Top

Published in:

01-02-2007 | Editorial

The strange case of TGN1412

Authors: L. Farzaneh, N. Kasahara, F. Farzaneh

Published in: Cancer Immunology, Immunotherapy | Issue 2/2007

Excerpt

A current focus of cancer research is the development of immunostimulatory therapeutic antibodies, based on the notion that increasing the number or activity of cytotoxic T lymphocytes, and in particular those directed against tumour-associated antigens, may achieve effective immune mediated tumour rejection. Unlike other techniques, such as the use of antibodies specific to tumour cells themselves, this approach does not rely on antigen-specificity, and accordingly is subject to risks of autoimmunity as a consequence of non-specific activation of T cells [1]. …

Gilboa E (2001) The risk of autoimmunity associated with tumor immunotherapy. Nat Immunol 2:789–792PubMedCrossRef

TGN1412 Investigator’s Brochure. http://www.mhra.gov.uk/home/groups/es-foi/documents/foidisclosure/con2023525.pdf

Beyersdorf N, Hanke T, Kerkau T, Hunig T (2005) Superagonistic anti-CD28 antibodies: potent activators of regulatory T cells for the therapy of autoimmune diseases. Ann Rheum Dis 64:91–95CrossRef

Luhder F, Huang Y, Dennehy KM, Guntermann C, Muller I, Winkler E, Kerkau T, Ikemizu S, Davis SJ, Hanke T, Hunig T (2003) Topological requirements and signaling properties of T cell-activating, anti-CD28 antibody superagonists. J Exp Med 197:949–953CrossRef

Lin C-H, Kerkau T, Guntermann C, Trischler M, Beyersdorf N, Scheuring Y, Tony H-P, Kneitz C, Wilhelm M, Mueller P, Huenig T, Hanke T (2004) Superagonistic anti-CD28 antibody TGN1412 as a potential immunotherapeutic for the treatment of B cell chronic lymphocytic leukemia. Blood 104:690A

MHRA Press release (2006) Investigations into adverse incidents during clinical trials of TGN1412: interim report. http://www.mhra.gov.uk/home/groups/comms-po/documents/websiteresources/con2023519.pdf

Linsley PS, Clark EA, Ledbetter JA (1990) T-cell antigen CD28 mediates adhesion with B-cells by interacting with activation antigen B7/B7-1. Proc Natl Acad Sci USA 87:5031–5035PubMedCrossRef

Gimmi CD, Freeman GJ, Gribben JG, Sugita K, Freedman AS, Morimoto C, Nadler LM (1991) B-cell surface antigen-B7 provides a costimulatory signal that induces T-cells to proliferate and secrete interleukin-2. Proc Natl Acad Sci USA 88:6575–6579PubMedCrossRef

Lenschow DJ, Walunas TL, Bluestone JA (1996) CD28/B7 system of T cell costimulation. Annu Rev Immunol 14:233–258PubMedCrossRef

10.

Koulova L, Clark EA, Shu G, Dupont B (1991) The CD28 ligand B7/BB1 provides costimulatory signal for alloactivation of CD4⁺ T-cells. J Exp Med 173:759–762PubMedCrossRef

11.

Linsley PS, Brady W, Grosmaire L, Aruffo A, Damle NK, Ledbetter JA (1991) Binding of the B-cell activation antigen B7 to CD28 costimulates T-cell proliferation and interleukin-2 messenger-RNA accumulation. J Exp Med 173:721–730PubMedCrossRef

12.

Bette M, Schafer MKH, Van Rooijen N, Weihe E, Fleischer B (1993) Distribution and kinetics of superantigen-induced cytokine gene-expression in mouse spleen. J Exp Med 178:1531–1540PubMedCrossRef

13.

Brinkmann V, Kinzel B, Kristofic C (1996) TCR-independent activation of human CD4⁽⁺⁾45RO⁽⁻⁾ T cells by anti-CD28 plus IL-2 – induction of clonal expansion and priming for a Th2 phenotype. J Immunol 156:4100–4106PubMed

14.

