Adoptive immunotherapy for cancer

Recent clinical success has underscored the potential for immunotherapy based on the adoptive cell transfer (ACT) of engineered T lymphocytes to mediate dramatic, potent, and durable clinical responses. This success has led to the broader evaluation of engineered T‐lymphocyte‐based adoptive cell therapy to treat a broad range of malignancies. In this review, we summarize concepts, successes, and challenges for the broader development of this promising field, focusing principally on lessons gleaned from immunological principles and clinical thought. We present ACT in the context of integrating T‐cell and tumor biology and the broader systemic immune response.

[1]  P. Veys,et al.  Functional characterization of alloreactive T cells identifies CD25 and CD71 as optimal targets for a clinically applicable allodepletion strategy. , 2010, Blood.

[2]  G. Coukos,et al.  In vivo persistence, tumor localization, and antitumor activity of CAR-engineered T cells is enhanced by costimulatory signaling through CD137 (4-1BB). , 2011, Cancer research.

[3]  John Condeelis,et al.  Macrophages: Obligate Partners for Tumor Cell Migration, Invasion, and Metastasis , 2006, Cell.

[4]  R. Siliciano,et al.  Endothelial Cell Stimulation Overcomes Restriction and Promotes Productive and Latent HIV-1 Infection of Resting CD4+ T Cells , 2013, Journal of Virology.

[5]  J. Wagner,et al.  4-1BB and CD28 signaling plays a synergistic role in redirecting umbilical cord blood T cells against B-cell malignancies. , 2010, Human gene therapy.

[6]  E. Kleinerman,et al.  Genetically modified T cells targeting interleukin-11 receptor α-chain kill human osteosarcoma cells and induce the regression of established osteosarcoma lung metastases. , 2012, Cancer research.

[7]  Stephanie Alexander,et al.  Cancer Invasion and the Microenvironment: Plasticity and Reciprocity , 2011, Cell.

[8]  M. Essand,et al.  T cells engineered with a T cell receptor against the prostate antigen TARP specifically kill HLA-A2+ prostate and breast cancer cells , 2012, Proceedings of the National Academy of Sciences.

[9]  M. Del Vecchio,et al.  Immunotherapy of Metastatic Melanoma Using Genetically Engineered GD2-Specific T cells , 2009, Clinical Cancer Research.

[10]  D. Powell,et al.  CD27 costimulation augments the survival and antitumor activity of redirected human T cells in vivo. , 2012, Blood.

[11]  Jinyuan Zhou,et al.  Suppression of Human Glioma Xenografts with Second-Generation IL13R-Specific Chimeric Antigen Receptor–Modified T Cells , 2012, Clinical Cancer Research.

[12]  F. Marincola,et al.  A human memory T-cell subset with stem cell-like properties , 2011, Nature Medicine.

[13]  N. Rufer,et al.  Transfer of the human telomerase reverse transcriptase (TERT) gene into T lymphocytes results in extension of replicative potential. , 2001, Blood.

[14]  Y. Ma,et al.  Specificity redirection by CAR with human VEGFR-1 affinity endows T lymphocytes with tumor-killing ability and anti-angiogenic potency , 2013, Gene Therapy.

[15]  S. Rosenberg,et al.  Survival, Persistence, and Progressive Differentiation of Adoptively Transferred Tumor-Reactive T Cells Associated with Tumor Regression , 2005, Journal of immunotherapy.

[16]  S. Sleijfer,et al.  Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  C. Rooney,et al.  Enhanced Tumor Trafficking of GD2 Chimeric Antigen Receptor T Cells by Expression of the Chemokine Receptor CCR2b , 2010, Journal of immunotherapy.

[18]  H. Heslop,et al.  T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. , 2009, Blood.

[19]  K. Jang,et al.  Tumor-infiltrating PD1-Positive Lymphocytes and FoxP3-Positive Regulatory T Cells Predict Distant Metastatic Relapse and Survival of Clear Cell Renal Cell Carcinoma. , 2013, Translational oncology.

[20]  B. Levine,et al.  Perspective: Assembly line immunotherapy , 2013, Nature.

[21]  M. Dhodapkar.  Harnessing human CD1d restricted T cells for tumor immunity: progress and challenges. , 2009, Frontiers in bioscience.

[22]  L. Naldini,et al.  Human T lymphocytes transduced by lentiviral vectors in the absence of TCR activation maintain an intact immune competence. , 2003, Blood.

[23]  F. Gage,et al.  In Vivo Gene Delivery and Stable Transduction of Nondividing Cells by a Lentiviral Vector , 1996, Science.

[24]  S. Gottschalk,et al.  Immunotherapy targeting HER2 with genetically modified T cells eliminates tumor-initiating cells in osteosarcoma , 2011, Cancer Gene Therapy.

[25]  S. Billet,et al.  Understanding the role of stromal fibroblasts in cancer progression , 2012, Cell adhesion & migration.

[26]  S. Rosenberg,et al.  CD8+ Enriched “Young” Tumor Infiltrating Lymphocytes Can Mediate Regression of Metastatic Melanoma , 2010, Clinical Cancer Research.

[27]  Ming-Ru Wu,et al.  An NKp30-Based Chimeric Antigen Receptor Promotes T Cell Effector Functions and Antitumor Efficacy In Vivo , 2012, The Journal of Immunology.

[28]  M. Tan,et al.  Rapid Immune Recovery and Graft-versus-Host Disease–like Engraftment Syndrome following Adoptive Transfer of Costimulated Autologous T Cells , 2009, Clinical Cancer Research.

[29]  C. Yee,et al.  IL-21 Influences the Frequency, Phenotype, and Affinity of the Antigen-Specific CD8 T Cell Response1 , 2005, The Journal of Immunology.

[30]  David L. Porter,et al.  T Cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced Leukemia , 2011, Science Translational Medicine.

[31]  M. Sadelain,et al.  Antigen-dependent CD28 Signaling Selectively Enhances Survival and Proliferation in Genetically Modified Activated Human Primary T Lymphocytes , 1998, The Journal of experimental medicine.

[32]  G. Coukos,et al.  A phase I clinical trial of adoptive transfer of folate receptor-alpha redirected autologous T cells for recurrent ovarian cancer , 2012, Journal of Translational Medicine.

[33]  J. Sampson,et al.  Selective modification of antigen-specific T cells by RNA electroporation. , 2008, Human gene therapy.

[34]  Thomas M. Schmitt,et al.  Transferred WT1-Reactive CD8+ T Cells Can Mediate Antileukemic Activity and Persist in Post-Transplant Patients , 2013, Science Translational Medicine.

[35]  Yuquan Wei,et al.  Cellular immunotherapy for carcinoma using genetically modified EGFR-specific T lymphocytes. , 2013, Neoplasia.

[36]  S. Forman,et al.  Specific Recognition and Killing of Glioblastoma Multiforme by Interleukin 13-Zetakine Redirected Cytolytic T Cells , 2004, Cancer Research.

