Interleukin 21: Combination strategies for cancer therapy

Nature Reviews Drug Discovery

Volumn 7, Issue 3, 2008, Pages 231-240

  Skak, Kresten ^a   Kragh, Michael ^b   Hausman, Diana ^c   Smyth, Mark J ^d   Sivakumar, Pallavur V ^c  

^a NOVO NORDISK A S   (Denmark)

^b In Vivo Pharmacology   (Denmark)

^c Department of Clinical Research ^*  (Australia)

^d PETER MACCALLUM CANCER CENTRE   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA GALACTOSYLCERAMIDE; BEVACIZUMAB; CD40 LIGAND MONOCLONAL ANTIBODY; CETUXIMAB; CYTOSTATIC AGENT; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; DEATH RECEPTOR 4; DEATH RECEPTOR 5; DENDRITIC CELL VACCINE; DOXORUBICIN; GEMCITABINE; INTERLEUKIN 12; INTERLEUKIN 15; INTERLEUKIN 2; INTERLEUKIN 21; IPILIMUMAB; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 1; MONOCLONAL ANTIBODY; PACLITAXEL; PERFORIN; PROTEIN TYROSINE KINASE INHIBITOR; RECOMBINANT INTERLEUKIN 2; RITUXIMAB; SORAFENIB; SUNITINIB; TICILIMUMAB; TRANSCRIPTION FACTOR FOXP3; TRASTUZUMAB; UNINDEXED DRUG; WART VIRUS VACCINE;

ADJUVANT CHEMOTHERAPY; ADOPTIVE TRANSFER; ANTIANGIOGENIC ACTIVITY; ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; B CELL LYMPHOMA; BREAST CANCER; CANCER IMMUNOTHERAPY; CANCER INHIBITION; CANCER SURVIVAL; CAPILLARY LEAK SYNDROME; CLINICAL TRIAL; COLON CANCER; COLON CARCINOMA; COMBINATION CHEMOTHERAPY; CYTOTOXIC T LYMPHOCYTE; DIARRHEA; DRUG MEGADOSE; DRUG POTENTIATION; DRUG RECEPTOR BINDING; HUMAN; HUMAN PAPILLOMAVIRUS TYPE 11; HUMAN PAPILLOMAVIRUS TYPE 16; HUMAN PAPILLOMAVIRUS TYPE 18; HUMAN PAPILLOMAVIRUS TYPE 6; HYPONATREMIA; HYPOPHOSPHATEMIA; HYPOTENSION; IMMUNE RESPONSE; IMMUNOMODULATION; IMMUNOSUPPRESSIVE TREATMENT; KIDNEY CARCINOMA; KIDNEY METASTASIS; MELANOMA; MONOTHERAPY; MULTIPLE CANCER; MULTIPLE CYCLE TREATMENT; NATURAL KILLER CELL; NAUSEA; NEOPLASM; NEUTROPENIA; NONHODGKIN LYMPHOMA; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; RECOMMENDED DRUG DOSE; REVIEW; SEPSIS; SIDE EFFECT; T LYMPHOCYTE ACTIVATION; TACHYCARDIA; THROMBOCYTOPENIA; TUMOR IMMUNITY; UNSPECIFIED SIDE EFFECT; UTERINE CERVIX CANCER; VIRUS INFECTION; VOMITING; WART VIRUS;

ANIMALS; ANTINEOPLASTIC AGENTS; CLINICAL TRIALS AS TOPIC; HUMANS; INTERLEUKINS; NEOPLASMS;

EID: 40049093723     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd2482     Document Type: Review

References (131)

