Are BiTEs the “missing link” in cancer therapy?

OncoImmunology

Volumn 4, Issue 6, 2015, Pages

  Suryadevara, Carter M ^a   Gedeon, Patrick C ^a,b   Sanchez Perez, Luis ^a   Verla, Terence ^a   Alvarez Breckenridge, Christopher ^c   Choi, Bryan D ^c   Fecci, Peter E ^a   Sampson, John H ^a,b  

^a DUKE UNIVERSITY MEDICAL CENTER   (United States)

^b Duke University   (United States)

^c MASSACHUSETTS GENERAL HOSPITAL   (United States)

Author keywords

Bispecific antibodies; Immunotherapy; Malignancies; T lymphocytes

Indexed keywords

BISPECIFIC T CELL ENGAGER ANTIBODY; BLINATUMOMAB; CD3 ANTIGEN; CHIMERIC ANTIGEN RECEPTOR; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; EPIDERMAL GROWTH FACTOR RECEPTOR; HIGH MOBILITY GROUP B1 PROTEIN; MONOCLONAL ANTIBODY; T LYMPHOCYTE RECEPTOR; UNCLASSIFIED DRUG;

ACUTE LYMPHOBLASTIC LEUKEMIA; ANTIBODY SPECIFICITY; ANTINEOPLASTIC ACTIVITY; CANCER IMMUNOTHERAPY; CANCER INFILTRATION; CD8+ T LYMPHOCYTE; CLINICAL TRIAL (TOPIC); COST EFFECTIVENESS ANALYSIS; DRUG SAFETY; HUMAN; IMMUNE RESPONSE; IMMUNOMODULATION; MAJOR HISTOCOMPATIBILITY COMPLEX; REVIEW; T LYMPHOCYTE; TUMOR CELL DESTRUCTION; TUMOR MICROENVIRONMENT;

EID: 84944472777     PISSN: 21624011     EISSN: 2162402X     Source Type: Journal    
DOI: 10.1080/2162402X.2015.1008339     Document Type: Review

References (115)

1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014; 64:9-29; PMID:24399786; http://dx.doi.org/10.3322/ caac.21208
2. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 2011; 331:1565-70; PMID:21436444; http://dx.doi.org/10.1126/ science.1203486
3. Mittal D, Gubin MM, Schreiber RD, Smyth MJ. New insights into cancer immunoediting and its three component phases-elimination, equilibrium and escape. Curr Opin Immunol 2014; 27C:16-25; PMID: 24531241; http://dx.doi.org/10.1016/j. coi.2014.01.004
4. Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol 2004; 22:329-60; PMID:15032581; http://dx.doi.org/ 10.1146/annurev.immunol.22.012703.104803
5. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002; 3:991-8; PMID:12407406; http://dx.doi.org/10.1038/ ni1102-991
6. Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry R, Restifo NP, Hubicki AM et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002; 298:850-4; PMID:12242449; http://dx.doi.org/10.1126/ science.1076514
7. Rosenberg SA. Raising the bar: the curative potential of human cancer immunotherapy. Sci Transl Med 2012; 4:127ps8; PMID:22461638; http://dx.doi.org/ 10.1126/scitranslmed.3003634
8. Sanchez-Perez LA, Choi BD, Archer GE, Cui X, Flores C, Johnson LA, Schmittling RJ, Snyder D, Herndon JE, 2nd, Bigner DD et al. Myeloablative temozolomide enhances CD8(+) T-cell responses to vaccine and is required for efficacy against brain tumors in mice. PloS One 2013; 8:e59082; PMID:23527092; http://dx.doi.org/10.1371/journal. pone.0059082
9. Rosenberg SA. Cell transfer immunotherapy for metastatic solid cancer-what clinicians need to know. Nat Rev Clin Oncol 2011; 8:577-85; PMID:21808266; http://dx.doi.org/10.1038/nrclinonc.2011.116
10. Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer 2008; 8:299-308; PMID:18354418; http://dx.doi. org/10.1038/nrc2355
11. Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, Citrin DE, Restifo NP, Robbins PF, Wunderlich JR et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res 2011; 17:4550-7; PMID:21498393; http://dx.doi.org/10.1158/1078-0432.CCR-11-0116
