbone DP. Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving dendritic cell function. Clin Cancer Res 1999; 5:2963–2970.

    PubMed  CAS  Google Scholar 

  79. von Mehren M, Arlen P, Gulley J, et al. The influence of granulocyte macrophage colony-stimulating factor and prior chemotherapy on the immunological response to a vaccine (ALVAC-CEA B7.1) in patients with metastatic carcinoma. Clin Cancer Res 2001; 7:1181–1191.

    Google Scholar 

  80. Thomas AM, Santarsiero LM, Lutz ER, et al. Mesothelin-specific CD8+ T cell responses provide evidence of in vivo cross-priming by antigen-presenting cells in vaccinated pancreatic cancer patients. J Exp Med 2004; 200:297–306.

    Article  PubMed  CAS  Google Scholar 

  81. Yuan L, Kuramitsu Y, Li Y, Kobayashi M, Hosokawa M. Restoration of interleukin-2 production in tumor-bearing rats through reduction of tumor-derived transforming growth factor β by treatment with Bleomycin. Cancer Immunol Immunother 1995; 41:355–341.

    Article  PubMed  CAS  Google Scholar 

  82. Gorelik L, Prokhorova A, and Mokyr MB. Low-dose melphalan-induced shift in the production of a Th2-type cytokine to a Th1-type cytokine in mice bearing a large MOPC-315 tumor. Cancer Immunol Immunother 1994; 39:117–125.

    PubMed  CAS  Google Scholar 

  83. Jovasevic VM, Mokyr MB. Melphalan-induced expression of IFN-β in MOPC-315 tumor-bearing mice and its importance for the up-regulation of TNF-α expression. J Immunol 2001; 167:4895–4901.

    PubMed  CAS  Google Scholar 

  84. Sojka DK, Donepudi M, Bluestone JA, Mokyr MB. Melphalan and other anticancer modalities up-regulate B7-1 gene expression in tumor cells. J Immunol 2000; 164:6230–5236.

    PubMed  CAS  Google Scholar 

  85. Serrano A, Tanzarella S, Lionello I, et al. Expression of HLA class I antigens and restoration of antigenspecific CTL response in melanoma cells following 5-aza-2′-deoxycytidine treatment. Int J Cancer 2001; 94:243–251.

    Article  PubMed  CAS  Google Scholar 

  86. Coral S, Sigalotti L, Altomonte M, et al. 5-Aza-2′-deoxycytidine-induced expression of functional cancer testis antigens in human renal cell carcinoma: immunotherapeutic implications. Clin Cancer Res 2002; 8:2690–2695.

    PubMed  CAS  Google Scholar 

  87. Correale P, Aquino A, Giuliani A, et al. Treatment of colon and breast carcinoma cells with 5-fluorouracil enhances expression of carcinoembryonic antigen and susceptibility to HLA-A*02.01 restricted, CEA-peptide-specific cytotoxic T cells in vitro. Int J Cancer 2003; 104:437–445.

    Article  PubMed  CAS  Google Scholar 

  88. Keane MM, Ettenberg SA, Nau MM, Russell EK, Lipkowitz S. Chemotherapy augments TRAIL-induced apoptosis in breast cell lines. Cancer Res 1999; 59:734–741.

    PubMed  CAS  Google Scholar 

  89. Zisman A, Ng CP, Pantuck AJ, Bonavida B, Belldegrun AS. Actinomycin D and Gemcitabine synergistically sensitize androgen-independent prostate cancer cells to Apo2/TRAIL-mediated apoptosis. J Immunother 2001; 24:459–471.

    Article  PubMed  CAS  Google Scholar 

  90. Nimmanapalli R, Perkins CL, Orlando M, O’Bryan E, Nguyen D, Bhalla KN. Pretreatment with Paclitaxel enhances Apo-2 ligand/tumor necrosis factor-related apoptosis ligand-induced apoptosis of prostate cancer cells by inducing death receptors 4 and 5 protein levels. Cancer Res 2001; 61:759–763.

    PubMed  CAS  Google Scholar 

  91. Demaria S, Volm MD, Shapiro RL, et al. Development of tumor-infiltrating lymphocytes in breast cancer after neoadjuvant paclitaxel chemotherapy. Clin Cancer Res 2001; 7:3025–3303.