1. + T-cell memory in tumor immunology and immunotherapy. Immunol. Rev. 211, 214-224 (2006).
2. Thomas, E. D. & Blume, K. G. Historical markers in the development of allogeneic hematopoietic cell transplantation. Biol. Blood Marrow Transplant. 5, 341-346 (1999).
3. Barrett, A. J. & Savani, B. N. Stem cell transplantation with reduced-intensity conditioning regimens: A review of ten years experience with new transplant concepts and new therapeutic agents. Leukemia 20, 1661-1672 (2006).
4. Barrett, J. Improving outcome of allogeneic stem cell transplantation by immunomodulation of the early post-transplant environment. Curr. Opin. Immunol. 18, 592-598 (2006).
5. Faries, M. B. & Morton, D. L. Therapeutic vaccines for melanoma: Current Status. BioDrugs 19, 247-260 (2005).
6. Dudley, M. E. & Rosenberg, S. A. Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nature Rev. Cancer 3, 666-675 (2003).
7. Atallah, E. & Flaherty, L. Treatment of metastatic malignant melanoma. Curr. Treat. Options Oncol. 6, 185-193 (2005).
8. Yang, J. C. & Childs, R. Immunotherapy for renal cell cancer. J. Clin. Oncol. 24, 5576-5583 (2006).
9. Parton, M., Gore, M. & Eisen, T. Role of cytokine therapy in 2006 and beyond for metastatic renal cell cancer. J. Clin. Oncol. 24, 5584-5592 (2006).
10. Cheson, B. D. Monoclonal antibody therapy for B-cell malignancies. Semin. Oncol. 33, S2-S14 (2006).
11. Jackisch, C. HER-2-positive metastatic breast cancer: Optimizing trastuzumab-based therapy. Oncologist 11 (Suppl. 1), 34-41 (2006).
12. Arsene, D., Galais, M. P., Bouhier-Leporrier, K. & Reimund, J. M. Recent developments in colorectal cancer treatment by monoclonal antibodies. Expert Opin. Biol. Ther. 6, 1175-1192 (2006).
13. Cvetkovic, R. S. & Perry, C. M. Spotlight on rituximab in non-Hodgkin lymphoma and chronic lymphocytic leukemia. BioDrugs 20, 253-257 (2006).
14. Plosker, G. L. & Keam, S. J. Spotlight on trastuzumab in the management of HER2-positive metastatic and early-stage breast cancer. BioDrugs 20, 259-262 (2006).
15. Dalgleish, A. G. & Whelan, M. A. Cancer vaccines as a therapeutic modality: The long trek. Cancer Immunol. Immunother. 55, 1025-1032 (2006).
16. Atkins, M. B., Regan, M. & McDermott, D. Update on the role of interleukin 2 and other cytokines in the treatment of patients with stage IV renal carcinoma. Clin. Cancer Res. 10, 6342S-6346S (2004).
17. Kirkwood, J. M. et al. Phase II trial of iboctadekin (rhIL- 18) on a daily x5 schedule in metastatic melanoma (MM). J. Clin. Oncol. 24 (Suppl.), 10043 (2006).
18. Gollob, J. A. et al. Phase I Trial of twice-weekly intravenous interleukin 12 in patients with metastatic renal cell cancer or malignant melanoma: Ability to maintain IFN-γ induction is associated with clinical response. Clin. Cancer Res. 6, 1678-1692 (2000).
19. Parrish-Novak, J. et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 408, 57-63 (2000).
20. Coquet, J. M. et al. IL-21 is produced by NKT cells and modulates NKT cell activation and cytokine production. J. Immunol. 178 2827-2834 (2007).
21. Chtanova, T. et al. T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/ Th2 effector cells that provide help for B cells. J. Immunol. 173, 68-78 (2004).
22. Ostiguy, V., Allard, E. L., Marquis, M., Leignadier, J. & Labrecque, N. IL-21 promotes T lymphocyte survival by activating the phosphatidylinositol-3 kinase signaling cascade. J. Leukoc. Biol. 82, 645-656 (2007).
23. Spolski, R. & Leonard, W. J. Interleukin-21: Basic biology and implications for cancer and autoimmunity. Annu. Rev. Immunol. 8 Nov 2007 (doi:10.1146/ annurev.immunol.26.021607.090316).
24. Brady, J., Hayakawa, Y., Smyth, M. J. & Nutt, S. L. IL-21 induces the functional maturation of murine NK cells. J. Immunol. 172, 2048-2058 (2004).
25. Toomey, J.A, Gays, F., Foster, D., Brooks, C. G. Cytokine requirements for the growth and development of mouse NK cells in vitro. J. Leucoc. Biol. 74, 233-242 (2003).