[37]  Jing Sun,et al.  Expression of a Functional CCR2 Receptor Enhances Tumor Localization and Tumor Eradication by Retargeted Human T cells Expressing a Mesothelin-Specific Chimeric Antibody Receptor , 2011, Clinical Cancer Research.

[38]  S. Riddell,et al.  Cellular immunotherapy for follicular lymphoma using genetically modified CD20-specific CD8+ cytotoxic T lymphocytes. , 2004, Molecular therapy : the journal of the American Society of Gene Therapy.

[39]  A. Boynton,et al.  Anti‐prostate specific membrane antigen designer T cells for prostate cancer therapy , 2004, The Prostate.

[40]  A. Lawson,et al.  In Vitro and In Vivo Antitumor Effect of Anti-CD33 Chimeric Receptor-Expressing EBV-CTL against CD33+ Acute Myeloid Leukemia , 2012, Advances in hematology.

[41]  H. Abken,et al.  Costimulation by chimeric antigen receptors revisited the T cell antitumor response benefits from combined CD28‐OX40 signalling , 2011, International journal of cancer.

[42]  S. Grupp,et al.  Treatment of advanced leukemia in mice with mRNA engineered T cells. , 2011, Human gene therapy.

[43]  S. Riddell,et al.  Development of a Treatment Regimen for Human Cytomegalovirus (CMV) Infection in Bone Marrow Transplantation Recipients by Adoptive Transfer of Donor‐Derived CMV‐Specific T Cell Clones Expanded In Vitro a , 1991, Annals of the New York Academy of Sciences.

[44]  Adam Bagg,et al.  Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. , 2013, Blood.

[45]  S. Rosenberg,et al.  Gene therapy using genetically modified lymphocytes targeting VEGFR-2 inhibits the growth of vascularized syngenic tumors in mice. , 2010, The Journal of clinical investigation.

[46]  Y. Simoni,et al.  Therapeutic manipulation of natural killer (NK) T cells in autoimmunity: are we close to reality? , 2013, Clinical and experimental immunology.

[47]  S. Rosenberg,et al.  Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells , 2005, The Journal of experimental medicine.

[48]  R. Rezzani,et al.  HLA class I antigen down-regulation in primary ovary carcinoma lesions: association with disease stage. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[49]  Gang Wang,et al.  A Phase I Study on Adoptive Immunotherapy Using Gene-Modified T Cells for Ovarian Cancer , 2006, Clinical Cancer Research.

[50]  J. Wolchok,et al.  At the Bedside: CTLA‐4‐ and PD‐1‐blocking antibodies in cancer immunotherapy , 2013, Journal of leukocyte biology.

[51]  A. Mantovani,et al.  Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm , 2010, Nature Immunology.

[52]  S. Rosenberg,et al.  Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[53]  R. Negrin,et al.  A novel population of expanded human CD3+CD56+ cells derived from T cells with potent in vivo antitumor activity in mice with severe combined immunodeficiency. , 1994, Journal of immunology.

[54]  A. Eggermont,et al.  Regression of advanced ovarian carcinoma by intraperitoneal treatment with autologous T lymphocytes retargeted by a bispecific monoclonal antibody. , 1995, Journal of the National Cancer Institute.

[55]  S. Larson,et al.  Genetically Targeted T Cells Eradicate Systemic Acute Lymphoblastic Leukemia Xenografts , 2007, Clinical Cancer Research.

[56]  P. Greenberg,et al.  Antigen Sensitivity of CD22-Specific Chimeric TCR Is Modulated by Target Epitope Distance from the Cell Membrane1 , 2008, The Journal of Immunology.

[57]  Qing He,et al.  CD19-Targeted T Cells Rapidly Induce Molecular Remissions in Adults with Chemotherapy-Refractory Acute Lymphoblastic Leukemia , 2013, Science Translational Medicine.

[58]  P. Hwu,et al.  T helper 17 cells promote cytotoxic T cell activation in tumor immunity. , 2009, Immunity.

[59]  David Allman,et al.  Ex vivo expansion of polyclonal and antigen-specific cytotoxic T lymphocytes by artificial APCs expressing ligands for the T-cell receptor, CD28 and 4-1BB , 2002, Nature Biotechnology.

[60]  S. Rosenberg,et al.  Recognition of Fresh Human Tumor by Human Peripheral Blood Lymphocytes Transduced with a Bicistronic Retroviral Vector Encoding a Murine Anti-p53 TCR , 2005, The Journal of Immunology.

[61]  J. Blattman,et al.  Restoration of CD28 Expression in CD28− CD8+ Memory Effector T Cells Reconstitutes Antigen-induced IL-2 Production , 2003, The Journal of experimental medicine.

[62]  N. Weng,et al.  IL-15 Activates Telomerase and Minimizes Telomere Loss and May Preserve the Replicative Life Span of Memory CD8+ T Cells In Vitro , 2005, The Journal of Immunology.

[63]  V. Koppaka,et al.  anti* , 2002, Annals of Internal Medicine.

[64]  Adrian P Gee,et al.  Inducible apoptosis as a safety switch for adoptive cell therapy. , 2011, The New England journal of medicine.

[65]  J. Orange,et al.  Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases , 2008, Nature Biotechnology.

[66]  A. Scott,et al.  Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[67]  J. Yoshida,et al.  Retrovirally engineered T‐cell‐based immunotherapy targeting type III variant epidermal growth factor receptor, a glioma‐associated antigen , 2010, Cancer science.

[68]  A. Wafelman,et al.  Generation and administration of HA-1-specific T-cell lines for the treatment of patients with relapsed leukemia after allogeneic stem cell transplantation: a pilot study , 2012, Haematologica.

[69]  J. Marx.  All in the Stroma: Cancer's Cosa Nostra , 2008, Science.

[70]  David A. Williams.  Foamy virus vectors come of age. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[71]  P. Lipsky,et al.  Stepwise Differentiation of CD4 Memory T Cells Defined by Expression of CCR7 and CD271 , 2005, The Journal of Immunology.

[72]  Tong Zhang,et al.  Generation of antitumor responses by genetic modification of primary human T cells with a chimeric NKG2D receptor. , 2006, Cancer research.

[73]  T. Waldmann,et al.  IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T Cells , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[74]  D. Lamm.  Comparison of BCG with other intravesical agents. , 1991, Urology.

[75]  G. Cheng,et al.  Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN. , 2009, Cancer cell.

[76]  Bruce L. Levine,et al.  Antiviral Effect and Ex Vivo CD4+ T Cell Proliferation in HIV-Positive Patients as a Result of CD28 Costimulation , 1996, Science.

[77]  Yi Li,et al.  Directed evolution of human T-cell receptors with picomolar affinities by phage display , 2005, Nature Biotechnology.

[78]  Derek S. Chan,et al.  The Pancreas Cancer Microenvironment , 2012, Clinical Cancer Research.

[79]  M. Sadelain,et al.  Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8+ T cell-mediated tumor eradication. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[80]  Matthew L Baker,et al.  TanCAR: A Novel Bispecific Chimeric Antigen Receptor for Cancer Immunotherapy , 2013, Molecular therapy. Nucleic acids.

