Deciphering CD137 (4-1BB) signaling in T-cell costimulation for translation into successful cancer immunotherapy

European Journal of Immunology

Volumn 46, Issue 3, 2016, Pages 513-522

  Sanchez Paulete, Alfonso R ^a,b   Labiano, Sara ^a,b   Rodriguez Ruiz, Maria E ^a,b,c   Azpilikueta, Arantza ^a,b   Etxeberria, Iñaki ^a,b   Bolaños, Elixabet ^a,b   Lang, Valérie ^d   Rodriguez, Manuel ^e,f,g   Aznar, M Angela ^a   Jure Kunkel, Maria ^h   Melero, Ignacio ^a,b,c  

^a UNIVERSITY OF NAVARRA   (Spain)

^b IdiSNA Navarra Institute for Health Research   (Spain)

^c UNIVERSITY CLINIC OF NAVARRA   (Spain)

^d Fundacion Inbiomed   (Spain)

^e UPS   (France)

^f UNIVERSITÉ PAUL SABATIER   (France)

^g CNRS   (France)

^h BRISTOL MYERS SQUIBB   (United States)

Author keywords

Cancer immunotherapy; CD137 (4 1BB); Costimulation; K63 polyubiquitin; TRAF 2

Indexed keywords

CD137 LIGAND; CD137 LIGAND MONOCLONAL ANTIBODY; MONOCLONAL ANTIBODY; UNCLASSIFIED DRUG; CD137 ANTIGEN;

ADOPTIVE IMMUNOTHERAPY; APOPTOSIS; ARTICLE; CANCER IMMUNOTHERAPY; HUMAN; IMMUNOSTIMULATION; MALIGNANT NEOPLASTIC DISEASE; NATURAL KILLER CELL; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN EXPRESSION; REGULATORY MECHANISM; T LYMPHOCYTE; ANIMAL; ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY; CYTOTOXIC T LYMPHOCYTE; IMMUNOLOGY; LYMPHOCYTE ACTIVATION; METABOLISM; MOUSE; NEOPLASMS; PROCEDURES; SIGNAL TRANSDUCTION;

ANIMALS; ANTIBODIES, MONOCLONAL; ANTIBODY-DEPENDENT CELL CYTOTOXICITY; ANTIGENS, CD137; CLINICAL TRIALS, PHASE II AS TOPIC; HUMANS; IMMUNOTHERAPY, ADOPTIVE; KILLER CELLS, NATURAL; LYMPHOCYTE ACTIVATION; MICE; NEOPLASMS; SIGNAL TRANSDUCTION; T-LYMPHOCYTES, CYTOTOXIC;

EID: 84959267529     PISSN: 00142980     EISSN: 15214141     Source Type: Journal    
DOI: 10.1002/eji.201445388     Document Type: Article

References (123)