26. + T cell expansion and function. J. Exp. Med. 201, 139-148 (2005).
27. Ozaki, K. et al. A critical role for IL21 in regulating immunoglobulin production. Science 298, 1630-1634 (2002).
28. + T cell-B cell collaboration. J. Immunol. 179, 5886-5896 (2007).
29. H-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nature Immunol. 8, 967-974 (2007).
30. H 17 cells. Nature 448, 484-487 (2007).
31. Nurieva, R. et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448, 480-483 (2007).
32. + CTL. Blood 5 Oct 2007 (doi:10.1182/blood-2007-05-089375).
33. Li, Y., Bleakley, M. & Yee, C. IL-21 Influences the frequency, phenotype, and affinity of the antigen-specific CD8 T cell response. J. Immunol. 175, 2261-2269 (2005).
34. Liu, S. et al. IL-21 synergizes with IL-7 to augment expansion and anti-tumor function of cytotoxic T cells. Int. Immunol. 19, 1213-1221 (2007).
35. + T lymphocytes. J. Immunol. 178, 732-739 (2007).
36. Leonard, W. J. & Spolski, R. Interleukin-21: A modulator of lymphoid proliferation, apoptosis and differentiation. Nature Rev. Immunol. 5, 688-698 (2005).
37. Nakano, H. et al. Interleukin-21 triggers both cellular and humoral immune responses leading to therapeutic antitumor effects against head and neck squamous cell carcinoma. J. Gene Med. 8 90-99 (2006).
38. Daga A et al. Glioma immunotherapy by IL-21 gene-modified cells or by recombinant IL-21 involves antibody responses. Int. J. Cancer 121, 1756-1763 (2007).
39. Wang, G. et al. In vivo antitumor activity of interleukin 21 mediated by natural killer cells. Cancer Res. 63, 9016-9022 (2003).
40. Takeda, K. et al. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nature Med. 7, 94-100 (2001).
41. Voskoboinik, I., Smyth, M. J. & Trapani, J. A. Perforin-mediated target-cell death and immune homeostasis. Nature Rev. Immunol. 6, 940-952 (2006).
42. Ma, H. L. et al. IL-21 activates both innate and adaptive immunity to generate potent antitumor responses that require perforin but are independent of IFN-γ. J. Immunol. 171, 608-615 (2003).
43. Roda, J. M. et al. Interleukin-21 enhances NK cell activation in response to antibody-coated targets. J. Immunol. 177, 120-129 (2006).
44. + cell precursors towards NK cells and acquisition of surface killer Ig-like receptors. Eur. J. Immunol. 33, 3439-3447 (2003).
45. + T cell responses to achieve durable tumor immunity: Comparative evaluation of IL-2, IL-15, and IL-21. J. Immunol. 173, 900-909 (2004).
46. + T cells and inhibits the growth of syngeneic tumors. Cancer Immunol. Immunother. 56, 1417-1428 (2007).
47. Ugai, S. et al. Expression of the interleukin-21 gene in murine colon carcinoma cells generates systemic immunity in the inoculated hosts. Cancer Gene Ther. 10, 187-192 (2003).
48. Di Carlo, E. et al. IL-21 induces tumor rejection by specific CTL and IFN-γ-dependent CXC chemokines in syngeneic mice. J. Immunol. 172, 1540-1547 (2004).
49. Furukawa, J. et al. Interleukin-21 gene transfection into mouse bladder cancer cells results in tumor rejection through the cytotoxic T lymphocyte response. J. Urol. 176, 1198-1203 (2006).
50. Davis, I. D. et al. An open-label, two-arm, phase I trial of recombinant human interleukin-21 in patients with metastatic melanoma. Clin. Cancer Res. 13, 3630-3636 (2007).
51. Casey, K. A. & Mescher, M. F. IL-21 promotes differentiation of naive CD8 T cells to a unique effector phenotype. J. Immunol. 178, 7640-7648 (2007).
52. Strengell, M. et al. IL-21 in synergy with IL-15 or IL-18 enhances IFN-γ production in human NK and T cells. J. Immunol. 170, 5464-5469 (2003).
53. Waldmann, T. A. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nature Rev. Immunol. 6, 595-601 (2006).
54. Atkins, M. B., Kunkel, L., Sznol, M. & Rosenberg, S. A. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J. Sci. Am. 6 (Suppl. 1), 11-14 (2000).
55. He, H. et al. Combined IL-21 and low-dos therapy induces anti-tumor immunity and long-term curative effects in a murine melanoma tumor model. J. Transt. Med. 4, 24 (2006).