[81]  B. Engels,et al.  Enhanced functionality of T cell receptor-redirected T cells is defined by the transgene cassette , 2008, Journal of Molecular Medicine.

[82]  S. Rosenberg,et al.  Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. , 1994, Journal of the National Cancer Institute.

[83]  M. Kalos,et al.  Identification of naturally processed CD8 T cell epitopes from prostein, a prostate tissue‐specific vaccine candidate , 2004, European journal of immunology.

[84]  A. Lawson,et al.  In Vitro Comparison of Three Different Chimeric Receptor-modified Effector T-cell Populations for Leukemia Cell Therapy , 2011, Journal of immunotherapy.

[85]  G. Coukos,et al.  Engineered artificial antigen presenting cells facilitate direct and efficient expansion of tumor infiltrating lymphocytes , 2011, Journal of Translational Medicine.

[86]  Qingsheng Li,et al.  The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin. , 2010, Immunity.

[87]  W. Wilson,et al.  Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. , 2010, Blood.

[88]  J. Ainsworth,et al.  Purification of cytomegalovirus‐specific CD8 T cells from peripheral blood using HLA–peptide tetramers , 2001, British journal of haematology.

[89]  S. Steinberg,et al.  Durable Complete Responses in Heavily Pretreated Patients with Metastatic Melanoma Using T-Cell Transfer Immunotherapy , 2011, Clinical Cancer Research.

[90]  Steven J. M. Jones,et al.  Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. , 2010, The New England journal of medicine.

[91]  D. Martorelli,et al.  Cancer vaccines in phase II/III clinical trials: state of the art and future perspectives. , 2011, Current cancer drug targets.

[92]  C. Klebanoff,et al.  Sorting Through Subsets: Which T-Cell Populations Mediate Highly Effective Adoptive Immunotherapy? , 2012, Journal of immunotherapy.

[93]  E. Estey,et al.  A distinct subset of self-renewing human memory CD8+ T cells survives cytotoxic chemotherapy. , 2009, Immunity.

[94]  T. Blankenstein,et al.  Transgenic mice with a diverse human T cell antigen receptor repertoire , 2010, Nature Medicine.

[95]  P. Stern,et al.  The Role of Extracellular Spacer Regions in the Optimal Design of Chimeric Immune Receptors: Evaluation of Four Different scFvs and Antigens , 2005, Journal of immunotherapy.

[96]  J. Keith Joung,et al.  FLASH Assembly of TALENs Enables High-Throughput Genome Editing , 2012, Nature Biotechnology.

[97]  Hans J. Stauss,et al.  Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer , 2001, Nature Immunology.

[98]  M. Karin,et al.  Tumor promotion via injury- and death-induced inflammation. , 2011, Immunity.

[99]  S. Steinberg,et al.  In vitro predictors of therapeutic response in melanoma patients receiving tumor-infiltrating lymphocytes and interleukin-2. , 1994, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[100]  K. Yanagihara,et al.  Synergistic and persistent effect of T‐cell immunotherapy with anti‐CD19 or anti‐CD38 chimeric receptor in conjunction with rituximab on B‐cell non‐Hodgkin lymphoma , 2010, British journal of haematology.

[101]  W. Uckert,et al.  Minimal Amino Acid Exchange in Human TCR Constant Regions Fosters Improved Function of TCR Gene-Modified T Cells , 2010, The Journal of Immunology.

[102]  Hao Liu,et al.  CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. , 2011, The Journal of clinical investigation.

[103]  A. Amir,et al.  PRAME-Specific Allo-HLA–Restricted T Cells with Potent Antitumor Reactivity Useful for Therapeutic T-Cell Receptor Gene Transfer , 2011, Clinical Cancer Research.

[104]  H. Heslop,et al.  T lymphocytes redirected against the kappa light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells. , 2006, Blood.

[105]  A. Rynda-Apple,et al.  NKG2D CAR T‐cell therapy inhibits the growth of NKG2D ligand heterogeneous tumors , 2013, Immunology and cell biology.

[106]  N. Restifo,et al.  Less is more: lymphodepletion followed by hematopoietic stem cell transplant augments adoptive T-cell-based anti-tumor immunotherapy. , 2005, Current opinion in immunology.

[107]  F. Bushman,et al.  Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. , 2008, The Journal of clinical investigation.

[108]  H. Schmidt,et al.  Adoptive transfer of allogeneic cytotoxic T lymphocytes equipped with a HLA-A2 restricted MART-1 T-cell receptor: a phase I trial in metastatic melanoma. , 2006, Clinical cancer research : an official journal of the American Association for Cancer Research.

[109]  M. Kester,et al.  Retroviral transfer of human CD20 as a suicide gene for adoptive T-cell therapy , 2009, Haematologica.

[110]  D. Levine,et al.  Successful Eradication of Established Peritoneal Ovarian Tumors in SCID-Beige Mice following Adoptive Transfer of T Cells Genetically Targeted to the MUC16 Antigen , 2010, Clinical Cancer Research.

[111]  S. Bicciato,et al.  IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors. , 2013, Blood.

[112]  F. Bushman,et al.  Antiviral effects of autologous CD4 T cells genetically modified with a conditionally replicating lentiviral vector expressing long antisense to HIV. , 2013, Blood.

[113]  B. Levine.  T lymphocyte engineering ex vivo for cancer and infectious disease. , 2008, Expert opinion on biological therapy.

[114]  Jinjuan Wang,et al.  Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. , 2008, Blood.

[115]  C. Le,et al.  Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. , 2005, Blood.

[116]  Michel Sadelain,et al.  Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. , 2011, Blood.

[117]  D. Schadendorf,et al.  Improved survival with ipilimumab in patients with metastatic melanoma. , 2010, The New England journal of medicine.

[118]  W. Coley,et al.  THE TREATMENT OF MALIGNAT TUMORS BY REPEATED INOCULATIONS OF ERYSIPELAS: WITH A REPORT OF TEN ORIGINAL CASES , 1893 .

[119]  M. Merino,et al.  T Cells Targeting Carcinoembryonic Antigen Can Mediate Regression of Metastatic Colorectal Cancer but Induce Severe Transient Colitis. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[120]  S. Karlsson,et al.  Combining CAR T cells and the Bcl-2 family apoptosis inhibitor ABT-737 for treating B-cell malignancy , 2013, Cancer Gene Therapy.

[121]  H. Dvorak.  Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. , 1986, The New England journal of medicine.

[122]  D. Landau,et al.  Depletion of T regulatory cells through selection of CD127-positive cells results in a population enriched in memory T cells: implications for anti-tumor cell therapy , 2012, Haematologica.

[123]  D. Campana,et al.  Natural killer cell reprogramming with chimeric immune receptors. , 2013, Methods in molecular biology.

[124]  L. Staudt,et al.  Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. , 2004, The New England journal of medicine.

[125]  Mike Gough,et al.  Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates. , 2008, The Journal of clinical investigation.