1. Uchida, S., Kwon, H. M., Yamauchi, A., Preston, A. S., Marumo, F. and Handler, J. S., Molecular cloning of the cDNA for an MDCK cell Na(+)- and Cl(-)-dependent taurine transporter that is regulated by hypertonicity. Proc. Natl. Acad. Sci. USA 1992. 89: 8230-8234.
2. Pollok, K. E., Kim, Y. J., Zhou, Z., Hurtado, J., Kim, K. K., Pickard, R. T. and Kwon, B. S., Inducible T cell antigen 4-1BB. Analysis of expression and function. J. Immunol. 1993. 150: 771-781.
3. DeBenedette, M. A., Chu, N. R., Pollok, K. E., Hurtado, J., Wade, W. F., Kwon, B. S. and Watts, T. H., Role of 4-1BB ligand in costimulation of T lymphocyte growth and its upregulation on M12 B lymphomas by cAMP. J. Exp. Med. 1995. 181: 985-992.
4. Zhou, Z., Kim, S., Hurtado, J., Lee, Z. H., Kim, K. K., Pollok, K. E. and Kwon, B. S., Characterization of human homologue of 4-1BB and its ligand. Immunol. Lett. 1995. 45: 67-73.
5. Lee, H. W., Park, S. J., Choi, B. K., Kim, H. H., Nam, K. O. and Kwon, B. S., 4-1BB promotes the survival of CD8+ T lymphocytes by increasing expression of Bcl-xL and Bfl-1. J. Immunol. 2002. 169: 4882-4888.
6. Alderson, M. R., Smith, C. A., Tough, T. W., Davis-Smith, T., Armitage, R. J., Falk, B., Roux, E. et al., Molecular and biological characterization of human 4-1BB and its ligand. Eur. J. Immunol. 1994. 24:2219-2227.
7. Goodwin, R. G., Din, W. S., Davis-Smith, T., Anderson, D. M., Gimpel, S. D., Sato, T. A., Maliszewski, C. R. et al., Molecular cloning of a ligand for the inducible T cell gene 4-1BB: a member of an emerging family of cytokines with homology to tumor necrosis factor. Eur. J. Immunol. 1993. 23: 2631-2641.
8. Chalupny, N. J., Peach, R., Hollenbaugh, D., Ledbetter, J. A., Farr, A. G. and Aruffo, A., T-cell activation molecule 4-1BB binds to extracellular matrix proteins. Proc. Natl. Acad. Sci. USA 1992. 89: 10360-10364.
9. Madireddi, S., Eun, S. Y., Lee, S. W., Nemcovicova, I., Mehta, A. K., Zajonc, D. M., Nishi, N. et al., Galectin-9 controls the therapeutic activity of 4-1BB-targeting antibodies. J. Exp. Med. 2014. 211: 1433-1448.
10. Arch, R. H. and Thompson, C. B., 4-1BB and Ox40 are members of a tumor necrosis factor (TNF)-nerve growth factor receptor subfamily that bind TNF receptor-associated factors and activate nuclear factor kappaB. Mol. Cell. Biol. 1998. 18: 558-565.
11. Jang, I. K., Lee, Z. H., Kim, Y. J., Kim, S. H. and Kwon, B. S., Human 4-1BB (CD137) signals are mediated by TRAF2 and activate nuclear factor-kappa B. Biochem. Biophys. Res. Commun. 1998. 242: 613-620.
12. Saoulli, K., Lee, S. Y., Cannons, J. L., Yeh, W. C., Santana, A., Goldstein, M. D., Bangia, N. et al., CD28-independent, TRAF2-dependent costimulation of resting T cells by 4-1BB ligand. J. Exp. Med. 1998. 187: 1849-1862.
13. Ye, H., Park, Y. C., Kreishman, M., Kieff, E. and Wu, H., The structural basis for the recognition of diverse receptor sequences by TRAF2. Mol. Cell. 1999. 4: 321-330.
14. Won, E. Y., Cha, K., Byun, J. S., Kim, D. U., Shin, S., Ahn, B., Kim, Y. H. et al., The structure of the trimer of human 4-1BB ligand is unique among members of the tumor necrosis factor superfamily. J. Biol. Chem. 2010. 285: 9202-9210.
15. Croft, M., Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nat. Rev. Immunol. 2003. 3: 609-620.
16. Martinez-Forero, I., Azpilikueta, A., Bolanos-Mateo, E., Nistal-Villan, E., Palazon, A., Teijeira, A., Perez-Chacon, G. et al., T cell costimulation with anti-CD137 monoclonal antibodies is mediated by K63-polyubiquitin-dependent signals from endosomes. J. Immunol. 2013. 190: 6694-6706.
17. Sabbagh, L., Pulle, G., Liu, Y., Tsitsikov, E. N. and Watts, T. H., ERK-dependent Bim modulation downstream of the 4-1BB-TRAF1 signaling axis is a critical mediator of CD8 T cell survival in vivo. J. Immunol. 2008. 180: 8093-8101.
18. Choudhary, S., Kalita, M., Fang, L., Patel, K. V., Tian, B., Zhao, Y., Edeh, C. B. et al., Inducible tumor necrosis factor (TNF) receptor-associated factor-1 expression couples the canonical to the non-canonical NF-kappaB pathway in TNF stimulation. J. Biol. Chem. 2013. 288: 14612-14623.