Tacke M, Hanke G, Hanke T, Hunig T (1997) CD28-mediated induction of proliferation in resting T cells in vitro and in vivo without engagement of the T cell receptor: evidence for functionally distinct forms of CD28. Eur J Immunol 27:239–247PubMed

15.

Raab M, Pfister S, Rudd CE (2001) CD28 signaling via VAV/SLP-76 adaptors: regulation of cytokine transcription independent of TCR ligation. Immunity 15:921–933PubMedCrossRef

16.

Faulkner L, Cooper A, Fantino C, Altmann DM, Sriskandan S (2005) The mechanism of superantigen-mediated toxic shock: not a simple Th1 cytokine storm. J Immunol 175:6870–6877PubMed

17.

Lin CH, Hunig T (2003) Efficient expansion of regulatory T cells in vitro and in vivo with a CD28 superagonist. Eur J Immunol 33:626–638PubMedCrossRef

18.

Beyersdorf N, Hanke T, Kerkau T, Hunig T (2006) CD28 superagonists put a break on autoimmunity by preferentially activating CD4⁽⁺⁾CD25⁽⁺⁾ regulatory T cells. Autoimmun Rev 5:40–45PubMedCrossRef

19.

Hunig T, Dennehy K (2005) CD28 superagonists: mode of action and therapeutic potential. Immunol Lett 100:21–28PubMedCrossRef

20.

Bluestone JA, Tang Q (2005) How do CD4⁺CD25⁺ regulatory T cells control autoimmunity? Curr Opin Immunol 17:638–642PubMedCrossRef

21.

Wei W-Z, Morris GP, Kong Y-CM (2004) Anti-tumour immunity and autoimmunity: a balancing act of regulatory T cells. Cancer Immunol Immunother 53:73–78PubMedCrossRef

22.

Chattopadhyay S, Chakraborty NG, Mukherji B (2005) Regulatory T cells and tumour immunity. Cancer Immunol Immunother 54:1153–1161PubMedCrossRef

23.

Chatila TA (2005) Role of regulatory T cells in human diseases. J Allergy Clin Immunol 116:949–959PubMedCrossRef

24.

Hsieh CS, Liang Y, Tyznik AJ, Self SG, Liggitt D, Rudensky AY (2004) Recognition of the peripheral self by naturally arising CD25⁽⁺⁾ CD4⁽⁺⁾ T cell receptors. Immunity 21:267–277PubMedCrossRef

25.

Tang Q, Henriksen KJ, Boden EK, Tooley AJ, Ye J, Subudhi SK, Zheng XX, Strom TB, Bluestone JA (2003) Cutting edge: CD28 controls peripheral homeostasis of CD4⁽⁺⁾CD25⁽⁺⁾. J Immunol 171:3348–3352PubMed

26.

Schmidt J, Elflein K, Stienekemeier M, Rodriguez-Palmero M, Schneider C, Toyka KV, Gold R, Hunig T (2003) Treatment and prevention of experimental autoimmune neuritis with superagonistic CD28-specific monoclonal antibodies. J Neuroimmunol 140:143–152PubMedCrossRef

27.

Beyersdorf N, Gaupp S, Balbach K, Schmidt J, Toyka KV, Lin CH, Hanke T, Hunig T, Kerkau T, Gold R (2005) Selective targeting of regulatory T cells with CD28 superagonists allows effective therapy of experimental autoimmune encephalomyelitis. J Exp Med 202:445–455PubMedCrossRef

28.

Dannull J, Su Z, Rizzieri D, Yang BK, Coleman D, Yancey D, Zhang A, Dahm P, Chao N, Gilboa E, Vieweg J (2005) Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J Clin Invest 115:3623–3633PubMedCrossRef

29.

Weinberg WC, Frazier-Jessen MR, Wu WJ, Weir A, Hartsough M, Keegan P, Fuchs C (2005) Development and regulation of monoclonal antibody products: challenges and opportunities. Cancer Metastasis Rev 24:569–584PubMedCrossRef

30.