    PubMed  CAS  Google Scholar 

  92. Kawasaki K, Akashi S, Shimazu R, Yoshida T, Miyake K, Nishijima M. Mouse toll-like receptor 4.MD-2 complex mediates lipopolysaccharide-mimetic signal transduction by Taxol. J Biol Chem 2000; 275:2251–2254.

    Article  PubMed  CAS  Google Scholar 

  93. Bryd-Leifer CA, Block EF, Takeda K, Akira S, Ding A. The role of MyD88 and TLR4 in the LPSmimetic activity of Taxol. Eur J Immunol 2001; 31:2448–2457.

    Article  Google Scholar 

  94. Wang J, Kobayashi M, Han M, et al. MyD88 is involved in the signaling pathway for Taxol-induced apoptosis and TNF-alpha expression in human myelomonocytic cells. Br J Haematol 2002; 118:638–645.

    Article  PubMed  CAS  Google Scholar 

  95. Hanahan D, Bergers G, Bergsland E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 2000; 105:1045–1047.

    Article  PubMed  CAS  Google Scholar 

  96. Bocci G, Nicolaou KC, Kerbel RS. Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic agents. Cancer Res 2002; 62:6938–6943.

    PubMed  CAS  Google Scholar 

  97. Nowak AK, Robinson BW, Lake RA. Gemcitabine exerts a selective effect on the humoral immune response: implications for combination chemo-immunotherapy. Cancer Res 2002; 62:2353–2358.

    PubMed  CAS  Google Scholar 

  98. Machiels J-PH, Reilly RT, Emens LA, et al. Cyclophosphamide, Doxorubicin, and Paclitaxel enhance the anti-tumor immune response of GM-CSF secreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Res 2001; 61:3689–3697.

    PubMed  CAS  Google Scholar 

  99. Schiavoni G, Mattei F, Di Pucchio T, Santini SM, Bracci L, Belardelli FE. Cyclophosphamide induced type I interferon and augments the number of CD44hi T lymphocytes in mice: implications for strategies of chemoimmunotherapy for cancer. Blood 2000; 95:20,224–20,230.

    Google Scholar 

  100. Ghiringhelli F, Larmonier N, Schmitt E, et al. CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to Cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol 2004; 34:336–344.

    Article  PubMed  CAS  Google Scholar 

  101. Mackall CL, Bare CV, Granger LA, Sharrow SO, Titus JA, Gress RE. Thymic-independent T cell regeneration occurs via antigen-driven expansion of peripheral T cells resulting in a repertoire that is limited in diversity and prone to skewing. J Immunol 1996; 156:4609–416.

    PubMed  CAS  Google Scholar 

  102. Eralp Y, Wang X, Wang JP, Maughan MF, Polo JM, Lachman LB. Doxorubicin and Paclitaxel enhance the antitumor efficacy of vaccines directed against HER-2/neu in a murine mammary carcinoma model. Breast Cancer Res 2004; 6:R275–R283.

    Article  PubMed  CAS  Google Scholar 

  103. Yu B, Kusmartsev S, Cheng F, et al. Effective combination of chemotherapy and dendritic cell administration for the treatment of advanced-stage experimental cancer. Clin Cancer Res 2003; 9:285–294.

    PubMed  CAS  Google Scholar 

  104. Nigam A, Yacavone RF, Zahurak ML, et al. Immunomodulatory properties of antineoplastic drugs administered in conjunction with GM-CSF-secreting cancer cell vaccines. Int J Cancer 1998; 12:161–170.

    CAS  Google Scholar 

  105. Reilly RT, Gottlieb MBC, Ercolini AM, et al. HER-2/neu is a tumor rejection target in tolerized HER-2/neu transgenic mice. Cancer Res 2000; 60:3569–3576.

    PubMed  CAS  Google Scholar 

  106. Ercolini AM, Machiels J-PH, Chen Y, et al. Identification and characterization of the immunodominant rat HER-2/neu MHC Class I epitope presented by spontaneous mammary tumors from HER-2/neu transgenic mice. J Immunol 2003; 170:4273–4280.