19. Zapata, J. M. and Reed, J. C., TRAF1: lord without a RING. Sci. STKE 2002. 2002: pe27.
20. McPherson, A. J., Snell, L. M., Mak, T. W. and Watts, T. H., Opposing roles for TRAF1 in the alternative versus classical NF-kappaB pathway in T cells. J. Biol. Chem. 2012. 287: 23010-23019.
21. Sabbagh, L., Andreeva, D., Laramee, G. D., Oussa, N. A., Lew, D., Bisson, N., Soumounou, Y. et al., Leukocyte-specific protein 1 links TNF receptor-associated factor 1 to survival signaling downstream of 4-1BB in T cells. J. Leukoc. Biol. 2013. 93: 713-721.
22. Bhoj, V. G. and Chen, Z. J., Ubiquitylation in innate and adaptive immunity. Nature 2009. 458: 430-437.
23. Shi, C. S. and Kehrl, J. H., Tumor necrosis factor (TNF)-induced germinal center kinase-related (GCKR) and stress-activated protein kinase (SAPK) activation depends upon the E2/E3 complex Ubc13-Uev1A/TNF receptor-associated factor 2 (TRAF2). J. Biol. Chem. 2003. 278: 15429-15434.
24. Yin, Q., Lamothe, B., Darnay, B. G. and Wu, H., Structural basis for the lack of E2 interaction in the RING domain of TRAF2. Biochemistry 2009. 48: 10558-10567.
25. Mace, P. D., Smits, C., Vaux, D. L., Silke, J. and Day, C. L., Asymmetric recruitment of cIAPs by TRAF2. J. Mol. Biol. 2010. 400: 8-15.
26. Giardino Torchia, M. L., Munitic, I., Castro, E., Herz, J., McGavern, D. B. and Ashwell, J. D., c-IAP ubiquitin protein ligase activity is required for 4-1BB signaling and CD8(+) memory T-cell survival. Eur. J. Immunol. 2015. 45: 2672-2682.
27. Chen, J. and Chen, Z. J., Regulation of NF-kappaB by ubiquitination. Curr. Opin. Immunol. 2013. 25: 4-12.
28. Chen, Z. J., Ubiquitination in signaling to and activation of IKK. Immunol. Rev. 2012. 246: 95-106.
29. Yuasa, T., Ohno, S., Kehrl, J. H. and Kyriakis, J. M., Tumor necrosis factor signaling to stress-activated protein kinase (SAPK)/Jun NH2-terminal kinase (JNK) and p38. Germinal center kinase couples TRAF2 to mitogen-activated protein kinase/ERK kinase kinase 1 and SAPK while receptor interacting protein associates with a mitogen-activated protein kinase kinase kinase upstream of MKK6 and p38. J. Biol. Chem. 1998. 273: 22681-22692.
30. Schichl, Y. M., Resch, U., Lemberger, C. E., Stichlberger, D. and de Martin, R., Novel phosphorylation-dependent ubiquitination of tristetraprolin by mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1 (MEKK1) and tumor necrosis factor receptor-associated factor 2 (TRAF2). J. Biol. Chem. 2011. 286: 38466-38477.
31. Stephan, M. T., Ponomarev, V., Brentjens, R. J., Chang, A. H., Dobrenkov, K. V., Heller, G. and Sadelain, M., T cell-encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection. Nat. Med. 2007. 13: 1440-1449.
32. Song, H. Y., Rothe, M. and Goeddel, D. V., The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation. Proc. Natl. Acad. Sci. USA 1996. 93: 6721-6725.
33. Tesio, M., Tang, Y., Mudder, K., Saini, M., von Paleske, L., Macintyre, E., Pasparakis, M. et al., Hematopoietic stem cell quiescence and function are controlled by the CYLD-TRAF2-p38MAPK pathway. J. Exp. Med. 2015. 212: 525-538.
34. Sharma, R. K., Schabowsky, R. H., Srivastava, A. K., Elpek, K. G., Madireddi, S., Zhao, H., Zhong, Z. et al., 4-1BB ligand as an effective multifunctional immunomodulator and antigen delivery vehicle for the development of therapeutic cancer vaccines. Cancer Res. 2010. 70: 3945-3954.
35. Eun, S. Y., Lee, S. W., Xu, Y. and Croft, M., 4-1BB ligand signaling to T cells limits T cell activation. J. Immunol. 2015. 194: 134-141.
36. Schwenzer, R., Siemienski, K., Liptay, S., Schubert, G., Peters, N., Scheurich, P., Schmid, R. M. et al., The human tumor necrosis factor (TNF) receptor-associated factor 1 gene (TRAF1) is up-regulated by cytokines of the TNF ligand family and modulates TNF-induced activation of NF-kappaB and c-Jun N-terminal kinase. J. Biol. Chem. 1999. 274: 19368-19374.
