Blockade of Programmed Death 1 Augments the Ability of Human T Cells Engineered to Target NY-ESO-1 to Control Tumor Growth after Adoptive Transfer
Tóm tắt
Purpose: Tumor-infiltrating lymphocytes (TILs) become hypofunctional, although the mechanisms are not clear. Our goal was to generate a model of human tumor-induced TIL hypofunction to study mechanisms and to test anti-human therapeutics.
Experimental Design: We transduced human T cells with a published, optimized T-cell receptor (TCR) that is directed to a peptide within the cancer testis antigen, NY-ESO-1. After demonstrating antigen-specific in vitro activity, these cells were used to target a human lung cancer line that expressed NY-ESO-1 in the appropriate HLA context growing in immunodeficient mice. The ability of anti-PD1 antibody to augment efficacy was tested.
Results: Injection of transgenic T cells had some antitumor activity, but did not eliminate the tumors. The injected T cells became profoundly hypofunctional accompanied by upregulation of PD1, Tim3, and Lag3 with coexpression of multiple inhibitory receptors in a high percentage of cells. This model allowed us to test reagents targeted specifically to human T cells. We found that injections of an anti-PD1 antibody in combination with T cells led to decreased TIL hypofunction and augmented the efficacy of the adoptively transferred T cells.
Conclusions: This model offers a platform for preclinical testing of adjuvant immunotherapeutics targeted to human T cells prior to transition to the bedside. Because the model employs engineering of human T cells with a TCR clone instead of a CAR, it allows for study of the biology of tumor-reactive TILs that signal through an endogenous TCR. The lessons learned from TCR-engineered TILs can thus be applied to tumor-reactive TILs. Clin Cancer Res; 22(2); 436–47. ©2015 AACR.
See related commentary by Yang, p. 275
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Tài liệu tham khảo
Morgan, 2006, Cancer regression in patients after transfer of genetically engineered lymphocytes, Science, 314, 126, 10.1126/science.1129003
June, 2014, Engineered T cells for cancer therapy, Cancer Immunol Immunother, 63, 969, 10.1007/s00262-014-1568-1
Maus, 2014, Antibody-modified T cells: CARs take the front seat for hematologic malignancies, Blood, 123, 2625, 10.1182/blood-2013-11-492231
Brocker, 2000, Chimeric Fv-zeta or Fv-epsilon receptors are not sufficient to induce activation or cytokine production in peripheral T cells, Blood, 96, 1999, 10.1182/blood.V96.5.1999
Geiger, 1999, The TCR zeta-chain immunoreceptor tyrosine-based activation motifs are sufficient for the activation and differentiation of primary T lymphocytes, J Immunol, 162, 5931, 10.4049/jimmunol.162.10.5931
Viola, 1996, T cell activation determined by T cell receptor number and tunable thresholds, Science, 273, 104, 10.1126/science.273.5271.104
Chodon, 2014, Adoptive transfer of MART-1 T-cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma, Clin Cancer Res, 20, 2457, 10.1158/1078-0432.CCR-13-3017
Zhang, 2014, Anti-melanoma activity of T cells redirected with a TCR-like chimeric antigen receptor, Sci Rep, 4, 3571, 10.1038/srep03571
Chinnasamy, 2011, A TCR targeting the HLA-A*0201-restricted epitope of MAGE-A3 recognizes multiple epitopes of the MAGE-A antigen superfamily in several types of cancer, J Immunol, 186, 685, 10.4049/jimmunol.1001775
Zhao, 2005, Primary human lymphocytes transduced with NY-ESO-1 antigen-specific TCR genes recognize and kill diverse human tumor cell lines, J Immunol, 174, 4415, 10.4049/jimmunol.174.7.4415
Parkhurst, 2011, T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis, Mol Ther, 19, 620, 10.1038/mt.2010.272
Robbins, 2011, Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1, J Clin Oncol, 29, 917, 10.1200/JCO.2010.32.2537
Fisher, 2006, Hurdles to lymphocyte trafficking in the tumor microenvironment: implications for effective immunotherapy, Immunol Invest, 35, 251, 10.1080/08820130600745430
Chappert, 2010, Induction of T cell anergy: integration of environmental cues and infectious tolerance, Curr Opin Immunol, 22, 552, 10.1016/j.coi.2010.08.005
Zou, 2005, Immunosuppressive networks in the tumour environment and their therapeutic relevance, Nat Rev Cancer, 5, 263, 10.1038/nrc1586
Baitsch, 2012, Extended co-expression of inhibitory receptors by human CD8 T-cells depending on differentiation, antigen-specificity and anatomical localization, PLoS One, 7, e30852, 10.1371/journal.pone.0030852
Jotereau, 2012, Adoptive transfer with high-affinity TCR to treat human solid tumors: how to improve the feasibility, Target Oncol, 7, 3, 10.1007/s11523-012-0207-z
Kunert, 2013, TCR-Engineered T cells meet new challenges to treat solid tumors: choice of antigen, T cell fitness, and sensitization of tumor milieu, Front Immunol, 4, 363, 10.3389/fimmu.2013.00363