    PubMed  CAS  Google Scholar 

  107. Ercolini AM, Ladle BH, Manning EA, et al. Recruitment of latent pools of high avidity CD8+ T-cells to the antitumor immune response. J Exp Med 2005; 201:1591–1602.

    Article  PubMed  CAS  Google Scholar 

  108. Emens LA, Armstrong DK, Biedrzycki B, et al. A phase I vaccine safety and chemotherapy dose-finding trial of an allogeneic GM-CSF-secreting breast cancer vaccine given in a specifically timed sequence with immunomodulatory doses of Cyclophosphamide and Doxorubicin. Human Gene Ther 2004; 15:313–337.

    Article  CAS  Google Scholar 

  109. Goldrath AW, Bogatzki LY, Bevan MJ. Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation. J Exp Med 2000; 192:557–564.

    Article  PubMed  CAS  Google Scholar 

  110. 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.

    Article  PubMed  CAS  Google Scholar 

  111. Hu HM, Poehlein CH, Urba WJ, Fox BA. Development of antitumor immune responses in reconstituted lymphopenic hosts. Cancer Res 2002; 62:3914–3919.

    PubMed  CAS  Google Scholar 

  112. Borrello I, Sotomayor EM, Rattis FM, Cooke SK, Gu L, Levitsky HI. Sustaining the graft-versustumor effect through posttransplant immunization with granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing tumor vaccines. Blood 2000; 95:3011–3019.

    PubMed  CAS  Google Scholar 

  113. Teshima T, Mach N, Hill GR, et al. Tumor cell vaccine elicits potent antitumor immunity after allogeneic T-cell-depleted bone marrow transplantation. Cancer Res 2001; 61:162–171.

    PubMed  CAS  Google Scholar 

  114. Dummer W, Niethammer AG, Baccala R, et al. T cell homeostatic proliferation elicits effective antitumor autoimmunity. J Clin Invest 2002; 110:185–192.

    Article  PubMed  CAS  Google Scholar 

  115. Luznik L, Slansky JE, Jalla S, et al. Successful therapy of metastatic cancer using tumor vaccines in mixed allogeneic bone marrow chimeras. Blood 2003; 101:1645–1652.

    Article  PubMed  CAS  Google Scholar 

  116. 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.

    Article  PubMed  CAS  Google Scholar 

  117. Chakarborty M, Abrams SI, Coleman CN, Camphausen K, Schlom J, Hodge JW. External beam radiation of tumors alters phenotype of tumor cells to render them susceptible to vaccine-mediated T-cell killing. Cancer Res 2004; 64:4328–4337.

    Article  Google Scholar 

  118. Garnett CT, Palena C, Chakarborty M, Tsang KY, Schlom J, Hodge JW. Sublethal irradiation of human tumor cells modulates phenotype resulting in enhanced killing by cytotoxic T lymphocytes. Cancer Res 2004; 64:7985–7994.

    Article  PubMed  CAS  Google Scholar 

  119. Gasparini G, Longo R, Sarmiento R, Morabito A. Inhibitors of cyclooxygenase 2: a new class of anticancer agents? Lancet Oncol 2003; 4:605–615.

    Article  PubMed  CAS  Google Scholar 

  120. Huang M, Stolina M, Sharma S, et al. Non-small cell lung cancer cyclooxygenase-2-dependent regulation of cytokine balance in lymphocytes and macrophages: up-regulation of interleukin 10 and down-regulation of interleukin 12 production. Cancer Res 1998; 58:1208–1216.

    PubMed  CAS  Google Scholar 

  121. Sharma S, Stolina M, Yang SC, et al. Tumor cyclooxygenase 2-dependent suppression of dendritic cell function. Clin Cancer Res 2003; 9:961–968.

    PubMed  CAS  Google Scholar 

  122. Pockaj BA, Basu GD, Pathangey LB, et al. Reduced T-cell and dendritic cell function is related to cyclooxygenase-2 overexpression and prostaglandin E2 secretion in patients with breast cancer. Ann Surg Oncol 2004; 11:328–339.

    Article  PubMed  Google Scholar 

  123. Stolina M, Sharma S, Lin Y, et al. Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis. J Immunol 2000; 164:361–370.