37. Shuford, W. W., Klussman, K., Tritchler, D. D., Loo, D. T., Chalupny, J., Siadak, A. W., Brown, T. J. et al., 4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses. J. Exp. Med. 1997. 186: 47-55.
38. Melero, I., Shuford, W. W., Newby, S. A., Aruffo, A., Ledbetter, J. A., Hellstrom, K. E., Mittler, R. S. et al., Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nat. Med. 1997. 3: 682-685.
39. Melero, I., Johnston, J. V., Shufford, W. W., Mittler, R. S. and Chen, L., NK1.1 cells express 4-1BB (CDw137) costimulatory molecule and are required for tumor immunity elicited by anti-4-1BB monoclonal antibodies. Cell Immunol. 1998. 190: 167-172.
40. Melero, I., Bach, N., Hellstrom, K. E., Aruffo, A., Mittler, R. S. and Chen, L., Amplification of tumor immunity by gene transfer of the co-stimulatory 4-1BB ligand: synergy with the CD28 co-stimulatory pathway. Eur. J. Immunol. 1998. 28: 1116-1121.
41. Murillo, O., Dubrot, J., Palazon, A., Arina, A., Azpilikueta, A., Alfaro, C., Solano, S. et al., In vivo depletion of DC impairs the anti-tumor effect of agonistic anti-CD137 mAb. Eur. J. Immunol. 2009. 39: 2424-2436.
42. Sanchez-Paulete, A. R., Cueto, F. J., Martinez-Lopez, M., Labiano, S., Morales-Kastresana, A., Rodriguez-Ruiz, M. E., Jure-Kunkel, M. et al., Cancer immunotherapy with immunomodulatory anti-CD137 and anti-PD-1 monoclonal antibodies requires Batf3-dependent dendritic cells. Cancer Discov. 2016. 6: 71-79.
43. Miller, R. E., Jones, J., Le, T., Whitmore, J., Boiani, N., Gliniak, B. and Lynch, D. H., 4-1BB-specific monoclonal antibody promotes the generation of tumor-specific immune responses by direct activation of CD8 T cells in a CD40-dependent manner. J. Immunol. 2002. 169: 1792-1800.
44. Choi, B. K., Kim, Y. H., Kang, W. J., Lee, S. K., Kim, K. H., Shin, S. M., Yokoyama, W. M. et al., Mechanisms involved in synergistic anticancer immunity of anti-4-1BB and anti-CD4 therapy. Cancer Res. 2007. 67: 8891-8899.
45. Sun, Y., Lin, X., Chen, H. M., Wu, Q., Subudhi, S. K., Chen, L. and Fu, Y. X., Administration of agonistic anti-4-1BB monoclonal antibody leads to the amelioration of experimental autoimmune encephalomyelitis. J. Immunol. 2002. 168: 1457-1465.
46. Foell, J., Strahotin, S., O'Neil, S. P., McCausland, M. M., Suwyn, C., Haber, M., Chander, P. N. et al., CD137 costimulatory T cell receptor engagement reverses acute disease in lupus-prone NZB x NZW F1 mice. J. Clin. Invest. 2003. 111: 1505-1518.
47. Seo, S. K., Choi, J. H., Kim, Y. H., Kang, W. J., Park, H. Y., Suh, J. H., Choi, B. K. et al., 4-1BB-mediated immunotherapy of rheumatoid arthritis. Nat. Med. 2004. 10: 1088-1094.
48. Sytwu, H. K., Lin, W. D., Roffler, S. R., Hung, J. T., Sung, H. S., Wang, C. H., Cheng, T. L. et al., Anti-4-1BB-based immunotherapy for autoimmune diabetes: lessons from a transgenic non-obese diabetic (NOD) model. J. Autoimmun. 2003. 21: 247-254.
49. Kachapati, K., Bednar, K. J., Adams, D. E., Wu, Y., Mittler, R. S., Jordan, M. B., Hinerman, J. M. et al., Recombinant soluble CD137 prevents type one diabetes in nonobese diabetic mice. J. Autoimmun. 2013. 47: 94-103.
50. Xu, K., Li, C., Pan, X. and Du, B., Study of relieving graft-versus-host disease by blocking CD137-CD137 ligand costimulatory pathway in vitro. Int. J. Hematol. 2007. 86: 84-90.
51. Dubrot, J., Milheiro, F., Alfaro, C., Palazon, A., Martinez-Forero, I., Perez-Gracia, J. L., Morales-Kastresana, A. et al., Treatment with anti-CD137 mAbs causes intense accumulations of liver T cells without selective antitumor immunotherapeutic effects in this organ. Cancer Immunol. Immunother. 2010. 59: 1223-1233.
52. + T cells with antitumor activity. J. Immunol. 2016. 196: 484-492.
53. Palazon, A., Martinez-Forero, I., Teijeira, A., Morales-Kastresana, A., Alfaro, C., Sanmamed, M. F., Perez-Gracia, J. L. et al., The HIF-1alpha hypoxia response in tumor-infiltrating T lymphocytes induces functional CD137 (4-1BB) for immunotherapy. Cancer Discov. 2012. 2: 608-623.