[126]  T. Naoe,et al.  A Single Minor Histocompatibility Antigen Encoded by UGT2B17 and Presented by Human Leukocyte Antigen-A*2902 and -B*4403 , 2007, Transplantation.

[127]  Yao-Tseng Chen,et al.  Cancer/testis (CT) antigens: Potential targets for immunotherapy , 2009, Cancer science.

[128]  Z. Trajanoski,et al.  Effector memory T cells, early metastasis, and survival in colorectal cancer. , 2005, The New England journal of medicine.

[129]  C. Coutant,et al.  In situ immune response after neoadjuvant chemotherapy for breast cancer predicts survival , 2011, The Journal of pathology.

[130]  D. Artis.  Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut , 2008, Nature Reviews Immunology.

[131]  Andrew K. Sewell,et al.  Human TCR-Binding Affinity is Governed by MHC Class Restriction1 , 2007, The Journal of Immunology.

[132]  F. Sallusto,et al.  Two subsets of memory T lymphocytes with distinct homing potentials and effector functions , 1999, Nature.

[133]  J. Wargo,et al.  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 , 2011, The Journal of Immunology.

[134]  J. Spicer,et al.  Selective Expansion of Chimeric Antigen Receptor-targeted T-cells with Potent Effector Function using Interleukin-4* , 2010, The Journal of Biological Chemistry.

[135]  S. Riddell,et al.  Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. , 1995, The New England journal of medicine.

[136]  S. Rosenberg,et al.  Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling. , 2007, The Journal of clinical investigation.

[137]  E. Shpall,et al.  Infusing CD19-directed T cells to augment disease control in patients undergoing autologous hematopoietic stem-cell transplantation for advanced B-lymphoid malignancies. , 2012, Human gene therapy.

[138]  C. Pui,et al.  NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[139]  C. Rossig,et al.  2B4 (CD244) signaling via chimeric receptors costimulates tumor-antigen specific proliferation and in vitro expansion of human T cells , 2009, Cancer Immunology, Immunotherapy.

[140]  C. Klebanoff,et al.  Paths to stemness: building the ultimate antitumour T cell , 2012, Nature Reviews Cancer.

[141]  S. Rosenberg,et al.  Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. , 2009, Blood.

[142]  S. Yoon,et al.  Adoptive immunotherapy using human peripheral blood lymphocytes transferred with RNA encoding Her-2/neu-specific chimeric immune receptor in ovarian cancer xenograft model , 2009, Cancer Gene Therapy.

[143]  S. Rosenberg,et al.  High Efficiency TCR Gene Transfer into Primary Human Lymphocytes Affords Avid Recognition of Melanoma Tumor Antigen Glycoprotein 100 and Does Not Alter the Recognition of Autologous Melanoma Antigens , 2003, The Journal of Immunology.

[144]  Michel Sadelain,et al.  Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells , 2012, Nature Biotechnology.

[145]  S. Rosenberg,et al.  Collapse of the tumor stroma is triggered by IL-12 induction of Fas. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[146]  P. Sinn,et al.  Gene Therapy Progress and Prospects: Development of improved lentiviral and retroviral vectors – design, biosafety, and production , 2005, Gene Therapy.

[147]  A. Marabelle,et al.  NK Cell immunotherapy for high‐risk neuroblastoma relapse after haploidentical HSCT , 2012, Pediatric blood & cancer.

[148]  K. Yanagihara,et al.  Activated T–cell-mediated Immunotherapy With a Chimeric Receptor Against CD38 in B-cell Non-Hodgkin Lymphoma , 2009, Journal of immunotherapy.

[149]  M. Kuroki,et al.  Construction and molecular characterization of human chimeric T-cell antigen receptors specific for carcinoembryonic antigen. , 2010, Anticancer research.

[150]  H. Ikeda,et al.  Improved expression and reactivity of transduced tumor-specific TCRs in human lymphocytes by specific silencing of endogenous TCR. , 2009, Cancer research.

[151]  W. Blackwelder,et al.  Restoration of immunity in lymphopenic individuals with cancer by vaccination and adoptive T-cell transfer , 2005, Nature Medicine.

[152]  M. Beyer,et al.  Regulatory T cells in cancer. , 2006, Blood.

[153]  S. Eccles,et al.  Dual Targeting of ErbB2 and MUC1 in Breast Cancer Using Chimeric Antigen Receptors Engineered to Provide Complementary Signaling , 2012, Journal of Clinical Immunology.

[154]  D. Talbot,et al.  Survivin in Solid Tumors: Rationale for Development of Inhibitors , 2012, Current Oncology Reports.

[155]  Sylvain Julien,et al.  Retargeting of Human T Cells to Tumor-Associated MUC1: The Evolution of a Chimeric Antigen Receptor1 , 2008, The Journal of Immunology.

[156]  Ariadni Mavrou,et al.  Development of cancer in patients with primary immunodeficiencies. , 2008, Anticancer research.

[157]  Srinivas Nagaraj,et al.  Myeloid-derived suppressor cells as regulators of the immune system , 2009, Nature Reviews Immunology.

[158]  Chien-Fu Hung,et al.  Expression of IL‐15RA or an IL‐15/IL‐15RA fusion on CD8+ T cells modifies adoptively transferred T‐cell function in cis , 2009, European journal of immunology.

[159]  S. Demaria,et al.  Invariant NKT Cells as Novel Targets for Immunotherapy in Solid Tumors , 2012, Clinical & developmental immunology.

[160]  E. Warren,et al.  The graft versus leukemia response after allogeneic hematopoietic stem cell transplantation. , 2003, Blood reviews.

[161]  Tongguang Wang,et al.  Cancer Regression and Neurological Toxicity Following Anti-MAGE-A3 TCR Gene Therapy , 2013, Journal of immunotherapy.

[162]  H. Heslop,et al.  Epstein Barr virus specific cytotoxic T lymphocytes expressing the anti-CD30zeta artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease. , 2007, Blood.

[163]  M. Ruella,et al.  Lymphocyte transformation and autoimmune disorders. , 2013, Autoimmunity reviews.

[164]  Marcela V Maus,et al.  A cell-based artificial antigen-presenting cell coated with anti-CD3 and CD28 antibodies enables rapid expansion and long-term growth of CD4 T lymphocytes. , 2002, Clinical immunology.

[165]  J. Thompson,et al.  Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: In vivo persistence, migration, and antitumor effect of transferred T cells , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[166]  A. Chang,et al.  Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. , 1985, The New England journal of medicine.

[167]  David L. Liu,et al.  Anti-GD3 Chimeric sFv-CD28/T-Cell Receptor ζ Designer T Cells for Treatment of Metastatic Melanoma and Other Neuroectodermal Tumors , 2010, Clinical Cancer Research.

[168]  R. Weichselbaum,et al.  Induced sensitization of tumor stroma leads to eradication of established cancer by T cells , 2007, The Journal of experimental medicine.

[169]  A. Zolopa,et al.  Patient monitoring and follow‐up in lentiviral clinical trials , 2013, The journal of gene medicine.