    PubMed  CAS  Google Scholar 

  124. Zeytin HE, Patel AC, Rogers CJ, et al. Combination of a poxvirus-based vaccine with a cyclooxygenase-2 inhibitor (Celecoxib) elicits antitumor immunity and long-term survival in CEA.Tg/MIN mice. Cancer Res 2004; 64:3668–3678.

    Article  PubMed  CAS  Google Scholar 

  125. Wang H, Cheng F, Cuenca A, et al. Imatinib mesylate (STI-571) enhances antigen presenting cell function and overcomes tumor-induced CD4+ T-cell tolerance. Blood 2004; 105:1135–1143.

    Article  PubMed  CAS  Google Scholar 

  126. Gentilli S, Abruzzese E, Fanelli A, et al. Imatinib plus CMLVAX100 (p210-derived multipeptide vaccine): Induction of complete molecular responses in patients with CML showing persistent residual disease during treatment with Imatinib Mesylate. Blood 2003; 102:30a.

    Google Scholar 

  127. Li Z, Qiao Y, Laska E, et al. Autologous leukocyte-derived heat shock protein 70-peptide complex as a vaccine for chronic myelogenous leukemia in chronic phase: an updated phase I study. Blood 2003; 102:911a.

    Google Scholar 

  128. Do Y, Hegde VL, Nagarkatti PS, Nagarkatti M. Bryostatin-1 enhances the maturation and antigenpresenting ability of murine and human dendritic cells. Cancer Res 2004; 64:6756–6765.

    Article  PubMed  CAS  Google Scholar 

  129. Kos FJ, Cornell DL, Lipke AB, Graham LJ, Bear HD. Protective role of IL-2 during activation of T cells with bryostatin 1. Int J Immunopharm 2000; 22:645–652.

    Article  CAS  Google Scholar 

  130. Parviz M, Chin CS, Graham LJ, et al. Successful adoptive immunotherapy with vaccine-sensitized T cells, despite no effect with vaccination alone in a weakly immunogenic tumor model. Cancer Immunol Immunother 2003; 52:739–750.

    Article  PubMed  CAS  Google Scholar 

  131. Geissmann F, Revy P, Brousse N, et al. Retinoids regulate survival and antigen presentation by immature dendritic cells. J Exp Med 2003; 198:623–634.

    Article  PubMed  CAS  Google Scholar 

  132. Vertuani S, De Geer A, Levitsky V, Kogner P, Kiessling R, Levitskaya J. Retinoids act as multistep modulators of the major histocompatibility class I presentation pathway and sensitize neuroblastomas to cytotoxic lymphocytes. Cancer Res 2003; 63:8006–8013.

    PubMed  CAS  Google Scholar 

  133. Kusmartsev S, Cheng F, Yu B, et al. All-trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination. Cancer Res 2003; 63:4441–4449.

    PubMed  CAS  Google Scholar 

  134. Westervelt P, Pollock JL, Oldfather KM, et al. Adaptive immunity cooperates with liposomal all-transretinoic acid (ATRA) to facilitate long-term molecular remissions in mice with acute promyelocytic leukemia. Proc Natl Acad Sci USA 2002; 99:9468–9473.

    Article  PubMed  CAS  Google Scholar 

  135. Zuany-Amorim C, Hastewell J, Walker C. Toll-like receptors as potential therapeutic targets for multiple diseases. Nat Rev Drug Discov 2002; 1:797–807.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Oncology, The Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD

    Leisha A. Emens MD, PhD & R. Todd Reilly PhD

  2. Department of Oncology, Immunolog, Pathology, and Pharmacology, The Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD

    Elizabeth M. Jaffee MD

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  1. Leisha A. Emens MD, PhD
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  2. R. Todd Reilly PhD
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  3. Elizabeth M. Jaffee MD
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Editors and Affiliations

  1. University of Washington School of Medicine, Seattle, WA

    Mary L. Disis MD

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© 2006 Humana Press Inc., Totowa, NJ

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Emens, L.A., Reilly, R.T., Jaffee, E.M. (2006). Manipulating Immunological Checkpoints to Maximize Antitumor Immunity. In: Disis, M.L. (eds) Immunotherapy of Cancer. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1385/1-59745-011-1:331

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