T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model

Blood - Tập 113 Số 25 - Trang 6392-6402 - 2009
Antonio Di Stasi1, Biagio De Angelis1, Cliona M. Rooney1,2,3,4, Lan Zhang1, Aruna Mahendravada1, Aaron E. Foster1, Helen E. Heslop1,2,5, Malcolm K. Brenner1,2,5, Gianpietro Dotti1,3,5, Barbara Savoldo1,2
1Center for Cell and Gene Therapy and
2Departments of Pediatrics
3Immunology, and
4Molecular Virology and Microbiology,
5Medicine, Baylor College of Medicine, Methodist Hospital and Texas Children's Hospital, Houston

Tóm tắt

AbstractFor the adoptive transfer of tumor-directed T lymphocytes to prove effective, there will probably need to be a match between the chemokines the tumor produces and the chemokine receptors the effector T cells express. The Reed-Stemberg cells of Hodgkin lymphoma (HL) predominantly produce thymus- and activation-regulated chemokine/CC chemokine ligand 17 (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22), which preferentially attract type 2 T helper (Th2) cells and regulatory T cells (Tregs) that express the TARC/MDC-specific chemokine receptor CCR4, thus generating an immunosuppressed tumor environment. By contrast, effector CD8+ T cells lack CCR4, are nonresponsive to these chemokines and are rarely detected at the tumor site. We now show that forced expression of CCR4 by effector T cells enhances their migration to HL cells. Furthermore, T lymphocytes expressing both CCR4 and a chimeric antigen receptor directed to the HL associated antigen CD30 sustain their cytotoxic function and cytokine secretion in vitro, and produce enhanced tumor control when infused intravenously in mice engrafted with human HL. This approach may be of value in patients affected by HL.

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Tài liệu tham khảo

Bollard, 2004, Cytotoxic T lymphocyte therapy for Epstein-Barr virus+ Hodgkin's disease., J Exp Med, 200, 1623, 10.1084/jem.20040890

Roskrow, 1998, Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes for the treatment of patients with EBV-positive relapsed Hodgkin's disease., Blood, 91, 2925, 10.1182/blood.V91.8.2925.2925_2925_2934

Wu, 1990, Detection of EBV gene expression in Reed-Sternberg cells of Hodgkin's disease., Int J Cancer, 46, 801, 10.1002/ijc.2910460509

Falini, 1995, CD30 (Ki-1) molecule: a new cytokine receptor of the tumor necrosis factor receptor superfamily as a tool for diagnosis and immunotherapy., Blood, 85, 1, 10.1182/blood.V85.1.1.bloodjournal8511

Hombach, 1998, An anti-CD30 chimeric receptor that mediates CD3-zeta-independent T-cell activation against Hodgkin's lymphoma cells in the presence of soluble CD30., Cancer Res, 58, 1116

Walker, 2000, Long-term in vivo survival of receptor-modified syngeneic T cells in patients with human immunodeficiency virus infection., Blood, 96, 467

Kershaw, 2002, Redirecting migration of T cells to chemokine secreted from tumors by genetic modification with CXCR2., Hum Gene Ther, 13, 1971, 10.1089/10430340260355374

Maggio, 2002, Common and differential chemokine expression patterns in rs cells of NLP, EBV positive and negative classical Hodgkin lymphomas., Int J Cancer, 99, 665, 10.1002/ijc.10399

van den Berg, 1999, High expression of the CC chemokine TARC in Reed-Sternberg cells: a possible explanation for the characteristic T-cell infiltrate in Hodgkin's lymphoma., Am J Pathol, 154, 1685, 10.1016/S0002-9440(10)65424-7

Ishida, 2006, Specific recruitment of CC chemokine receptor 4-positive regulatory T cells in Hodgkin lymphoma fosters immune privilege., Cancer Res, 66, 5716, 10.1158/0008-5472.CAN-06-0261

Curiel, 2004, Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival., Nat Med, 10, 942, 10.1038/nm1093

Iellem, 2001, Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T cells., J Exp Med, 194, 847, 10.1084/jem.194.6.847

D'Ambrosio, 1998, Selective up-regulation of chemokine receptors CCR4 and CCR8 upon activation of polarized human type 2 Th cells., J Immunol, 161, 5111, 10.4049/jimmunol.161.10.5111