Moon, 2014, Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric antigen receptor-transduced human T cells in solid tumors, Clin Cancer Res, 20, 4262, 10.1158/1078-0432.CCR-13-2627
Reichert, 2002, Signaling abnormalities, apoptosis, and reduced proliferation of circulating and tumor-infiltrating lymphocytes in patients with oral carcinoma, Clin Cancer Res, 8, 3137
Zhang, 2010, Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer, Cell Mol Immunol, 7, 389, 10.1038/cmi.2010.28
Lee, 1999, Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients, Nat Med, 5, 677, 10.1038/9525
Robbins, 2008, Single and dual amino acid substitutions in TCR CDRs can enhance antigen-specific T cell functions, J Immunol, 180, 6116, 10.4049/jimmunol.180.9.6116
Ho, 1989, Site-directed mutagenesis by overlap extension using the polymerase chain reaction, Gene, 77, 51, 10.1016/0378-1119(89)90358-2
Carpenito, 2009, Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains, Proc Natl Acad Sci U S A, 106, 3360, 10.1073/pnas.0813101106
Vazquez-Cintron, 2010, Tumor-induced disruption of proximal TCR-mediated signal transduction in tumor-infiltrating CD8+ lymphocytes inactivates antitumor effector phase, J Immunol, 185, 7133, 10.4049/jimmunol.1001157
Schietinger, 2014, Tolerance and exhaustion: defining mechanisms of T cell dysfunction, Trends Immunol, 35, 51, 10.1016/j.it.2013.10.001
Crespo, 2013, T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment, Curr Opin Immunol, 25, 214, 10.1016/j.coi.2012.12.003
Chiou, 2005, Current concepts of tumor-infiltrating lymphocytes in human malignancies, J Reprod Immunol, 67, 35, 10.1016/j.jri.2005.06.002
Prinz, 2010, High DGK-alpha and disabled MAPK pathways cause dysfunction of human tumor-infiltrating CD8+ T cells that is reversible by pharmacologic intervention, J Immunol, 188, 5990, 10.4049/jimmunol.1103028
Rabinowich, 1996, Expression and activity of signaling molecules in T lymphocytes obtained from patients with metastatic melanoma before and after interleukin 2 therapy, Clin Cancer Res, 2, 1263
Matsuzaki, 2010, Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer, Proc Natl Acad Sci U S A, 107, 7875, 10.1073/pnas.1003345107
Wang, 2011, Early T cell signalling is reversibly altered in PD-1+ T lymphocytes infiltrating human tumors, PLoS One, 6, e17621, 10.1371/journal.pone.0017621
Ghebeh, 2006, The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors, Neoplasia, 8, 190, 10.1593/neo.05733
Ma, 2012, Tumor-infiltrating gammadelta T lymphocytes predict clinical outcome in human breast cancer, J Immunol, 189, 5029, 10.4049/jimmunol.1201892
Matsuda, 1995, Alterations in the signal-transducing molecules of T cells and NK cells in colorectal tumor-infiltrating, gut mucosal and peripheral lymphocytes: correlation with the stage of the disease, Int J Cancer, 61, 765, 10.1002/ijc.2910610605
Sato, 2005, Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer, Proc Natl Acad Sci U S A, 102, 18538, 10.1073/pnas.0509182102
Robbins, 2015, A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T cell receptor: Long term follow up and correlates with response, Clin Cancer Res, 21, 1019, 10.1158/1078-0432.CCR-14-2708
Osanto, 2000, Vaccination of melanoma patients with an allogeneic, genetically modified interleukin 2-producing melanoma cell line, Hum Gene Ther, 11, 739, 10.1089/10430340050015635
Germeau, 2005, High frequency of antitumor T cells in the blood of melanoma patients before and after vaccination with tumor antigens, J Exp Med, 201, 241, 10.1084/jem.20041379
Wang, 2014, Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity, Cancer Immunol Res, 2, 154, 10.1158/2326-6066.CIR-13-0027
Okazaki, 2006, The PD-1-PD-L pathway in immunological tolerance, Trends Immunol, 27, 195, 10.1016/j.it.2006.02.001
Fourcade, 2010, Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients, J Exp Med, 207, 2175, 10.1084/jem.20100637
Sakuishi, 2010, Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity, J Exp Med, 207, 2187, 10.1084/jem.20100643
Grosso, 2009, Functionally distinct LAG-3 and PD-1 subsets on activated and chronically stimulated CD8 T cells, J Immunol, 182, 6659, 10.4049/jimmunol.0804211
John, 2013, Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells, Clin Cancer Res, 19, 5636, 10.1158/1078-0432.CCR-13-0458
Jungbluth, 2001, Immunohistochemical analysis of NY-ESO-1 antigen expression in normal and malignant human tissues, Int J Cancer, 92, 856, 10.1002/ijc.1282
Wolchok, 2013, Nivolumab plus ipilimumab in advanced melanoma, N Engl J Med, 369, 122, 10.1056/NEJMoa1302369
Alcantar-Orozco, 2013, Potential limitations of the NSG humanized mouse as a model system to optimize engineered human T cell therapy for cancer, Hum Gene Ther Methods, 24, 310, 10.1089/hgtb.2013.022
Volk, 2012, Comparison of three humanized mouse models for adoptive T cell transfer, J Gene Med, 14, 540, 10.1002/jgm.2652