54. So, T., Lee, S. W. and Croft, M., Immune regulation and control of regulatory T cells by OX40 and 4-1BB. Cytokine Growth Factor Rev. 2008. 19: 253-262.
55. Myers, L. M. and Vella, A. T., Interfacing T-cell effector and regulatory function through CD137 (4-1BB) co-stimulation. Trends Immunol. 2005. 26: 440-446.
56. Li, F. and Ravetch, J. V., Inhibitory Fcgamma receptor engagement drives adjuvant and anti-tumor activities of agonistic CD40 antibodies. Science 2011. 333: 1030-1034.
57. Li, F. and Ravetch, J. V., Antitumor activities of agonistic anti-TNFR antibodies require differential FcgammaRIIB coengagement in vivo. Proc. Natl. Acad. Sci. USA 2013. 110: 19501-19506.
58. Vonderheide, R. H. and Glennie, M. J., Agonistic CD40 antibodies and cancer therapy. Clin. Cancer Res. 2013. 19: 1035-1043.
59. White, A. L., Chan, H. T., Roghanian, A., French, R. R., Mockridge, C. I., Tutt, A. L., Dixon, S. V. et al., Interaction with FcgammaRIIB is critical for the agonistic activity of anti-CD40 monoclonal antibody. J. Immunol. 2011. 187: 1754-1763.
60. Wilcox, R. A., Flies, D. B., Zhu, G., Johnson, A. J., Tamada, K., Chapoval, A. I., Strome, S. E. et al., Provision of antigen and CD137 signaling breaks immunological ignorance, promoting regression of poorly immunogenic tumors. J. Clin. Invest. 2002. 109: 651-659.
61. Bartkowiak, T., Singh, S., Yang, G., Galvan, G., Haria, D., Ai, M., Allison, J. P. et al., Unique potential of 4-1BB agonist antibody to promote durable regression of HPV+ tumors when combined with an E6/E7 peptide vaccine. Proc. Natl. Acad. Sci. USA 2015. 112: E5290-E5299.
62. Ito, F., Li, Q., Shreiner, A. B., Okuyama, R., Jure-Kunkel, M. N., Teitz-Tennenbaum, S. and Chang, A. E., Anti-CD137 monoclonal antibody administration augments the antitumor efficacy of dendritic cell-based vaccines. Cancer Res. 2004. 64: 8411-8419.
63. Tirapu, I., Arina, A., Mazzolini, G., Duarte, M., Alfaro, C., Feijoo, E., Qian, C. et al., Improving efficacy of interleukin-12-transfected dendritic cells injected into murine colon cancer with anti-CD137 monoclonal antibodies and alloantigens. Int. J. Cancer 2004. 110: 51-60.
64. Cuadros, C., Dominguez, A. L., Lollini, P. L., Croft, M., Mittler, R. S., Borgstrom, P. and Lustgarten, J., Vaccination with dendritic cells pulsed with apoptotic tumors in combination with anti-OX40 and anti-4-1BB monoclonal antibodies induces T cell-mediated protective immunity in Her-2/neu transgenic mice. Int. J Cancer 2005. 116: 934-943.
65. Kim, Y. H., Choi, B. K., Kim, K. H., Kang, S. W. and Kwon, B. S., Combination therapy with cisplatin and anti-4-1BB: synergistic anticancer effects and amelioration of cisplatin-induced nephrotoxicity. Cancer Res. 2008. 68: 7264-7269.
66. Kim, Y. H., Choi, B. K., Oh, H. S., Kang, W. J., Mittler, R. S. and Kwon, B. S., Mechanisms involved in synergistic anticancer effects of anti-4-1BB and cyclophosphamide therapy. Mol. Cancer Ther. 2009. 8: 469-478.
67. Shi, W. and Siemann, D. W., Augmented antitumor effects of radiation therapy by 4-1BB antibody (BMS-469492) treatment. Anticancer Res. 2006. 26: 3445-3453.
68. Belcaid, Z., Phallen, J. A., Zeng, J., See, A. P., Mathios, D., Gottschalk, C., Nicholas, S. et al., Focal radiation therapy combined with 4-1BB activation and CTLA-4 blockade yields long-term survival and a protective antigen-specific memory response in a murine glioma model. PLoS One 2014. 9: e101764.
69. Verbrugge, I., Hagekyriakou, J., Sharp, L. L., Galli, M., West, A., McLaughlin, N. M., Duret, H. et al., Radiotherapy increases the permissiveness of established mammary tumors to rejection by immunomodulatory antibodies. Cancer Res. 2012. 72: 3163-3174.
70. Arribillaga, L., Sarobe, P., Arina, A., Gorraiz, M., Borras-Cuesta, F., Ruiz, J., Prieto, J. et al., Enhancement of CD4 and CD8 immunity by anti-CD137 (4-1BB) monoclonal antibodies during hepatitis C vaccination with recombinant adenovirus. Vaccine 2005. 23: 3493-3499.