12. Zippel DB, Besser M, Shapira R, Ben-Nun A, Goitein D, Davidson T, Treves AJ, Markel G, Schachter J, Papa MZ. Adoptive cell therapy with autologous tumor-infiltrating lymphocytes and high-dose interleukin-2 for metastatic melanoma: The surgeon's perspective. Exp Ther Med 2012; 3:898-902; PMID:22969990; http:dx.doi.org/10.3892/ etm.2012.498
13. Coccoris M, de Witte MA, Schumacher TN. Prospects and limitations of T cell receptor gene therapy. Curr Gene Ther 2005; 5:583-93; PMID:16457648; http://dx.doi.org/10.2174/156652305774964730
14. Morgan RA, Chinnasamy N, Abate-Daga D, Gros A, Robbins PF, Zheng Z, Dudley ME, Feldman SA, Yang JC, Sherry RM et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother 2013; 36:133-51; PMID:23377668; http://dx.doi.org/10.1097/ CJI.0b013e3182829903
15. Duval L, Schmidt H, Kaltoft K, Fode K, Jensen JJ, Sorensen SM, Nishimura MI, von der Maase H. Adoptive transfer of allogeneic cytotoxic T lymphocytes equipped with a HLA-A2 restricted MART-1 Tcell receptor: a phase I trial in metastatic melanoma. Clin Cancer Res 2006; 12:1229-36; PMID:16489078; http://dx.doi.org/10.1158/1078-0432.CCR-05-1485
16. Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian SL, Kammula US, Restifo NP et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 2006; 314:126-9; PMID:16946036; http://dx.doi.org/10.1126/ science.1129003
17. Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U S A 1989; 86:10024-8; PMID:2513569; http://dx.doi.org/10.1073/ pnas.86.24.10024
18. Cartellieri M, Bachmann M, Feldmann A, Bippes C, Stamova S, Wehner R, Temme A, Schmitz M. Chimeric antigen receptor-engineered T cells for immunotherapy of cancer. J Biomed Biotechnol 2010; 2010:956304; PMID:20467460; http://dx.doi.org/ 10.1155/2010/956304
19. Bubenik J. MHC class I down-regulation: tumour escape from immune surveillance? (review). Int J Oncol 2004; 25:487-91; PMID:15254748; http://dx. doi.org/10.3892/ijo.25.2.487.
20. Hicklin DJ, Marincola FM, Ferrone S. HLA class I antigen downregulation in human cancers: T-cell immunotherapy revives an old story. Mol Med Today 1999; 5:178-86; PMID:10203751; http://dx.doi.org/ 10.1016/S1357-4310(99)01451-3
21. Kageshita T, Hirai S, Ono T, Hicklin DJ, Ferrone S. Down-regulation of HLA class I antigen-processing molecules in malignant melanoma: association with disease progression. Am J Pathol 1999; 154:745-54; PMID:10079252; http://dx.doi.org/10.1016/S0002-9440(10)65321-7
22. Rees RC, Mian S. Selective MHC expression in tumours modulates adaptive and innate antitumour responses. Cancer Immunol Immunother 1999; 48:374-81; PMID:10501850; http://dx.doi.org/ 10.1007/s002620050589
23. Cabrera CM, Jimenez P, Cabrera T, Esparza C, Ruiz-Cabello F, Garrido F. Total loss of MHC class I in colorectal tumors can be explained by two molecular pathways: beta2-microglobulin inactivation in MSIpositive tumors and LMP7/TAP2 downregulation in MSI-negative tumors. Tissue Antigens 2003; 61:211-9; PMID:12694570; http://dx.doi.org/10.1034/ j.1399-0039.2003.00020.x
24. Johnsen AK, Templeton DJ, Sy M, Harding CV. Deficiency of transporter for antigen presentation (TAP) in tumor cells allows evasion of immune surveillance and increases tumorigenesis. J Immunol 1999; 163:4224-31; PMID: 10510359.
