The TNFRs OX40, 4-1BB, and CD40 As Targets for Cancer Immunotherapy

Overview

Journal Curr Opin Immunol

Publisher Elsevier

Specialty Allergy & Immunology

Date 2013 Feb 19

PMID 23414607

Citations 80

Authors

Amy E Moran

Magdalena Kovacsovics-Bankowski

Andrew D Weinberg

Affiliations

Soon will be listed here.

Abstract

T cell-mediated rejection of tumors requires signals from the T cell receptor and co-stimulatory molecules to license effector functions of tumor-antigen specific T cells. There is also an array of immune suppressive mechanisms within the tumor microenvironment that can suppress anti-tumor immunity. The use of monoclonal antibodies to overcome this suppression and/or enhance tumor-antigen specific T cell responses has shown promise in clinical trials. In particular, targeting co-stimulatory members of the tumor necrosis factor receptor (TNFR) family with agonist Abs enhances T cell function, which has led to encouraging therapeutic results in cancer-bearing hosts. These encouraging data establish TNFRs as important targets for enhancing tumor-specific immune responses in mice and man. This review will focus on agonists that target the TNFRs OX40, 4-1BB, and CD40.

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References

Paterson D, Jefferies W, Green J, Brandon M, Corthesy P, Puklavec M . Antigens of activated rat T lymphocytes including a molecule of 50,000 Mr detected only on CD4 positive T blasts. Mol Immunol. 1987; 24(12):1281-90. DOI: 10.1016/0161-5890(87)90122-2. View

Vonderheide R, Dutcher J, Anderson J, Eckhardt S, Stephans K, Razvillas B . Phase I study of recombinant human CD40 ligand in cancer patients. J Clin Oncol. 2001; 19(13):3280-7. DOI: 10.1200/JCO.2001.19.13.3280. View

Chen A, McAdam A, Buhlmann J, Scott S, Lupher Jr M, Greenfield E . Ox40-ligand has a critical costimulatory role in dendritic cell:T cell interactions. Immunity. 2000; 11(6):689-98. DOI: 10.1016/s1074-7613(00)80143-0. View

Karin M, Gallagher E . TNFR signaling: ubiquitin-conjugated TRAFfic signals control stop-and-go for MAPK signaling complexes. Immunol Rev. 2009; 228(1):225-40. DOI: 10.1111/j.1600-065X.2008.00755.x. View

Yang Y, Liu C, Peng W, Lizee G, Overwijk W, Liu Y . Antitumor T-cell responses contribute to the effects of dasatinib on c-KIT mutant murine mastocytoma and are potentiated by anti-OX40. Blood. 2012; 120(23):4533-43. PMC: 3512233. DOI: 10.1182/blood-2012-02-407163. View

Anderson M, Zhao S, Freud A, Czerwinski D, Kohrt H, Alizadeh A . CD137 is expressed in follicular dendritic cell tumors and in classical Hodgkin and T-cell lymphomas: diagnostic and therapeutic implications. Am J Pathol. 2012; 181(3):795-803. PMC: 3432425. DOI: 10.1016/j.ajpath.2012.05.015. View

Gramaglia I, Jember A, Pippig S, Weinberg A, Killeen N, Croft M . The OX40 costimulatory receptor determines the development of CD4 memory by regulating primary clonal expansion. J Immunol. 2000; 165(6):3043-50. DOI: 10.4049/jimmunol.165.6.3043. View

Ramstad T, Lawnicki L, Vetto J, Weinberg A . Immunohistochemical analysis of primary breast tumors and tumor-draining lymph nodes by means of the T-cell costimulatory molecule OX-40. Am J Surg. 2000; 179(5):400-6. DOI: 10.1016/s0002-9610(00)00361-5. View

Furman R, Forero-Torres A, Shustov A, Drachman J . A phase I study of dacetuzumab (SGN-40, a humanized anti-CD40 monoclonal antibody) in patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2009; 51(2):228-35. DOI: 10.3109/10428190903440946. View

10.

Beatty G, Chiorean E, Fishman M, Saboury B, Teitelbaum U, Sun W . CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011; 331(6024):1612-6. PMC: 3406187. DOI: 10.1126/science.1198443. View

11.

Flynn S, Toellner K, Raykundalia C, Goodall M, Lane P . CD4 T cell cytokine differentiation: the B cell activation molecule, OX40 ligand, instructs CD4 T cells to express interleukin 4 and upregulates expression of the chemokine receptor, Blr-1. J Exp Med. 1998; 188(2):297-304. PMC: 2212448. DOI: 10.1084/jem.188.2.297. View

12.

Brahmer J, Tykodi S, Chow L, Hwu W, Topalian S, Hwu P . Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012; 366(26):2455-65. PMC: 3563263. DOI: 10.1056/NEJMoa1200694. View

13.

Mittler R, S Bailey T, Klussman K, TrailSmith M, Hoffmann M . Anti-4-1BB monoclonal antibodies abrogate T cell-dependent humoral immune responses in vivo through the induction of helper T cell anergy. J Exp Med. 1999; 190(10):1535-40. PMC: 2195697. DOI: 10.1084/jem.190.10.1535. View

14.

Hong H, Lee J, Park S, Kang Y, Chang S, Kim K . A humanized anti--4-1BB monoclonal antibody suppresses antigen-induced humoral immune response in nonhuman primates. J Immunother. 2001; 23(6):613-21. DOI: 10.1097/00002371-200011000-00002. View

15.

Palazon A, Teijeira A, Martinez-Forero I, Hervas-Stubbs S, Roncal C, Penuelas I . Agonist anti-CD137 mAb act on tumor endothelial cells to enhance recruitment of activated T lymphocytes. Cancer Res. 2011; 71(3):801-11. DOI: 10.1158/0008-5472.CAN-10-1733. View

16.

Ruby C, Montler R, Zheng R, Shu S, Weinberg A . IL-12 is required for anti-OX40-mediated CD4 T cell survival. J Immunol. 2008; 180(4):2140-8. DOI: 10.4049/jimmunol.180.4.2140. View

17.

Hodi F, ODay S, Mcdermott D, Weber R, Sosman J, Haanen J . Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363(8):711-23. PMC: 3549297. DOI: 10.1056/NEJMoa1003466. View

18.

Diehl L, den Boer A, Schoenberger S, van der Voort E, Schumacher T, Melief C . CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy. Nat Med. 1999; 5(7):774-9. DOI: 10.1038/10495. View

19.

Balasubramani A, Mukasa R, Hatton R, Weaver C . Regulation of the Ifng locus in the context of T-lineage specification and plasticity. Immunol Rev. 2010; 238(1):216-32. PMC: 3096439. DOI: 10.1111/j.1600-065X.2010.00961.x. View

20.

Hussein M, Berenson J, Niesvizky R, Munshi N, Matous J, Sobecks R . A phase I multidose study of dacetuzumab (SGN-40; humanized anti-CD40 monoclonal antibody) in patients with multiple myeloma. Haematologica. 2010; 95(5):845-8. PMC: 2864394. DOI: 10.3324/haematol.2009.008003. View