71. Quetglas, J. I., Dubrot, J., Bezunartea, J., Sanmamed, M. F., Hervas-Stubbs, S., Smerdou, C. and Melero, I., Immunotherapeutic synergy between anti-CD137 mAb and intratumoral administration of a cytopathic Semliki Forest virus encoding IL-12. Mol. Ther. 2012. 20: 1664-1675.
72. John, L. B., Howland, L. J., Flynn, J. K., West, A. C., Devaud, C., Duong, C. P., Stewart, T. J. et al., Oncolytic virus and anti-4-1BB combination therapy elicits strong antitumor immunity against established cancer. Cancer Res. 2012. 72: 1651-1660.
73. Chen, S. H., Pham-Nguyen, K. B., Martinet, O., Huang, Y., Yang, W., Thung, S. N., Chen, L. et al., Rejection of disseminated metastases of colon carcinoma by synergism of IL-12 gene therapy and 4-1BB costimulation. Mol. Ther. 2000. 2: 39-46.
74. Dubrot, J., Palazon, A., Alfaro, C., Azpilikueta, A., Ochoa, M. C., Rouzaut, A., Martinez-Forero, I. et al., Intratumoral injection of interferon-alpha and systemic delivery of agonist anti-CD137 monoclonal antibodies synergize for immunotherapy. Int. J. Cancer 2011. 128: 105-118.
75. May, K. F., Jr., Chen, L., Zheng, P. and 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: 3459-3465.
76. Chacon, J. A., Wu, R. C., Sukhumalchandra, P., Molldrem, J. J., Sarnaik, A., Pilon-Thomas, S., Weber, J. et al., Co-stimulation through 4-1BB/CD137 improves the expansion and function of CD8(+) melanoma tumor-infiltrating lymphocytes for adoptive T-cell therapy. PLoS One 2013. 8: e60031.
77. Weigelin, B., Bolanos, E., Teijeira, A., Martinez-Forero, I., Labiano, S., Azpilikueta, A., Morales-Kastresana, A. et al., Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb. Proc. Natl. Acad. Sci. USA 2015. 112: 7551-7556.
78. Srivastava, A. K., Dinc, G., Sharma, R. K., Yolcu, E. S., Zhao, H. and Shirwan, H., SA-4-1BBL and monophosphoryl lipid A constitute an efficacious combination adjuvant for cancer vaccines. Cancer Res. 2014. 74: 6441-6451.
79. Turnis, M. E., Andrews, L. P. and Vignali, D. A., Inhibitory receptors as targets for cancer immunotherapy. Eur. J. Immunol. 2015. 45: 1892-1905.
80. Kocak, E., Lute, K., Chang, X., May, K. F., Jr., Exten, K. R., Zhang, H., Abdessalam, S. F. et al., Combination therapy with anti-CTL antigen-4 and anti-4-1BB antibodies enhances cancer immunity and reduces autoimmunity. Cancer Res. 2006. 66: 7276-7284.
81. Wei, H., Zhao, L., Hellstrom, I., Hellstrom, K. E. and Guo, Y., Dual targeting of CD137 co-stimulatory and PD-1 co-inhibitory molecules for ovarian cancer immunotherapy. Oncoimmunology 2014. 3: e28248.
82. Dai, M., Yip, Y. Y., Hellstrom, I. and Hellstrom, K. E., Curing mice with large tumors by locally delivering combinations of immunomodulatory antibodies. Clin. Cancer Res. 2015. 21: 1127-1138.
83. Uno, T., Takeda, K., Kojima, Y., Yoshizawa, H., Akiba, H., Mittler, R. S., Gejyo, F. et al., Eradication of established tumors in mice by a combination antibody-based therapy. Nat. Med. 2006. 12: 693-698.
84. Takeda, K., Kojima, Y., Uno, T., Hayakawa, Y., Teng, M. W., Yoshizawa, H., Yagita, H. et al., Combination therapy of established tumors by antibodies targeting immune activating and suppressing molecules. J. Immunol. 2010. 184: 5493-5501.
85. Adler, A. J. and Vella, A. T., Betting on improved cancer immunotherapy by doubling down on CD134 and CD137 co-stimulation. Oncoimmunology 2013. 2: e22837.
86. Dai, M., Yip, Y. Y., Hellstrom, I. and Hellstrom, K. E., Curing mice with large tumors by locally delivering combinations of immunomodulatory antibodies. Clin. Cancer Res. 2015. 21: 1127-1138.
87. Morales-Kastresana, A., Sanmamed, M. F., Rodriguez, I., Palazon, A., Martinez-Forero, I., Labiano, S., Hervas-Stubbs, S. et al., Combined immunostimulatory monoclonal antibodies extend survival in an aggressive transgenic hepatocellular carcinoma mouse model. Clin. Cancer Res. 2013. 19: 6151-6162.