[170]  Ralf-Holger Voss,et al.  Facilitating matched pairing and expression of TCR chains introduced into human T cells. , 2007, Blood.

[171]  A. Jawad,et al.  Adoptive Transfer of Autologous T Cells Improves T-cell Repertoire Diversity and Long-term B-cell Function in Pediatric Patients with Neuroblastoma , 2012, Clinical Cancer Research.

[172]  R. A. Evans,et al.  CD40 immunotherapy for pancreatic cancer , 2013, Cancer Immunology, Immunotherapy.

[173]  D. Kranz,et al.  T cell receptor engineering. , 2012, Methods in enzymology.

[174]  Jeffry D Sander,et al.  FLAsH assembly of TALeNs for high-throughput genome editing , 2022 .

[175]  S. Orsulic,et al.  Mouse models of cancer. , 2011, Annual review of pathology.

[176]  T. Schumacher,et al.  Lethal graft-versus-host disease in mouse models of T cell receptor gene therapy , 2010, Nature Medicine.

[177]  A. Barber,et al.  Treatment of multiple myeloma with adoptively transferred chimeric NKG2D receptor-expressing T cells , 2011, Gene Therapy.

[178]  H. Abken,et al.  OX40 costimulation by a chimeric antigen receptor abrogates CD28 and IL-2 induced IL-10 secretion by redirected CD4+ T cells , 2012, Oncoimmunology.

[179]  S. Olivares,et al.  Reprogramming CD19-specific T cells with IL-21 signaling can improve adoptive immunotherapy of B-lineage malignancies. , 2011, Cancer research.

[180]  D. McNeel,et al.  The SSX Family of Cancer-Testis Antigens as Target Proteins for Tumor Therapy , 2010, Clinical & developmental immunology.

[181]  S. Rosenberg,et al.  Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[182]  Hao Liu,et al.  Antitumor effects of chimeric receptor engineered human T cells directed to tumor stroma. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[183]  D. Scheinberg,et al.  Targeting the Intracellular WT1 Oncogene Product with a Therapeutic Human Antibody , 2013, Science Translational Medicine.

[184]  D. Porter,et al.  Chimeric Antigen Receptor Therapy for B-cell Malignancies , 2011, Journal of Cancer.

[185]  H. Shiku,et al.  Novel adoptive T-cell immunotherapy using a WT1-specific TCR vector encoding silencers for endogenous TCRs shows marked antileukemia reactivity and safety. , 2011, Blood.

[186]  A. Barber,et al.  Collaboration of chimeric antigen receptor (CAR)-expressing T cells and host T cells for optimal elimination of established ovarian tumors , 2013, Oncoimmunology.

[187]  Yun Ji,et al.  Adoptively transferred effector cells derived from naïve rather than central memory CD8+ T cells mediate superior antitumor immunity , 2009, Proceedings of the National Academy of Sciences.

[188]  M. Raffeld,et al.  Cancer Regression and Autoimmunity in Patients After Clonal Repopulation with Antitumor Lymphocytes , 2002, Science.

[189]  M. Sadelain.  T-cell engineering for cancer immunotherapy. , 2009, Cancer journal.

[190]  C. June,et al.  The Inducible Costimulator (ICOS) Is Critical for the Development of Human TH17 Cells , 2010, Science Translational Medicine.

[191]  H. Heslop,et al.  Adoptive T cell therapy of cancer. , 2010, Current opinion in immunology.

[192]  Bernd Hauck,et al.  Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. , 2013, The New England journal of medicine.

[193]  R. Jain.  Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[194]  P. Romero,et al.  Molecular Design of the Cαβ Interface Favors Specific Pairing of Introduced TCRαβ in Human T Cells1 , 2008, The Journal of Immunology.

[195]  D. Porter,et al.  Reduced-intensity hematopoietic stem cell transplants for malignancies: harnessing the graft-versus-tumor effect. , 2013, Annual review of medicine.

[196]  H. Ikeda,et al.  Generation of tumor-specific, HLA class I-restricted human Th1 and Tc1 cells by cell engineering with tumor peptide-specific T-cell receptor genes. , 2005, Blood.

[197]  M. Zhang,et al.  Cytoreduction and sequential resection: A hope for unresectable primary liver cancer , 1991, Journal of surgical oncology.

[198]  Shuang-yin Han,et al.  Chimeric antigen receptor containing ICOS signaling domain mediates specific and efficient antitumor effect of T cells against EGFRvIII expressing glioma , 2013, Journal of Hematology & Oncology.

[199]  S. Rosenberg,et al.  High-efficiency transfection of primary human and mouse T lymphocytes using RNA electroporation. , 2006, Molecular therapy : the journal of the American Society of Gene Therapy.

[200]  F. Orso,et al.  T cell receptor (TCR) gene transfer with lentiviral vectors allows efficient redirection of tumor specificity in naive and memory T cells without prior stimulation of endogenous TCR. , 2009, Human gene therapy.

[201]  Hao Liu,et al.  Adoptive Transfer of EBV-specific T Cells Results in Sustained Clinical Responses in Patients With Locoregional Nasopharyngeal Carcinoma , 2010, Journal of immunotherapy.

[202]  S. Rosenberg,et al.  Increased intensity lymphodepletion and adoptive immunotherapy—how far can we go? , 2006, Nature Clinical Practice Oncology.

[203]  C. Craddock,et al.  Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA–peptide tetramers , 2005, The Journal of experimental medicine.

[204]  Steven A. Rosenberg,et al.  Cell transfer immunotherapy for metastatic solid cancer—what clinicians need to know , 2011, Nature Reviews Clinical Oncology.

[205]  W. Wilson,et al.  B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. , 2012, Blood.

[206]  F. Marincola,et al.  Redirecting migration of T cells to chemokine secreted from tumors by genetic modification with CXCR2. , 2002, Human gene therapy.

[207]  C. Turtle,et al.  Generation of CD19-chimeric antigen receptor modified CD8+ T cells derived from virus-specific central memory T cells. , 2012, Blood.

[208]  Alfred L George,et al.  PiggyBac transposon-mediated gene transfer in human cells. , 2007, Molecular therapy : the journal of the American Society of Gene Therapy.

[209]  M. Hansmann,et al.  Resistance of mature T cells to oncogene transformation. , 2008, Blood.

[210]  M. Kalos,et al.  Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. , 2013, Immunity.

[211]  Luigi Naldini,et al.  A foundation for universal T-cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR. , 2012, Blood.

[212]  S. Rosenberg,et al.  Cancer Regression in Patients After Transfer of Genetically Engineered Lymphocytes , 2006, Science.

[213]  M. Kalos.  Tumor antigen-specific T cells and cancer immunotherapy: current issues and future prospects. , 2003, Vaccine.

[214]  Jianhong Cao,et al.  Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. , 2008, The New England journal of medicine.

[215]  C. Rooney,et al.  Combining T-cell immunotherapy and anti-androgen therapy for prostate cancer , 2013, Prostate Cancer and Prostatic Diseases.

[216]  Z. Trajanoski,et al.  Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome , 2006, Science.