56. + T cells. J. Immunol. 175, 755-762 (2005).
57. Kishida, T. et al. Interleukin (IL)-21 and IL-15 genetic transfer synergistically augments therapeutic antitumor immunity and promotes regression of metastatic lymphoma. Mol. Ther. 8, 552-558 (2003).
58. Crum, C., Jones, C. & Kirkpatrick, P. Quadrivalent human papillomavirus recombinant vaccine. Nature Rev Drug Discov. 5, 629-630 (2006).
59. Bolesta, E. et al. Increased level and longevity of protective immune responses induced by DNA vaccine expressing the HIV-1 Env glycoprotein when combined with IL-21 and IL-15 gene delivery. J. Immunol. 177, 177-191 (2006).
60. Johnston, J. B. et al. Targeting the EGFR pathway for cancer therapy. Curr. Med. Chem. 13, 3483-3492 (2006).
61. Cartron, G., Watier, H., Golay, J. & Solal-Celigny, P. From the bench to the bedside: Ways to improve rituximab efficacy. Blood 104, 2635-2642 (2004).
62. Dall'Ozzo, S. et al. Rituximab-dependent cytotoxicity by natural killer cells: Influence of FCGR3A polymorphism on the concentration-effect relationship. Cancer Res. 64, 4664-4669 (2004).
63. Cartron, G. et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in lgG Fc receptor FcγRIIIa gene. Blood 99, 754-758 (2002).
64. Weng, W. K. & Levy, R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J. Clin. Oncol. 21, 3940-3947 (2003).
65. Clynes, R. A., Towers, T. L., Presta, L. G. & Ravetch, J. V. Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nature Med. 6, 443-446 (2000).
66. Carson, W. E. et al. Interleukin-2 enhances the natural killer cell response to Herceptin-coated Her2/neu-positive breast cancer cells. Eur. J. Immunol. 31, 3016-3025 (2001).
67. Yamaguchi, Y. et al. HER2-specific cytotoxic activity of lymphokine-activated killer cells in the presence of trastuzumab. Anticancer Res. 25, 827-832 (2005).
68. Kawaguchi, Y. et al. Cetuximab induce antibody-dependent cellular cytotoxicity against EGFR-expressing esophageal squamous cell carcinoma. Int. J. Cancer 120, 781-787 (2007).
69. Frumento, G., Piazza, T., Di, C. E. & Ferrini, S. Targeting tumor-related immunasuppression for cancer immunotherapy. Endocr. Metab. Immune Disord. Drug Targets. 6, 233-237 (2006).
70. Peggs, K. S., Quezada, S. A., Korman, A. J. & Allison, J. P. Principles and use of anti-CTLA4 antibody in human cancer immunotherapy. Curr. Opin. Immunol. 18, 206-213 (2006).
71. Tivol, E. A. et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3, 541-547 (1995).
72. + T cells. Immunity 7, 885-895 (1997).
73. Robinson, M. R. et al. Cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma: A new cause of uveitis. J. Immunother. 27, 478-479 (2004).
74. Sanderson, K. et al. Autoimmunity in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and montanide ISA 51 for patients with resected stages III and IV melanoma. J. Clin. Oncol. 23, 741-750 (2005).
75. Phan, G. Q. 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 100, 8372-8377 (2003).
76. Beyer, M. & Schultze, J. L. Regulatory T cells in cancer. Blood 108, 804-811 (2006).
77. Needham, D. J., Lee, J. X. & Beilharz, M. W. Intratumoural regulatory T cells: A potential new target in cancer immunotherapy. Biochem. Biophys. Res. Commun. 343, 684-691 (2006).
78. + regulatory T cells enhances interleukin-2-induced antitumor immunity in a mouse model of colon adenocarcinoma. Cancer Sci. 98, 416-423 (2007).
79. + regulatory T cell depletion augments immunotherapy of micrometastases by an IL-21-secreting cellular vaccine. J. Immunol. 176, 1750-1758 (2006).
80. Godfrey, D. I., MacDonald, H. R., Kronenberg, M., Smyth, M. J. & Van, K. L. NKT cells: What's in a name? Nature Rev. Immunol. 4, 231-237 (2004).
81. Smyth, M. J. & Godfrey, D. I. NKT cells and tumor immunity - a double-edged sword. Nature Immunol. 1, 459-460 (2000).
82. Godfrey, D. I. & Kronenberg, M. Going both ways: Immune regulation via CD1d-dependent NKT cells. J. Clin. Invest. 114, 1379-1388 (2004).