25. Ritz U, Momburg F, Pilch H, Huber C, Maeurer MJ, Seliger B. Deficient expression of components of the MHC class I antigen processing machinery in human cervical carcinoma. Int J Oncol 2001; 19:1211-20; PMID:11713591; http://dx.doi.org/10.3892/ ijo.19.6.1211
26. Irving BA, Weiss A. The cytoplasmic domain of the T cell receptor zeta chain is sufficient to couple to receptor-associated signal transduction pathways. Cell 1991; 64:891-901; PMID:1705867; http://dx.doi. org/10.1016/0092-8674(91)90314-O
27. Eshhar Z, Waks T, Gross G, Schindler DG. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibodybinding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci U S A 1993; 90:720-4; PMID:8421711; http://dx.doi.org/10.1073/pnas.90.2.720
28. Kershaw MH, Westwood JA, Parker LL, Wang G, Eshhar Z, Mavroukakis SA, White DE, Wunderlich JR, Canevari S, Rogers-Freezer L et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res 2006; 12:6106-15; PMID:17062687; http://dx.doi.org/ 10.1158/1078-0432.CCR-06-1183
29. Lamers CH, Sleijfer S, Vulto AG, Kruit WH, Kliffen M, Debets R, Gratama JW, Stoter G, Oosterwijk E. Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. J Clin Oncol 2006; 24:e20-2; PMID:16648493; http://dx.doi.org/10.1200/JCO.2006.05.9964
30. Till BG, Jensen MC, Wang J, Chen EY, Wood BL, Greisman HA, Qian X, James SE, Raubitschek A, Forman SJ et al. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood 2008; 112:2261-71; PMID:18509084; http://dx.doi.org/10.1182/blood-2007-12-128843
31. Maher J, Brentjens RJ, Gunset G, Riviere I, Sadelain M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta /CD28 receptor. Nat Biotechnol 2002; 20:70-5; PMID:11753365; http://dx.doi.org/10.1038/ nbt0102-70
32. Pule MA, Straathof KC, Dotti G, Heslop HE, Rooney CM, Brenner MK. A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells. Mol Ther 2005; 12:933-41; PMID:15979412; http://dx.doi. org/10.1016/j.ymthe.2005.04.016
33. Imai C, Mihara K, Andreansky M, Nicholson IC, Pui CH, Geiger TL, Campana D. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 2004; 18:676-84; PMID:14961035; http://dx. doi.org/10.1038/sj.leu.2403302
34. Zhao Y, Wang QJ, Yang S, Kochenderfer JN, Zheng Z, Zhong X, Sadelain M, Eshhar Z, Rosenberg SA, Morgan RA. A herceptin-based chimeric antigen receptor with modified signaling domains leads to enhanced survival of transduced T lymphocytes and antitumor activity. J Immunol 2009; 183:5563-74; PMID: 19843940; http://dx.doi.org/10.4049/ jimmunol.0900447
35. Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, Bartido S, Stefanski J, Taylor C, Olszewska M et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapyrefractory acute lymphoblastic leukemia. Sci Transl Med 2013; 5:177ra38; PMID:23515080; http://dx. doi.org/10.1126/scitranslmed.3005930
36. Cruz CR, Micklethwaite KP, Savoldo B, Ramos CA, Lam S, Ku S, Diouf O, Liu E, Barrett AJ, Ito S et al. Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study. Blood 2013; 122:2965-73; PMID:24030379; http://dx.doi. org/10.1182/blood-2013-06-506741
37. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 2013; 368:1509-18; PMID:23527958; http://dx.doi. org/10.1056/NEJMoa1215134
38. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 2011; 365:725-33; PMID:21830940; http://dx.doi.org/10.1056/ NEJMoa1103849
39. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 2014; 371:1507-17; PMID:25317870; http://dx.doi.org/ 10.1056/NEJMoa1407222
40. Pule MA, Savoldo B, Myers GD, Rossig C, Russell HV, Dotti G, Huls MH, Liu E, Gee AP, Mei Z et al. Virus-specific T cells engineered to coexpress tumorspecific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med 2008; 14:1264-70; PMID:18978797; http://dx.doi.org/ 10.1038/nm.1882