[217]  F. Bushman,et al.  Decade-Long Safety and Function of Retroviral-Modified Chimeric Antigen Receptor T Cells , 2012, Science Translational Medicine.

[218]  M. Koch,et al.  Role of tumor endothelium in CD4+ CD25+ regulatory T cell infiltration of human pancreatic carcinoma. , 2007, Journal of the National Cancer Institute.

[219]  S. Rosenberg,et al.  Increased Intensity Lymphodepletion Enhances Tumor Treatment Efficacy of Adoptively Transferred Tumor-specific T Cells , 2010, Journal of immunotherapy.

[220]  J. Massagué,et al.  Adapting a transforming growth factor beta-related tumor protection strategy to enhance antitumor immunity. , 2002, Blood.

[221]  D. Powell,et al.  A universal strategy for adoptive immunotherapy of cancer through use of a novel T-cell antigen receptor. , 2012, Cancer research.

[222]  D. Teachey,et al.  Maude SL, Teachey DT, Porter DL, Grupp SA. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood. 2015;125(26):4017-4023. , 2016, Blood.

[223]  A. Schambach,et al.  Design and production of retro- and lentiviral vectors for gene expression in hematopoietic cells. , 2009, Methods in molecular biology.

[224]  V. Jendrossek,et al.  Targeting the tumour stroma to increase efficacy of chemo- and radiotherapy , 2009, Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico.

[225]  S. Rosenberg,et al.  A Herceptin-Based Chimeric Antigen Receptor with Modified Signaling Domains Leads to Enhanced Survival of Transduced T Lymphocytes and Antitumor Activity1 , 2009, The Journal of Immunology.

[226]  G. Coukos,et al.  Redirected antitumor activity of primary human lymphocytes transduced with a fully human anti-mesothelin chimeric receptor. , 2012, Molecular therapy : the journal of the American Society of Gene Therapy.

[227]  B. Shalmon,et al.  Clinical Responses in a Phase II Study Using Adoptive Transfer of Short-term Cultured Tumor Infiltration Lymphocytes in Metastatic Melanoma Patients , 2010, Clinical Cancer Research.

[228]  S. Rosenberg,et al.  Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. , 1988, The New England journal of medicine.

[229]  Bent K Jakobsen,et al.  Identification of a Titin-Derived HLA-A1–Presented Peptide as a Cross-Reactive Target for Engineered MAGE A3–Directed T Cells , 2013, Science Translational Medicine.

[230]  E. Warren,et al.  Analysis of transgene-specific immune responses that limit the in vivo persistence of adoptively transferred HSV-TK-modified donor T cells after allogeneic hematopoietic cell transplantation. , 2006, Blood.

[231]  A. Scott,et al.  Gene-modified T cells as immunotherapy for multiple myeloma and acute myeloid leukemia expressing the Lewis Y antigen , 2010, Gene Therapy.

[232]  E. Appella,et al.  A mutated beta-catenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes , 1996, The Journal of experimental medicine.

[233]  H. Ikeda,et al.  [Targeting cancer antigen (MAGE-A4, NY-ESO -1) for immunotherapy]. , 2012, Nihon rinsho. Japanese journal of clinical medicine.

[234]  Drew M. Pardoll,et al.  The blockade of immune checkpoints in cancer immunotherapy , 2012, Nature Reviews Cancer.

[235]  David C. Smith,et al.  Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. , 2012, The New England journal of medicine.

[236]  M. Tan,et al.  Combination immunotherapy using adoptive T-cell transfer and tumor antigen vaccination on the basis of hTERT and survivin after ASCT for myeloma. , 2011, Blood.

[237]  P. Lowenstein,et al.  Treg Depletion Inhibits Efficacy of Cancer Immunotherapy: Implications for Clinical Trials , 2008, PloS one.

[238]  Alan D. Roberts,et al.  Differential contributions of central and effector memory T cells to recall responses , 2005, The Journal of experimental medicine.

[239]  M. Pirmohamed,et al.  Challenges and approaches for the development of safer immunomodulatory biologics , 2013, Nature Reviews Drug Discovery.

[240]  B. Levine,et al.  Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor. , 2010, Cancer research.

[241]  P. Stern,et al.  Combination of Vaccination and Chimeric Receptor Expressing T Cells Provides Improved Active Therapy of Tumors1 , 2006, The Journal of Immunology.

[242]  B. Jakobsen,et al.  Different affinity windows for virus and cancer‐specific T‐cell receptors: Implications for therapeutic strategies , 2012, European journal of immunology.

[243]  M. Sadelain,et al.  In vivo inhibition of human CD19-targeted effector T cells by natural T regulatory cells in a xenotransplant murine model of B cell malignancy. , 2011, Cancer research.

[244]  M. Kalos,et al.  Mesothelin, a novel immunotherapy target for triple negative breast cancer , 2012, Breast Cancer Research and Treatment.

[245]  P. Friedl,et al.  Cancer invasion and resistance: interconnected processes of disease progression and therapy failure. , 2012, Trends in molecular medicine.

[246]  M. Bevan,et al.  Defective CD8 T Cell Memory Following Acute Infection Without CD4 T Cell Help , 2003, Science.

[247]  Bilian Jin,et al.  DNA methylation as a target of epigenetic therapeutics in cancer. , 2013, Anti-cancer agents in medicinal chemistry.

[248]  E. Simard,et al.  Cumulative incidence of cancer among individuals with acquired immunodeficiency syndrome in the United States , 2011, Cancer.

[249]  I. Pastan,et al.  Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains , 2009, Proceedings of the National Academy of Sciences.

[250]  C. Drake,et al.  Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. , 2012, The New England journal of medicine.

[251]  Michael Kalos,et al.  T cell-based gene therapy of cancer. , 2013, Translational research : the journal of laboratory and clinical medicine.

[252]  K. Shimizu,et al.  Tumor-Infiltrating Foxp3+ Regulatory T Cells are Correlated with Cyclooxygenase-2 Expression and are Associated with Recurrence in Resected Non-small Cell Lung Cancer , 2010, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[253]  Christian Stemberger,et al.  Stem cell-like plasticity of naïve and distinct memory CD8+ T cell subsets. , 2009, Seminars in immunology.

[254]  D. Hart,et al.  Retroviral transfer of a dominant TCR prevents surface expression of a large proportion of the endogenous TCR repertoire in human T cells , 2008, Gene Therapy.

[255]  A. Letai,et al.  Targeting the B-cell lymphoma/leukemia 2 family in cancer. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[256]  F. Marincola,et al.  IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors. , 2011, The Journal of clinical investigation.

[257]  Wayne W. Hancock,et al.  Substrate Rigidity Regulates Human T Cell Activation and Proliferation , 2012, The Journal of Immunology.

[258]  P. Allavena,et al.  Tumor‐associated macrophages (TAM) as major players of the cancer‐related inflammation , 2009, Journal of leukocyte biology.

[259]  A. Lawson,et al.  Activation of Resting Human Primary T Cells with Chimeric Receptors: Costimulation from CD28, Inducible Costimulator, CD134, and CD137 in Series with Signals from the TCRζ Chain , 2004, The Journal of Immunology.