83. Brigl, M. & Brenner, M. B. CD1: Antigen presentation and T cell function. Annu. Rev. Immunol. 22, 817-890 (2004).
84. Hayakawa, Y., Godfrey, D. I. & Smyth, M. J. α-Galactosylceramide: potential immunomodulatory activity and future application. Curr. Med. Chem. 11, 241-252 (2004).
85. Fujii, S., Shimizu, K., Smith, C., Bonifaz, L. & Steinman, R. M. Activation of natural killer T cells by α-galactosylceramide rapidly induces the full maturation of dendritic cells in vivo and thereby acts as an adjuvant for combined CD4 and CD8 T cell immunity to a coadministered protein. J. Exp. Med. 198, 267-279 (2003).
86. Kitamura, H. et al. The natural killer T (NKT) cell ligand α-galactosylceramide demonstrates its immunopotentiating effect by inducing interleukin (IL)-12 production by dendritic cells and IL-12 receptor expression on NKT cells. J. Exp. Med. 189, 1121-1128 (1999).
87. Giaccone, G. et al. A phase I study of the natural killer T-cell ligand α-galactosylceramide (KRN7000) in patients with solid tumors. Clin. Cancer Res. 8, 3702-3709 (2002).
88. Chang, D. H. et al. Sustained expansion of NKT cells and antigen-specific T cells after injection of α-galactosyl-ceramide loaded mature dendritic cells in cancer patients. J. Exp. Med. 201, 1503-1517 (2005).
89. + NKT cells in human subjects results in highly coordinated secondary activation of acquired and innate immunity. Blood 103, 383-389 (2004).
90. Smyth, M. J. et al. Sequential activation of NKT cells and NK cells provides effective innate immunotherapy of cancer. J. Exp. Med. 201, 1973-1985 (2005).
91. Chaudhari, B. R., Murphy, R. F. & Agrawal, D. K. Following the TRAIL to apoptosis. Immunol. Res. 35, 249-262 (2006).
92. Duiker, E. W. et al. The clinical trail of TRAIL. Eur. J. Cancer 42, 2233-2240 (2006).
93. Buchsbaum, D. J., Zhou, T. & Lobuglio, A. F. TRAIL receptor-targeted therapy. Future Oncol. 2, 493-508 (2006).
94. Buchsbaum, D. J. et al. Antitumor efficacy of TRA-8 anti-DR5 monoclonal antibody alone or in combination with chemotherapy and/or radiation therapy in a human breast cancer model. Clin. Cancer Res. 9, 3731-3741 (2003).
95. Naka, T. et al. Effects of tumor necrosis factor-related apoptosis-inducing ligand alone and in combination with chemotherapeutic agents on patients' colon tumors grown in SCID mice. Cancer Res. 62, 5800-5806 (2002).
96. Ichikawa, K. et al. Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity. Nature Med. 7, 954-960 (2001).
97. Takeda, K. et al. Induction of tumor-specific T cell immunity by anti-DR5 antibody therapy. J. Exp. Med. 199, 437-448 (2004).
98. Smyth, M. J. et al. IL-21 enhances tumor-specific CTL induction by anti-DR5 antibody therapy. J. Immunol. 176, 6347-6355 (2006).
99. Lake, R. A. & Robinson, B. W. Immunotherapy and chemotherapy - a practical partnership. Nature Rev. Cancer 5, 397-405 (2005).
100. Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nature Med. 13, 54-61 (2007).
101. Pressley J. S. & Elgert, K. D. Post-chemotherapeutic administration of interleukin-12 retards tumor growth and enhances immune cell function: combination therapy using paclitaxel and IL- 12. Cancer Invest. 24, 351-359 (2006).
102. Ewers, A. et al. Doxorubicin plus interleukin-2 chemoimmunotherapy against breast cancer in mice. Cancer Res. 66, 5419-5426 (2006).
103. Nowak, A. K., Robinson, B. W. & Lake, R. A. Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors. Cancer Res. 63, 4490-4496 (2003).
104. Fabian, M. A. et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nature Biotech. 23, 329-336 (2005).
105. Wilhelm, S. et al. Discovery and development of sorafenib: A multikinase inhibitor for treating cancer. Nature Rev. Drug Discov. 5, 835-844 (2006).
106. Mendel, D. B. et al. In vivo antitumor activity ofSU 11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: Determination of a pharmacokinetic/pharmacodynamic relationship. Clin. Cancer Res. 9, 327-337 (2003).