88. Martinet, O., Ermekova, V., Qiao, J. Q., Sauter, B., Mandeli, J., Chen, L. and Chen, S. H., Immunomodulatory gene therapy with interleukin 12 and 4-1BB ligand: long- term remission of liver metastases in a mouse model. J. Natl. Cancer Inst. 2000. 92: 931-936.
89. Xu, D. P., Sauter, B. V., Huang, T. G., Meseck, M., Woo, S. L. and Chen, S. H., The systemic administration of Ig-4-1BB ligand in combination with IL-12 gene transfer eradicates hepatic colon carcinoma. Gene Ther. 2005. 12: 1526-1533.
90. Ye, Z., Hellstrom, I., Hayden-Ledbetter, M., Dahlin, A., Ledbetter, J. A. and Hellstrom, K. E., Gene therapy for cancer using single-chain Fv fragments specific for 4-1BB. Nat. Med. 2002. 8: 343-348.
91. Yang, Y., Yang, S., Ye, Z., Jaffar, J., Zhou, Y., Cutter, E., Lieber, A. et al., Tumor cells expressing anti-CD137 scFv induce a tumor-destructive environment. Cancer Res. 2007. 67: 2339-2344.
92. Gopal, A. K., Bartlett, N. L., Levy, R., Houot, R., Smith, S. D., Segal, N. H., Thall, A. D. et al., A phase I study of PF-05082566 (anti-4-1BB) + rituximab in patients with CD20+NHL. J. Clin. Oncol. 2015. 33.
93. Sznol, M., Hodi, F. S., Margolin, K., McDermott, D. F., Ernstoff, M. S., Kirkwood, J. M., Wojtaszek, C. et al., Phase I study of BMS-663513, a fully human anti-CD137 agonist monoclonal antibody, in patients (pts) with advanced cancer (CA). J. Clin. Oncol. 2008. 26.
94. Ascierto, P. A., Simeone, E., Sznol, M., Fu, Y. X. and Melero, I., Clinical experiences with anti-CD137 and anti-PD1 therapeutic antibodies. Semin. Oncol. 2010. 37: 508-516.
95. Lamberts, T. E., Menke-van der Houven van Oordt, C. W., Ter Weele, E. J., Bensch, F., Smeenk, M. M., Voortman, J., Hoekstra, O. S. et al., ImmunoPET with anti-mesothelin antibody in patients with pancreatic and ovarian cancer before anti-mesothelin antibody-drug conjugate treatment. Clin. Cancer Res. 2015. In press. DOI:10.1158/1078-0432.CCR-15-1272.
96. Kamath, A. V., Williams, S. P., Bullens, S., Cowan, K. J., Stenberg, Y., Cherry, S. R., Rendig, S. et al., Pharmacokinetics and biodistribution of a human monoclonal antibody to oxidized LDL in cynomolgus monkey using PET imaging. PloS One 2012. 7: e45116.
97. Melero, I., Berman, D. M., Aznar, M. A., Korman, A. J., Perez Gracia, J. L. and Haanen, J., Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat. Rev. Cancer 2015. 15: 457-472.
98. Sanmamed, M. F., Rodriguez, I., Schalper, K. A., Onate, C., Azpilikueta, A., Rodriguez-Ruiz, M. E., Morales-Kastresana, A. et al., Nivolumab and urelumab enhance antitumor activity of human T lymphocytes engrafted in Rag2-/-IL2Rgammanull immunodeficient mice. Cancer Res. 2015. 75: 3466-3478.
99. Houot, R., Kohrt, H. E., Marabelle, A. and Levy, R., Targeting immune effector cells to promote antibody-induced cytotoxicity in cancer immunotherapy. Trends Immunol. 2011. 32: 510-516.
100. Kohrt, H. E., Houot, R., Goldstein, M. J., Weiskopf, K., Alizadeh, A. A., Brody, J., Muller, A. et al., CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies. Blood 2011. 117: 2423-2432.
101. Kohrt, H. E., Houot, R., Weiskopf, K., Goldstein, M. J., Scheeren, F., Czerwinski, D., Colevas, A. D. et al., Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer. J. Clin. Invest. 2012. 122: 1066-1075.
102. Kohrt, H. E., Colevas, A. D., Houot, R., Weiskopf, K., Goldstein, M. J., Lund, P., Mueller, A. et al., Targeting CD137 enhances the efficacy of cetuximab. J. Clin. Invest. 2014. 124: 2668-2682.
103. Rosenberg, S. A. and Restifo, N. P., Adoptive cell transfer as personalized immunotherapy for human cancer. Science 2015. 348: 62-68.
104. Wolfl, M., Kuball, J., Eyrich, M., Schlegel, P. G. and Greenberg, P. D., Use of CD137 to study the full repertoire of CD8+ T cells without the need to know epitope specificities. Cytometry A 2008. 73: 1043-1049.
105. Wolfl, M., Kuball, J., Ho, W. Y., Nguyen, H., Manley, T. J., Bleakley, M. and Greenberg, P. D., Activation-induced expression of CD137 permits detection, isolation, and expansion of the full repertoire of CD8+ T cells responding to antigen without requiring knowledge of epitope specificities. Blood 2007. 110: 201-210.