Pascolo S (2005) HLA class I transgenic mice: development, utilisation and improvement. Expert Opin Biol Ther 5:919–938PubMedCrossRef

31.

Alegre ML, Frauwirth KA, Thompson CB (2001) T-cell regulation by CD28 and CTLA-4. Nat Rev Immunol 1:220–228PubMedCrossRef

32.

Brunner MC, Chambers CA, Chan FK, Hanke J, Winoto A, Allison JP (1999) CTLA-4-mediated inhibition of early events of T cell proliferation. J Immunol 162:5813–5820PubMed

33.

Gribben JG, Freeman GJ, Boussiotis VA, Rennertt P, Jellist CL, Greenfieldt E, Barber M, Restivo VA, Ke X, Grayt GS, Nadler LM (1995) CTLA4 mediates antigen-specific apoptosis of human T-cells. Proc Nat Acad Sci USA 92:811–815PubMedCrossRef

34.

Walunas TL, Bakker CY, Bluestone JA (1996) CTLA-4 ligation blocks CD28-dependent T cell activation. J Exp Med 183:2541–2550PubMedCrossRef

35.

Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA (1991) CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 174:561–569PubMedCrossRef

36.

Krummel MF, Allison JP (1996) CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells. J Exp Med 183:2533–2540PubMedCrossRef

37.

Alegre ML, Shiels H, Thompson CB, Gajewski TF (1998) Expression and function of CTLA-4 in Th1 and Th2 cells. J Immunol 161:3347–3356PubMed

38.

Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S (2000) Immunologic self-tolerance maintained by CD25⁽⁺⁾CD4⁽⁺⁾ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 192:303–310PubMedCrossRef

39.

Allison JP, Krummel MF (1995) The Yin and Yang of T-Cell costimulation. Science 270:932–933PubMedCrossRef

40.

Krummel MF, Sullivan TJ, Allison JP (1996) Superantigen responses and co-stimulation: CD28 and CTLA-4 have opposing effects on T cell expansion in vitro and in vivo. Int Immunol 8:519–523PubMed

41.

Blair PJ, Riley JL, Levine BL, Lee KP, Craighead N, Francomano T, Perfetto SJ, Gray GS, Carreno BM, June CH (1998) CTLA-4 ligation delivers a unique signal to resting human CD4 T cells that inhibits interleukin-2 secretion but allows Bcl-X(L) induction. J Immunol 160:12–15PubMed

42.

Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH (1995) Loss of Ctla-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3:541–547PubMedCrossRef

43.

Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW (1995) Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4. Science 270:985–988PubMedCrossRef

44.

Donner H, Braun J, Seidl C, Rau H, Finke R, Ventz M, Walfish PG, Usadel KH, Badenhoop K (1997) CTLA4 alanine-17 confers genetic susceptibility to Graves’ disease and to type 1 diabetes mellitus. J Clin Endocrinol Metab 82:143–146PubMedCrossRef

45.

Hurwitz AA, SullivanTJ, Krummel MF, Sobel RA, Allison JP (1997) Specific blockade of CTLA-4/B7 interactions results in exacerbated clinical and histologic disease in an actively-induced model of experimental allergic encephalomyelitis. J Neuroimmunol 73:57–62PubMedCrossRef

46.

van Elsas A, Hurwitz AA, Allison JP (1999) Combination immunotherapy of B16 melanoma using anti-cytotoxic 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 190:355–366PubMedCrossRef

47.

Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ, Restifo NP, Haworth LR, Seipp CA, Freezer LJ, Morton KE, Mavroukakis SA, Duray PH, Steinberg SM, Allison JP, Davis TA, Rosenberg SA (2003) Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 100:8372–8377PubMedCrossRef

48.

Sanderson K, Scotland R, Lee P, Liu D, Groshen S, Snively J, Sian S, Nichol G, Davis T, Keler T, Yellin M, Weber J (2005) 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 23:741–750PubMedCrossRef

49.