[260]  J. McCubrey,et al.  Transfer of specificity by murine alpha and beta T-cell receptor genes. , 1986, Nature.

[261]  Alexander Perl,et al.  A phase 1 trial of donor lymphocyte infusions expanded and activated ex vivo via CD3/CD28 costimulation. , 2006, Blood.

[262]  H. Abken,et al.  Building better chimeric antigen receptors for adoptive T cell therapy. , 2010, Current gene therapy.

[263]  B. Shalmon,et al.  Establishment and Large-scale Expansion of Minimally cultured “Young” Tumor Infiltrating Lymphocytes for Adoptive Transfer Therapy , 2011, Journal of immunotherapy.

[264]  Martin Pule,et al.  Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. , 2011, Blood.

[265]  H. Abken,et al.  Adoptive immunotherapy with genetically engineered T cells: modification of the IgG1 Fc ‘spacer’ domain in the extracellular moiety of chimeric antigen receptors avoids ‘off-target’ activation and unintended initiation of an innate immune response , 2010, Gene Therapy.

[266]  Leonardo M. R. Ferreira.  Gammadelta T Cells: Innately Adaptive Immune Cells? , 2013, International reviews of immunology.

[267]  G. Görgün,et al.  Intrinsic modulation of lymphocyte function by stromal cell network: advance in therapeutic targeting of cancer. , 2011, Immunotherapy.

[268]  Xiaoliu Zhang,et al.  Genetically modified T cells targeting neovasculature efficiently destroy tumor blood vessels, shrink established solid tumors and increase nanoparticle delivery , 2013, International journal of cancer.

[269]  S. Eccles,et al.  Flexible Targeting of ErbB Dimers That Drive Tumorigenesis by Using Genetically Engineered T Cells , 2012, Molecular medicine.

[270]  S. Forman,et al.  Antigen-independent and antigen-dependent methods to numerically expand CD19-specific CD8+ T cells. , 2007, Experimental hematology.

[271]  L. Tentori,et al.  Ipilimumab: a novel immunostimulatory monoclonal antibody for the treatment of cancer. , 2012, Pharmacological research.

[272]  P. Chomez,et al.  A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. , 1991, Science.

[273]  M. Raffeld,et al.  B-cell Maturation Antigen Is a Promising Target for Adoptive T-cell Therapy of Multiple Myeloma , 2013, Clinical Cancer Research.

[274]  T. Schumacher,et al.  Requirements for Effective Antitumor Responses of TCR Transduced T Cells1 , 2008, The Journal of Immunology.

[275]  P. Romero,et al.  Molecular design of the Calphabeta interface favors specific pairing of introduced TCRalphabeta in human T cells. , 2008, Journal of immunology.

[276]  F. Marincola,et al.  A Phase I Study of Nonmyeloablative Chemotherapy and Adoptive Transfer of Autologous Tumor Antigen-Specific T Lymphocytes in Patients With Metastatic Melanoma , 2002, Journal of immunotherapy.

[277]  M. Raffeld,et al.  Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[278]  L. Hurton,et al.  Bispecific T-cells expressing polyclonal repertoire of endogenous γδ T-cell receptors and introduced CD19-specific chimeric antigen receptor. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[279]  M. Sadelain,et al.  Artificial antigen presenting cells that express prevalent HLA alleles: A step towards the broad application of antigen-specific adoptive cell therapies. , 2009, Discovery medicine.

[280]  Christof von Kalle,et al.  A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. , 2003, The New England journal of medicine.

[281]  S. Rosenberg,et al.  Enhanced antitumor activity of T cells engineered to express T-cell receptors with a second disulfide bond. , 2007, Cancer research.

[282]  Yangbing Zhao,et al.  Enhanced antitumor activity of murine-human hybrid T-cell receptor (TCR) in human lymphocytes is associated with improved pairing and TCR/CD3 stability. , 2006, Cancer research.

[283]  M. Slovak,et al.  Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. , 2007, Molecular therapy : the journal of the American Society of Gene Therapy.

[284]  H. Heslop,et al.  A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[285]  M. Brenner,et al.  Addition of the CD28 signaling domain to chimeric T-cell receptors enhances chimeric T-cell resistance to T regulatory cells , 2006, Leukemia.

[286]  W. Leonard,et al.  IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy. , 2008, Blood.

[287]  R. Motzer,et al.  Phase iii randomized trial of interleukin‐2 with or without lymphokine‐activated killer cells in the treatment of patients with advanced renal cell carcinoma , 1995, Cancer.

[288]  S. Rosenberg,et al.  Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. , 2009, Blood.

[289]  S. Sleijfer,et al.  Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[290]  H. Heslop,et al.  An inducible caspase 9 safety switch for T-cell therapy. , 2005, Blood.

[291]  M. Sadelain,et al.  Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. , 2012, Blood.

[292]  P. Hand,et al.  Anti-tumor activity of human T cells expressing the CC49-zeta chimeric immune receptor. , 1999, Human gene therapy.

[293]  P. Rao,et al.  piggyBac transposon/transposase system to generate CD19-specific T cells for the treatment of B-lineage malignancies. , 2010, Human gene therapy.

[294]  C. June,et al.  Adoptive T cell therapy for cancer in the clinic. , 2007, The Journal of clinical investigation.

[295]  S. Rosenberg,et al.  Simultaneous targeting of tumor antigens and the tumor vasculature using T lymphocyte transfer synergize to induce regression of established tumors in mice. , 2013, Cancer research.

[296]  C. Klebanoff,et al.  Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy. , 2005, Trends in immunology.

[297]  Izhak Haviv,et al.  Co-evolution of tumor cells and their microenvironment. , 2009, Trends in genetics : TIG.

[298]  W. Piacibello,et al.  Cytokine induced killer cells as adoptive immunotherapy strategy to augment graft versus tumor after hematopoietic cell transplantation , 2009, Expert opinion on biological therapy.

[299]  P. Allavena,et al.  The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. , 2008, Critical reviews in oncology/hematology.

[300]  M. Wiese,et al.  Collaborating with the Enemy: Function of Macrophages in the Development of Neoplastic Disease , 2013, Mediators of inflammation.

[301]  W. Gillanders,et al.  The presence of programmed death 1 (PD-1)-positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer , 2013, Breast Cancer Research and Treatment.

[302]  J. East,et al.  Artificial Antigen Presenting Cell (aAPC) Mediated Activation and Expansion of Natural Killer T Cells , 2012, Journal of visualized experiments : JoVE.

[303]  Richard P. Junghans,et al.  Second-Generation Anti–Carcinoembryonic Antigen Designer T Cells Resist Activation-Induced Cell Death, Proliferate on Tumor Contact, Secrete Cytokines, and Exhibit Superior Antitumor Activity In vivo: A Preclinical Evaluation , 2008, Clinical Cancer Research.