41. Morgan RA, Johnson LA, Davis JL, Zheng Z, Woolard KD, Reap EA, Feldman SA, Chinnasamy N, Kuan CT, Song H et al. Recognition of glioma stem cells by genetically modified T cells targeting EGFRvIII and development of adoptive cell therapy for glioma. Hum Gene Ther 2012; 23:1043-53; PMID:22780919; http://dx.doi.org/10.1089/ hum.2012.041
42. Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther 2010; 18:843-51; PMID:20179677; http://dx.doi.org/10.1038/ mt.2010.24
43. Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, Friedman HS, Gilbert MR, Herndon JE, 2nd, McLendon RE, Mitchell DA 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; 28:4722-9; PMID:20921459; http://dx.doi.org/10.1200/ JCO.2010.28.6963
44. Sampson JH, Choi BD, Sanchez-Perez L, Suryadevara CM, Snyder DJ, Flores CT, Schmittling RJ, Nair SK, Reap EA, Norberg PK et al. EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss. Clin Cancer Res 2014; 20:972-84; PMID:24352643; http://dx.doi.org/10.1158/ 1078-0432.CCR-13-0709
45. Curtin JF, Liu N, Candolfi M, Xiong W, Assi H, Yagiz K, Edwards MR, Michelsen KS, Kroeger KM, Liu C et al. HMGB1 mediates endogenous TLR2 activation and brain tumor regression. PLoS Med 2009; 6:e10; PMID:19143470; http://dx.doi.org/ 10.1371/journal.pmed.1000010
46. Ingber DE. Can cancer be reversed by engineering the tumor microenvironment? Semin Cancer Biol 2008; 18:356-64; PMID:18472275; http://dx.doi.org/ 10.1016/j.semcancer.2008.03.016
47. Folkman J, Watson K, Ingber D, Hanahan D. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 1989; 339:58-61; PMID:2469964; http://dx.doi.org/10.1038/ 339058a0
48. Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 1986; 315:1650-9; PMID:3537791; http://dx.doi.org/10.1056/ NEJM198612253152606
49. van Kempen LC, Ruiter DJ, van Muijen GN, Coussens LM. The tumor microenvironment: a critical determinant of neoplastic evolution. Eur J Cell Biol 2003; 82:539-48; PMID:14703010; http://dx.doi. org/10.1078/0171-9335-00346
50. Shiao SL, Ganesan AP, Rugo HS, Coussens LM. Immune microenvironments in solid tumors: new targets for therapy. Genes Dev 2011; 25:2559-72; PMID:22190457; http://dx.doi.org/10.1101/ gad.169029.111
51. Qin Z, Richter G, Schuler T, Ibe S, Cao X, Blankenstein T. B cells inhibit induction of T cell-dependent tumor immunity. Nat Med 1998; 4:627-30; PMID:9585241; http://dx.doi.org/10.1038/nm0598-627
52. Inoue S, Leitner WW, Golding B, Scott D. Inhibitory effects of B cells on antitumor immunity. Cancer Res 2006; 66:7741-7; PMID:16885377; http://dx.doi. org/10.1158/0008-5472.CAN-05-3766
53. Halder RC, Aguilera C, Maricic I, Kumar V. Type II NKT cell-mediated anergy induction in type I NKT cells prevents inflammatory liver disease. J Clin Invest 2007; 117:2302-12; PMID:17641782; http://dx.doi. org/10.1172/JCI31602
54. Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 2013; 14:1014-22; PMID:24048123; http://dx.doi.org/10.1038/ni.2703
55. DeNardo DG, Andreu P, Coussens LM. Interactions between lymphocytes and myeloid cells regulate proversus anti-tumor immunity. Cancer Metastasis Rev 2010; 29:309-16; PMID:20405169; http://dx.doi. org/10.1007/s10555-010-9223-6
56. Motz GT, Coukos G. The parallel lives of angiogenesis and immunosuppression: cancer and other tales. Nat Rev Immunol 2011; 11:702-11; PMID:21941296; http://dx.doi.org/10.1038/nri3064
57. Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nat Rev Cancer 2011; 11:393-410; PMID:21606941; http://dx.doi.org/10.1038/ nrc3064
58. Facciabene A, Motz GT, Coukos G. T-regulatory cells: key players in tumor immune escape and angiogenesis. Cancer Res 2012; 72:2162-71; PMID:22549946; http://dx.doi.org/10.1158/0008-5472.CAN-11-3687
59. Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A, Wang LP, Gimotty PA, Gilks CB, Lal P, Zhang L et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 2011; 475:226-30; PMID:21753853; http://dx.doi. org/10.1038/nature10169
60. Arreygue-Garcia NA, Daneri-Navarro A, del Toro-Arreola A, Cid-Arregui A, Gonzalez-Ramella O, Jave-Suarez LF, Aguilar-Lemarroy A, Troyo-Sanroman R, Bravo-Cuellar A, Delgado-Rizo V et al. Augmented serum level of major histocompatibility complex class I-related chain A (MICA) protein and reduced NKG2D expression on NK and T cells in patients with cervical cancer and precursor lesions. BMC Cancer 2008; 8:16; PMID:18208618; http://dx.doi.org/ 10.1186/1471-2407-8-16
61. Raulet DH. Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol 2003; 3:781-90; PMID:14523385; http://dx.doi.org/10.1038/nri1199
62. Siemens DR, Hu N, Sheikhi AK, Chung E, Frederiksen LJ, Pross H, Graham CH. Hypoxia increases tumor cell shedding of MHC class I chain-related molecule: role of nitric oxide. Cancer Res 2008; 68:4746-53; PMID:18559521; http://dx.doi.org/ 10.1158/0008-5472.CAN-08-0054
63. Barsoum IB, Smallwood CA, Siemens DR, Graham CH. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res 2014; 74:665-74; PMID:24336068; http://dx.doi.org/ 10.1158/0008-5472.CAN-13-0992
64. Li MC, Hertz R, Bergenstal DM. Therapy of choriocarcinoma and related trophoblastic tumors with folic acid and purine antagonists. N Engl J Med 1958; 259:66-74; PMID:13566422; http://dx.doi.org/ 10.1056/NEJM195807102590204
65. Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol 2004; 4:336-47; PMID:15122199; http:// dx.doi.org/10.1038/nri1349
66. Melero I, Hervas-Stubbs S, Glennie M, Pardoll DM, Chen L. Immunostimulatory monoclonal antibodies for cancer therapy. Nat Rev Cancer 2007; 7:95-106; PMID:17251916; http://dx.doi.org/10.1038/ nrc2051
67. Sheridan C. TeGenero fiasco prompts regulatory rethink. Nat Biotechnol 2006; 24:475-6; PMID:16680111; http://dx.doi.org/10.1038/ nbt0506-475
68. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, Panoskaltsis N. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 2006; 355:1018-28; PMID:16908486; http://dx.doi. org/10.1056/NEJMoa063842
69. Attia P, Phan GQ, Maker AV, Robinson MR, Quezado MM, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol 2005; 23:6043-53; PMID:16087944; http://dx.doi.org/10.1200/ JCO.2005.06.205
70. Fischkoff SA, Hersh E, Weber J, Powderly J, Khan K, Pavlick A, Samlowski W, O'Day S, Nichol G, Yellin M. Durable responses and long-term progression-free survival observed in a phase II study of MOX-010 alone or in combination with dacarbazine (DTIC) in metastatic melanoma. J Clin Oncol 2005; 23:716s.
71. Maker AV, Phan GQ, Attia P, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE, Haworth LR, Levy C et al. Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study. Ann Surg Oncol 2005; 12:1005-16; PMID:16283570; http://dx.doi.org/10.1245/ ASO.2005.03.536
72. Bafaloukos D, Gogas H. The treatment of brain metastases in melanoma patients. Cancer Treat Rev 2004; 30:515-20; PMID:15325032; http://dx.doi. org/10.1016/j.ctrv.2004.05.001
73. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363:711-23; PMID:20525992; http://dx.doi.org/10.1056/NEJMoa1003466
74. Mandel JJ, Olar A, Aldape KD, Tremont-Lukats IW. Lambrolizumab induced central nervous system (CNS) toxicity. J Neurol Sci 2014; 344:229-31; PMID:24980937; http://dx.doi.org/10.1016/j. jns.2014.06.023
75. Glennie MJ, McBride HM, Worth AT, Stevenson GT. Preparation and performance of bispecific F(ab' gamma)2 antibody containing thioether-linked Fab' gamma fragments. J Immunol 1987; 139:2367-75.