Maker AV, Phan GQ, Attia P, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE, Haworth LR, Levy C, Kleiner D, Mavroukakis SA, Yellin M, Rosenberg SA (2005) 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 12:1005–1016PubMedCrossRef

50.

Blansfield JA, Beck KE, Tran K, Yang JC, Hughes MS, Kammula US, Royal RE, Topalian SL, Haworth LR, Levy C, Rosenberg SA, Sherry RM (2005) Cytotoxic T-Lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother 28:593–598PubMedCrossRef

51.

Maker AV, Attia P, Rosenberg SA (2005) Analysis of the cellular mechanism of antitumor responses and autoimmunity in patients treated with CTLA-4 blockade. J Immunol 175:7746–7754PubMed

52.

Riley JL, Mao M, Kobayashi S, Biery M, Burchard J, Cavet G, Gregson BP, June CH, Linsley PS (2002). Modulation of TCR-induced transcriptional profiles by ligation of CD28, ICOS, and CTLA-4 receptors. Proc Natl Acad Sci USA 99:11790–11795PubMedCrossRef

53.

Diehn M, Alizadeh AA, Rando OJ, Liu CL, Stankunas K, Botstein D, Crabtree GR, Brown PO (2002) Genomic expression programs and the integration of the CD28 costimulatory signal in T cell activation. Proc Natl Acad Sci USA 99:11796–11801PubMedCrossRef

54.

Panelli MC, White R, Foster M, Martin B, Wang E, Smith K, Marincola FM (2004). Forecasting the cytokine storm following systemic interleukin (IL)-2 administration. J Transl Med 2:17PubMedCrossRef

55.

Chan L, Hardwick N, Darling D, Galea-Lauri J, Gaken J, Devereux S, Kemeny M, Mufti G, Farzaneh F (2005) IL-2/B7.1 (CD80) fusagene transduction of AML blasts by a self-inactivating lentiviral vector stimulates T cell responses in vitro: a strategy to generate whole cell vaccines for AML. Mol Ther 11:120–131PubMedCrossRef

56.

Kaufman HL, Cohen S, Cheung K, DeRaffele G, Mitcham J, Moroziewicz D, Schlom J, Hesdorffer C (2006) Local delivery of vaccinia virus expressing multiple costimulatory molecules for the treatment of established tumors. Hum Gene Ther 17:239–244PubMedCrossRef

57.

Garnett CT, Greiner JW, Tsang KY, Kudo-Saito C, Grosenbach DW, Chakraborty M, Gulley JL, Arlen PM, Schlom J, Hodge JW (2006) TRICOM vector based cancer vaccines. Curr Pharm Des 12:351–361PubMedCrossRef

58.

Yu X, Fournier S, Allison JP, Sharpe AH, Hodes RJ (2000) The role of B7 costimulation in CD4/CD8 T cell homeostasis. J Immunol 164:3543–3553PubMed

Title: The strange case of TGN1412
Authors: L. Farzaneh
N. Kasahara
F. Farzaneh
Publication date: 01-02-2007
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 2/2007
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-006-0189-8

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Excerpt

Please log in to get access to this content

Other articles of this Issue 2/2007

Induction of an effective anti-tumor immune response and tumor regression by combined administration of IL-18 and Apoptin

Melanocyte differentiation antigen RAB38/NY-MEL-1 induces frequent antibody responses exclusively in melanoma patients

Human interleukin 24 (MDA-7/IL-24) protein kills breast cancer cells via the IL-20 receptor and is antagonized by IL-10

Analysis of naïve and memory CD4 and CD8 T cell populations in breast cancer patients receiving a HER2/neu peptide (E75) and GM-CSF vaccine

Endowing self-binding feature restores the activities of a loss-of-function chimerized anti-GM2 antibody

Immune selective pressure and HLA class I antigen defects in malignant lesions

Keynote webinar | Spotlight on antibody–drug conjugates in cancer