Marshall, 2004, Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma., Blood, 103, 1755, 10.1182/blood-2003-07-2594

Rossig, 2002, Epstein-Barr virus-specific human T lymphocytes expressing antitumor chimeric T-cell receptors: potential for improved immunotherapy., Blood, 99, 2009, 10.1182/blood.V99.6.2009

Savoldo, 2007, Epstein Barr virus specific cytotoxic T lymphocytes expressing the anti-CD30zeta artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease., Blood, 110, 2620, 10.1182/blood-2006-11-059139

Pule, 2005, A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells., Mol Ther, 12, 933, 10.1016/j.ymthe.2005.04.016

Vera, 2006, T-lymphocytes redirected against the kappa light chain of human immunoglobulin efficiently kill mature B-lymphocyte derived malignant cells., Blood, 108, 3890, 10.1182/blood-2006-04-017061

Dotti, 2005, Human cytotoxic T lymphocytes with reduced sensitivity to Fas-induced apoptosis., Blood, 105, 4677, 10.1182/blood-2004-08-3337

Godfrey, 2004, In vitro-expanded human CD4(+)CD25(+) T-regulatory cells can markedly inhibit allogeneic dendritic cell-stimulated MLR cultures., Blood, 104, 453, 10.1182/blood-2004-01-0151

Quintarelli, 2007, Co-expression of cytokine and suicide genes to enhance the activity and safety of tumor-specific cytotoxic T lymphocytes., Blood, 110, 2793, 10.1182/blood-2007-02-072843

Dewan, 2005, Hodgkin's lymphoma cells are efficiently engrafted and tumor marker CD30 is expressed with constitutive nuclear factor-kappaB activity in unconditioned NOD/SCID/gammac(null) mice., Cancer Sci, 96, 466, 10.1111/j.1349-7006.2005.00079.x

Pule, 2008, Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma., Nat Med, 14, 1264, 10.1038/nm.1882

Bollard, 2007, Complete responses of relapsed lymphoma following genetic modification of tumor-antigen presenting cells and T-lymphocyte transfer., Blood, 110, 2838, 10.1182/blood-2007-05-091280

Maher, 2002, Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta /CD28 receptor., Nat Biotechnol, 20, 70, 10.1038/nbt0102-70

Zhang, 2007, 4-1BB is superior to CD28 costimulation for generating CD8+ cytotoxic lymphocytes for adoptive immunotherapy., J Immunol, 179, 4910, 10.4049/jimmunol.179.7.4910

Landmeier, 2007, Gene-engineered varicella-zoster virus reactive CD4+ cytotoxic T cells exert tumor-specific effector function., Cancer Res, 67, 8335, 10.1158/0008-5472.CAN-06-4426

Cooper, 2005, Enhanced antilymphoma efficacy of CD19-redirected influenza MP1-specific CTLs by cotransfer of T cells modified to present influenza MP1., Blood, 105, 1622, 10.1182/blood-2004-03-1208

Bromley, 2008, Orchestrating the orchestrators: chemokines in control of T cell traffic., Nat Immunol, 9, 970, 10.1038/ni.f.213

Niens, 2008, Serum chemokine levels in Hodgkin lymphoma patients: highly increased levels of CCL17 and CCL22., Br J Haematol, 140, 527, 10.1111/j.1365-2141.2007.06964.x

Weihrauch, 2005, Elevated serum levels of CC thymus and activation-related chemokine (TARC) in primary Hodgkin's disease: potential for a prognostic factor., Cancer Res, 65, 5516, 10.1158/0008-5472.CAN-05-0100

Reiss, 2001, CC chemokine receptor (CCR)4 and the CCR10 ligand cutaneous T cell-attracting chemokine (CTACK) in lymphocyte trafficking to inflamed skin., J Exp Med, 194, 1541, 10.1084/jem.194.10.1541

Kunkel, 2002, Chemokines and the tissue-specific migration of lymphocytes., Immunity, 16, 1, 10.1016/S1074-7613(01)00261-8

Yamaguchi, 2006, Expression of chemokines and chemokine receptors in cutaneous CD30+ lymphoproliferative disorders., Br J Dermatol, 154, 904, 10.1111/j.1365-2133.2005.07039.x

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Blood

Tập 113 Số 25

6392-6402

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