76. Kriangkum J, Xu B, Nagata LP, Fulton RE, Suresh MR. Bispecific and bifunctional single chain recombinant antibodies. Biomol Eng 2001; 18:31-40; PMID:11535414; http://dx.doi.org/10.1016/S1389-0344(01)00083-1
77. Holliger P, Prospero T, Winter G. "Diabodies:" small bivalent and bispecific antibody fragments. Proc Natl Acad Sci U S A 1993; 90:6444-8; PMID:8341653; http://dx.doi.org/10.1073/pnas.90.14.6444
78. Atwell JL, Pearce LA, Lah M, Gruen LC, Kortt AA, Hudson PJ. Design and expression of a stable bispecific scFv dimer with affinity for both glycophorin and N9 neuraminidase. Mol Immunol 1996; 33:1301-12; PMID:9171890; http://dx.doi.org/10.1016/S0161-5890(96)00097-1
79. De Jonge J, Brissinck J, Heirman C, Demanet C, Leo O, Moser M, Thielemans K. Production and characterization of bispecific single-chain antibody fragments. Mol Immunol 1995; 32:1405-12; PMID:8643110; http://dx.doi.org/10.1016/0161-5890(95)00089-5
80. Mack M, Riethmuller G, Kufer P. A small bispecific antibody construct expressed as a functional singlechain molecule with high tumor cell cytotoxicity. Proc Natl Acad Sci U S A 1995; 92:7021-5; PMID:7624362; http://dx.doi.org/10.1073/ pnas.92.15.7021
81. Wolf E, Hofmeister R, Kufer P, Schlereth B, Baeuerle PA. BiTEs: bispecific antibody constructs with unique anti-tumor activity. Drug Discov Today 2005; 10:1237-44; PMID:16213416; http://dx.doi.org/ 10.1016/S1359-6446(05)03554-3
82. Choi BD, Cai M, Bigner DD, Mehta AI, Kuan CT, Sampson JH. Bispecific antibodies engage T cells for antitumor immunotherapy. Expert Opin Biol Ther 2011; 11:843-53; PMID:21449821; http://dx.doi. org/10.1517/14712598.2011.572874
83. Dustin ML, Shaw AS. Costimulation: building an immunological synapse. Science 1999; 283:649-50; PMID:9988658; http://dx.doi.org/10.1126/ science.283.5402.649
84. Stinchcombe JC, Bossi G, Booth S, Griffiths GM. The immunological synapse of CTL contains a secretory domain and membrane bridges. Immunity 2001; 15:751-61; PMID:11728337; http://dx.doi.org/ 10.1016/S1074-7613(01)00234-5
85. Offner S, Hofmeister R, Romaniuk A, Kufer P, Baeuerle PA. Induction of regular cytolytic T cell synapses by bispecific single-chain antibody constructs on MHC class I-negative tumor cells. Mol Immunol 2006; 43:763-71; PMID:16360021; http://dx.doi. org/10.1016/j.molimm.2005.03.007
86. Mack M, Gruber R, Schmidt S, Riethmuller G, Kufer P. Biologic properties of a bispecific single-chain antibody directed against 17-1A (EpCAM) and CD3: tumor cell-dependent T cell stimulation and cytotoxic activity. J Immunol 1997; 158:3965-70; PMID: 9103467.