106. Gros, A., Robbins, P. F., Yao, X., Li, Y. F., Turcotte, S., Tran, E., Wunderlich, J. R. et al., PD-1 identifies the patient-specific CD8(+) tumor-reactive repertoire infiltrating human tumors. J. Clin. Invest. 2014. 124: 2246-2259.
107. Maus, M. V., Thomas, A. K., Leonard, D. G., Allman, D., Addya, K., Schlienger, K., Riley, J. L. et al., Ex vivo expansion of polyclonal and antigen-specific cytotoxic T lymphocytes by artificial APCs expressing ligands for the T-cell receptor, CD28 and 4-1BB. Nat. Biotechnol. 2002. 20: 143-148.
108. Seaman, S., Stevens, J., Yang, M. Y., Logsdon, D., Graff-Cherry, C. and St Croix, B., Genes that distinguish physiological and pathological angiogenesis. Cancer Cell 2007. 11: 539-554.
109. Palazon, A., Teijeira, A., Martinez-Forero, I., Hervas-Stubbs, S., Roncal, C., Penuelas, I., Dubrot, J. et al., Agonist anti-CD137 mAb act on tumor endothelial cells to enhance recruitment of activated T lymphocytes. Cancer Res. 2011. 71: 801-811.
110. Carpenito, C., Milone, M. C., Hassan, R., Simonet, J. C., Lakhal, M., Suhoski, M. M., Varela-Rohena, A. et al., Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc. Natl. Acad. Sci. USA 2009. 106: 3360-3365.
111. Song, D. G., Ye, Q., Carpenito, C., Poussin, M., Wang, L. P., Ji, C., Figini, M. et al., In vivo persistence, tumor localization, and antitumor activity of CAR-engineered T cells is enhanced by costimulatory signaling through CD137 (4-1BB). Cancer Res. 2011. 71: 4617-4627.
112. Long, A. H., Haso, W. M., Shern, J. F., Wanhainen, K. M., Murgai, M., Ingaramo, M., Smith, J. P. et al., 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat. Med. 2015. 21: 581-590.
113. Song, D. G., Ye, Q., Poussin, M., Harms, G. M., Figini, M. and Powell, D. J., Jr., CD27 costimulation augments the survival and antitumor activity of redirected human T cells in vivo. Blood 2012. 119: 696-706.
114. Kalos, M., Levine, B. L., Porter, D. L., Katz, S., Grupp, S. A., Bagg, A. and June, C. H., T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci. Transl. Med. 2011. 3: 95ra73.
115. Grupp, S. A., Kalos, M., Barrett, D., Aplenc, R., Porter, D. L., Rheingold, S. R., Teachey, D. T. et al., Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 2013. 368: 1509-1518.
116. Maude, S. L., Frey, N., Shaw, P. A., Aplenc, R., Barrett, D. M., Bunin, N. J., Chew, A. et al., Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 2014. 371: 1507-1517.
117. Garfall, A. L., Maus, M. V., Hwang, W. T., Lacey, S. F., Mahnke, Y. D., Melenhorst, J. J., Zheng, Z. et al., Chimeric antigen receptor T cells against CD19 for multiple myeloma. N. Engl. J. Med 2015. 373: 1040-1047.
118. Vuillefroy de Silly, R., Ducimetiere, L., Yacoub Maroun, C., Dietrich, P. Y., Derouazi, M. and Walker, P. R., Phenotypic switch of CD8(+) T cells reactivated under hypoxia toward IL-10 secreting, poorly proliferative effector cells. Eur. J. Immunol. 2015. 45: 2263-2275.
119. Jiang, X. and Chen, Z. J., The role of ubiquitylation in immune defence and pathogen evasion. Nat. Rev.. Immunol. 2012. 12: 35-48.
120. Martinez-Forero, I., Rouzaut, A., Palazon, A., Dubrot, J. and Melero, I., Lysine 63 polyubiquitination in immunotherapy and in cancer-promoting inflammation. Clin. Cancer Res. 2009. 15: 6751-6757.
121. Antonia, S. J., Larkin, J. and Ascierto, P. A., Immuno-oncology combinations: a review of clinical experience and future prospects. Clin. Cancer Res. 2014. 20: 6258-6268.
122. Mahoney, K. M., Rennert, P. D. and Freeman, G. J., Combination cancer immunotherapy and new immunomodulatory targets. Nat. Rev. Drug Discov. 2015. 14: 561-584.
123. Melero, I., Murillo, O., Dubrot, J., Hervas-Stubbs, S. and Perez-Gracia, J. L., Multi-layered action mechanisms of CD137 (4-1BB)-targeted immunotherapies. Trends Pharmacol. Sci. 2008. 29: 383-390.