107. Liu, L. et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 66, 11851-11858 (2006).
108. Potapova, O. et al. Contribution of individual targets to the antitumor efficacy of the multitargeted receptor tyrosine kinase inhibitor SU 11248. Mol. Cancer Ther. 5, 1280-1289 (2006).
109. Chang, Y. S. et al. Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother. Pharmacol. 59, 561-574 (2007).
110. Jain, R. K. Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science 307, 58-62 (2005).
111. Taieb, J. et al. A novel dendritic cell subset involved in tumor immunosurveillance. Nature Med. 12, 214-219 (2006).
112. Gao, H. et al. Imatinib mesylate suppresses cytokine synthesis by activated CD4 T cells of patients with chronic myelogenous leukemia. Leukemia 19, 1905-1911 (2005).
113. Seggewiss, R. et al. Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner. Blood 105, 2473-2479 (2005).
114. Yang, S. & Haluska, F. G. Treatment of melanoma with 5-fluorouracil or dacarbazinc in vitro sensitizes cells to antigen-specific CTL lysis through perforin/ granzyme- and Fas-mediated pathways. J. Immunol. 172, 4599-4608, (2004).
115. Nowak, A. K. et al. Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells. J. Immunol. 170, 4905-4913 (2003).
116. Nowak, A. K., Robinson, B. W. & Lake, R. A. Gemcitabine exerts a selective effect on the humoral immune response: Implications for combination chemoimmunotherapy. Cancer Res. 62, 2353-2358 (2002).
117. Thompson, J. A. et al. Interleukin-21 (IL-21): Tolerability and anti-tumor activity following two 5-day cycles in patients with stage IV melanoma (MM) or renal cell carcinoma (RCC). J. Clin. Oncol. 24 (Suppl.), 2505 (2006).
118. Reiner, S. L. Development in motion: Helper T cells at work. Cell 129, 33-36 (2007).
119. Suto, A. et al. Interleukin 21 prevents antigen-induced IgE production by inhibiting germ line C(epsilon) transcription of IL-4-stimulated B cells. Blood 100, 4565-4573 (2002).
120. Wurster, A. L. et al. Interleukin 21 is a T helper (Th) cell 2 cytokine that specifically inhibits the differentiation of naive Th cells into interferon γ-producing Th1 cells. J. Exp. Med. 196 969-977 (2002).
121. Strengell, M., Sareneva, T., Foster, D., Julkunen, I. & Matikainen, S. IL-21 up-regulates the expression of genes associated with innate immunity and Th1 response. J. Immunol. 169, 3600-3605 (2002).
122. Ozaki, K. et al. Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. J. Immunol. 173, 5361-5371 (2004).
123. Good, K. L., Bryant, V. L. & Tangye, S. G. Kinetics of human B cell behavior and amplification of proliferative responses following stimulation with IL-21. J. Immunol. 177, 5236-5247 (2006).
124. Jin, H., Carrio, R., Yu, A. & Malek, T. R. Distinct activation signals determine whether IL-21 induces B cell costimulation, growth arrest, or Bim-dependent apoptosis. J. Immunol. 173, 657-665 (2004).
125. Ettinger, R. et al. IL-21 induces differentiation of human naive and memory B cells into antibody-secreting plasma cells. J. Immunol. 175, 7867-7879 (2005).
126. Mehta, D. S. et al. IL-21 Induces the apoptosis of resting and activated primary B cells. J. Immunol. 170, 4111 (2003).
127. Pene, J. et al. IL-21 is a switch factor for the production of IgG1 and IgG3 by human B cells. J. Immunol. 172, 5154-5157 (2004).
128. Brandt, K., Bulfone-Paus, S., Foster, D. C. & Ruckert, R. Interleukin-21 inhibits dendritic cell activation and maturation. Blood 102 4090-4098 (2003).
129. Brandt, K. et al. Interleukin-21 inhibits dendritic cell-mediated T cell activation and induction of contact hypersensitivity in vivo. J. Invest. Dermatol. 121, 1379-1382 (2003).
130. Pelletier, M., Bouchard, A. & Girard, D. In vivo and in vitro roles of IL-21 in inflammation. J. Immunol. 173, 7521-7530 (2004).
131. Pesce, J. et al. The IL-21 receptor augments Th2 effector function and alternative macrophage activation. J. Clin. Invest. 116, 2044-2055 (2006).