87. Choi BD, Kuan CT, Cai M, Archer GE, Mitchell DA, Gedeon PC, Sanchez-Perez L, Pastan I, Bigner DD, Sampson JH. Systemic administration of a bispecific antibody targeting EGFRvIII successfully treats intracerebral glioma. Proc Natl Acad Sci U S A 2013; 110:270-5; PMID:23248284; http://dx.doi.org/ 10.1073/pnas.1219817110
88. Brandl C, Haas C, d'Argouges S, Fisch T, Kufer P, Brischwein K, Prang N, Bargou R, Suzich J, Baeuerle PA, et al. The effect of dexamethasone on polyclonal T cell activation and redirected target cell lysis as induced by a CD19/CD3-bispecific single-chain antibody construct. Cancer Immunol Immunother 2007; 56:1551-63; PMID:17310380; http://dx.doi.org/ 10.1007/s00262-007-0298-z
89. Nagorsen D, Kufer P, Baeuerle PA, Bargou R. Blinatumomab: a historical perspective. Pharmacol Ther 2012; 136:334-42; PMID:22940266; http://dx.doi. org/10.1016/j.pharmthera.2012.07.013
90. Dreier T, Lorenczewski G, Brandl C, Hoffmann P, Syring U, Hanakam F, Kufer P, Riethmuller G, Bargou R, Baeuerle PA. Extremely potent, rapid and costimulation-independent cytotoxic T-cell response against lymphoma cells catalyzed by a single-chain bispecific antibody. Int J Cancer 2002; 100:690-7; PMID:12209608; http://dx.doi.org/10.1002/ ijc.10557
91. Browne KA, Blink E, Sutton VR, Froelich CJ, Jans DA, Trapani JA. Cytosolic delivery of granzyme B by bacterial toxins: evidence that endosomal disruption, in addition to transmembrane pore formation, is an important function of perforin. Mol Cell Biol 1999; 19:8604-15; PMID:10567584
92. Haas C, Krinner E, Brischwein K, Hoffmann P, Lutterbuse R, Schlereth B, Kufer P, Baeuerle PA. Mode of cytotoxic action of T cell-engaging BiTE antibody MT110. Immunobiology 2009; 214:441-53; PMID:19157637; http://dx.doi.org/10.1016/j. imbio.2008.11.014
93. Gruen M, Bommert K, Bargou RC. T-cell-mediated lysis of B cells induced by a CD19xCD3 bispecific single-chain antibody is perforin dependent and death receptor independent. Cancer Immunol Immunother 2004; 53:625-32; PMID:15175907; http://dx.doi. org/10.1007/s00262-003-0496-2
94. Choi BD, Gedeon PC, Sanchez-Perez L, Bigner DD, Sampson JH. Regulatory T cells are redirected to kill glioblastoma by an EGFRvIII-targeted bispecific antibody. Oncoimmunology 2013; 2:e26757; PMID:24475376; http://dx.doi.org/10.4161/ onci.26757
95. Choi BD, Gedeon PC, Herndon JE, 2nd, Archer GE, Reap EA, Sanchez-Perez L, Mitchell DA, Bigner DD, Sampson JH. Human regulatory T cells kill tumor cells through granzyme-dependent cytotoxicity upon retargeting with a bispecific antibody. Cancer Immunol Res 2013; 1:163; PMID:24570975; http://dx.doi. org/10.1158/2326-6066.CIR-13-0049
96. Brischwein K, Parr L, Pflanz S, Volkland J, Lumsden J, Klinger M, Locher M, Hammond SA, Kiener P, Kufer P et al. Strictly target cell-dependent activation of T cells by bispecific single-chain antibody constructs of the BiTE class. J immunother 2007; 30:798-807; PMID:18049331; http://dx.doi.org/ 10.1097/CJI.0b013e318156750c
97. Brischwein K, Schlereth B, Guller B, Steiger C, Wolf A, Lutterbuese R, Offner S, Locher M, Urbig T, Raum T, et al. MT110: a novel bispecific single-chain antibody construct with high efficacy in eradicating established tumors. Mol Immunol 2006; 43:1129-43; PMID:16139892; http://dx.doi.org/10.1016/j. molimm.2005.07.034
98. Nah JH, Kim HJ, Lee HN, Lee MJ, Choi SS, Kim ES. Identification and biotechnological application of novel regulatory genes involved in Streptomyces polyketide overproduction through reverse engineering strategy. Biomed Res Int 2013; 2013:549737; PMID:23555090; http://dx.doi.org/10.1155/2013/ 549737
99. Yu F, Wang X, Guo ZS, Bartlett DL, Gottschalk SM, Song XT. T-cell engager-armed oncolytic vaccinia virus significantly enhances antitumor therapy. Mol Ther 2014; 22:102-11; PMID:24135899; http://dx. doi.org/10.1038/mt.2013.240
100. Nagorsen D, Baeuerle PA. Immunomodulatory therapy of cancer with T cell-engaging BiTE antibody blinatumomab. Exp Cell Res 2011; 317:1255-60; PMID:21419116; http://dx.doi.org/10.1016/j. yexcr.2011.03.010
101. Bargou R, Leo E, Zugmaier G, Klinger M, Goebeler M, Knop S, Noppeney R, Viardot A, Hess G, Schuler M et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science 2008; 321:974-7; PMID:18703743; http://dx.doi. org/10.1126/science.1158545
102. Schlegel P, Lang P, Zugmaier G, Ebinger M, Kreyenberg H, Witte KE, Feucht J, Pfeiffer M, Teltschik HM, Kyzirakos C et al. Pediatric posttransplant relapsed/refractory B-precursor acute lymphoblastic leukemia shows durable remission by therapy with the T-cell engaging bispecific antibody blinatumomab. Haematologica 2014; 99:1212-19.
103. Wong R, Pepper C, Brennan P, Nagorsen D, Man S, Fegan C. Blinatumomab induces autologous T-cell killing of chronic lymphocytic leukemia cells. Haematologica 2013; 98:1930-8; PMID:23812940; http:// dx.doi.org/10.3324/haematol.2012.082248
104. Maloney DG, Grillo-Lopez AJ,White CA, Bodkin D, Schilder RJ, Neidhart JA, Janakiraman N, Foon KA, Liles TM, Dallaire BK et al. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood 1997; 90:2188-95; PMID:9310469
105. Hudis CA. Trastuzumab-mechanism of action and use in clinical practice. N Engl J Med 2007; 357:39-51; PMID:17611206; http://dx.doi.org/10.1056/ NEJMra043186
106. Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, Berry SR, Krahn M, Price T, Simes RJ et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007; 357:2040-8; PMID:18003960; http://dx.doi.org/10.1056/ NEJMoa071834
107. Aggarwal RS. What's fueling the biotech engine-2012 to 2013. Nat Biotechnol 2014; 32:32-9; PMID:24406926; http://dx.doi.org/10.1038/ nbt.2794
108. Baeuerle PA, Kufer P, Bargou R. BiTE: teaching antibodies to engage T-cells for cancer therapy. Curr Opin Mol Ther 2009; 11:22-30; PMID:19169956
109. Topp MGN, Kufer P et al. Treatment with anti-CD19 BiTE antibody blinatumomab (MT103/ MEDI-538) is able to eliminate minimal residual disease (MRD) in patients with B-precursor acute lmphoblastic leukemia (ALL): First results of ongoing phase 2 study ASH Annual Meeting: Blood, 2008:1926.
110. Calzascia T, Masson F, Di Berardino-Besson W, Contassot E, Wilmotte R, Aurrand-Lions M, Ruegg C, Dietrich PY, Walker PR. Homing phenotypes of tumor-specific CD8 T cells are predetermined at the tumor site by crosspresenting APCs. Immunity 2005; 22:175-84; PMID:15723806; http://dx.doi.org/ 10.1016/j.immuni.2004.12.008
111. Gedeon PC, Choi BD, Hodges TR, Mitchell DA, Bigner DD, Sampson JH. An EGFRvIII-targeted bispecific T-cell engager overcomes limitations of the standard of care for glioblastoma. Expert Rev Clin Pharmacol 2013; 6:375-86; PMID:23927666; http:// dx.doi.org/10.1586/17512433.2013.811806
112. Choi BD, Pastan I, Bigner DD, Sampson JH. A novel bispecific antibody recruits T cells to eradicate tumors in the "immunologically privileged" central nervous system. Oncoimmunology 2013; 2:e23639; PMID:23734318; http://dx.doi.org/10.4161/ onci.23639
113. Choi BD, Archer GE, Mitchell DA, Heimberger AB, McLendon RE, Bigner DD, Sampson JH. EGFRvIII-targeted vaccination therapy of malignant glioma. Brain Pathol 2009; 19:713-23; PMID:19744042; http://dx.doi.org/10.1111/ j.1750-3639.2009.00318.x
114. Congdon KL, Gedeon PC, Suryadevara CM, Caruso HG, Cooper LJ, Heimberger AB, Sampson JH. Epidermal growth factor receptor and variant III targeted immunotherapy. Neuro-oncol 2014; 16:viii20-viii5; PMID:25342601; http://dx.doi.org/10.1093/neuonc/ nou236
115. Gedeon PC, Riccione KA, Fecci PE, Sampson JH. Antibody-based immunotherapy for malignant glioma. Seminn Oncol 2014; 41:496-510; PMID:25173142; http://dx.doi.org/10.1053/j. seminoncol.2014.06.004