[304]  T. Waldmann,et al.  Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[305]  N. Mitchison.  STUDIES ON THE IMMUNOLOGICAL RESPONSE TO FOREIGN TUMOR TRANSPLANTS IN THE MOUSE , 1955, The Journal of experimental medicine.

[306]  Chien-Fu Hung,et al.  Tumor-Targeted Delivery of IL-2 by NKG2D Leads to Accumulation of Antigen-Specific CD8+ T Cells in the Tumor Loci and Enhanced Anti-Tumor Effects , 2012, PloS one.

[307]  E. Rieber,et al.  Targeting of tumor cells expressing the prostate stem cell antigen (PSCA) using genetically engineered T‐cells , 2007, The Prostate.

[308]  M. Ponzoni,et al.  In vitro and in vivo model of a novel immunotherapy approach for chronic lymphocytic leukemia by anti-CD23 chimeric antigen receptor. , 2011, Blood.

[309]  Eric Vivier,et al.  Targeting natural killer cells and natural killer T cells in cancer , 2012, Nature Reviews Immunology.

[310]  N. Bander,et al.  Cancer patient T cells genetically targeted to prostate-specific membrane antigen specifically lyse prostate cancer cells and release cytokines in response to prostate-specific membrane antigen. , 1999, Neoplasia.

[311]  S. Riddell,et al.  The use of anti-CD3 and anti-CD28 monoclonal antibodies to clone and expand human antigen-specific T cells. , 1990, Journal of immunological methods.

[312]  Smaroula Dilioglou,et al.  Correction of multi-gene deficiency in vivo using a single 'self-cleaving' 2A peptide–based retroviral vector , 2004, Nature Biotechnology.

[313]  D. Gilham,et al.  Retroviral transduction of human peripheral blood lymphocytes with bcl-xL promotes in vitro lymphocyte survival in pro-apoptotic conditions , 2002, Gene Therapy.

[314]  Bent K. Jakobsen,et al.  Single and Dual Amino Acid Substitutions in TCR CDRs Can Enhance Antigen-Specific T Cell Functions , 2008, The Journal of Immunology.

[315]  Chiara Bonini,et al.  The suicide gene therapy challenge: how to improve a successful gene therapy approach. , 2007, Molecular therapy : the journal of the American Society of Gene Therapy.

[316]  Jinjuan Wang,et al.  CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results. , 2012, Blood.

[317]  B. Groner,et al.  Growth retardation of tumors by adoptive transfer of cytotoxic T lymphocytes reprogrammed by CD44V6‐specific SCFV: ζ‐chimera , 1996, International journal of cancer.

[318]  W. Fisher,et al.  Engineered T cells for pancreatic cancer treatment. , 2011, HPB : the official journal of the International Hepato Pancreato Biliary Association.

[319]  C. Rooney,et al.  Human cytotoxic T lymphocytes with reduced sensitivity to Fas-induced apoptosis. , 2005, Blood.

[320]  Hao Liu,et al.  T cells redirected against CD70 for the immunotherapy of CD70-positive malignancies. , 2011, Blood.

[321]  S. Jameson,et al.  Effector-like CD8⁺ T cells in the memory population mediate potent protective immunity. , 2013, Immunity.

[322]  O. Leavy.  Therapeutic antibodies: past, present and future , 2010, Nature Reviews Immunology.

[323]  S. Rosenberg,et al.  Evaluation of &ggr;-Retroviral Vectors That Mediate the Inducible Expression of IL-12 for Clinical Application , 2012, Journal of immunotherapy.

[324]  R. Grossman,et al.  T cells redirected to EphA2 for the immunotherapy of glioblastoma. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[325]  W. Burns,et al.  Human effector CD8+ T cells derived from naive rather than memory subsets possess superior traits for adoptive immunotherapy. , 2011, Blood.

[326]  H. Shiku,et al.  Development of a novel redirected T-cell-based adoptive immunotherapy targeting human telomerase reverse transcriptase for adult T-cell leukemia. , 2013, Blood.

[327]  M. Miyasaka,et al.  Chemokines in tumor progression and metastasis , 2005, Cancer science.

[328]  Z. Eshhar,et al.  Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[329]  M. Kalos,et al.  Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. , 2010, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[330]  M. Bevan,et al.  Cutting Edge: Long-Lived CD8 Memory and Protective Immunity in the Absence of CD40 Expression on CD8 T Cells1 , 2004, The Journal of Immunology.

[331]  C. Dunbar,et al.  Persistence and expression of the adenosine deaminase gene for 12 years and immune reaction to gene transfer components: long-term results of the first clinical gene therapy trial. , 2003, Blood.

[332]  P. Tonnerre,et al.  Endothelial Cell Activation and Proliferation Modulate NKG2D Activity by Regulating MICA Expression and Shedding , 2013, Journal of Innate Immunity.

[333]  S. Riddell,et al.  A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells. , 2011, Blood.

[334]  S. Takamoto,et al.  Adoptive Immunotherapy for Advanced Non-small Cell Lung Cancer Using Zoledronate-expanded &ggr;&dgr; T Cells: A Phase I Clinical Study , 2011, Journal of immunotherapy.

[335]  H. Abken,et al.  T cells that target carcinoembryonic antigen eradicate orthotopic pancreatic carcinomas without inducing autoimmune colitis in mice. , 2012, Gastroenterology.

[336]  Hao Liu,et al.  Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma , 2008, Nature Medicine.

[337]  H. Abken,et al.  Adoptive immunotherapy with redirected T cells produces CCR7- cells that are trapped in the periphery and benefit from combined CD28-OX40 costimulation. , 2013, Human gene therapy.

[338]  C. Rooney,et al.  PiggyBac-mediated cancer immunotherapy using EBV-specific cytotoxic T-cells expressing HER2-specific chimeric antigen receptor. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[339]  S. Rosenberg,et al.  Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. , 2005, The Journal of clinical investigation.

[340]  H. Inoue,et al.  Co-Introduced Functional CCR2 Potentiates In Vivo Anti-Lung Cancer Functionality Mediated by T Cells Double Gene-Modified to Express WT1-Specific T-Cell Receptor , 2013, PloS one.

[341]  S. Rosenberg,et al.  Personalized cell transfer immunotherapy for B-cell malignancies and solid cancers. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[342]  S. Turley,et al.  Stromal and hematopoietic cells in secondary lymphoid organs: partners in immunity , 2013, Immunological reviews.

[343]  S. Riddell,et al.  Receptor Affinity and Extracellular Domain Modifications Affect Tumor Recognition by ROR1-Specific Chimeric Antigen Receptor T Cells , 2013, Clinical Cancer Research.

[344]  S. Mather,et al.  Trafficking of CAR-Engineered Human T Cells Following Regional or Systemic Adoptive Transfer in SCID Beige Mice , 2011, Journal of Clinical Immunology.

[345]  D. Gabrilovich,et al.  Coordinated regulation of myeloid cells by tumours , 2012, Nature Reviews Immunology.

[346]  C. Meijer,et al.  Codon modification of T cell receptors allows enhanced functional expression in transgenic human T cells. , 2006, Clinical immunology.

[347]  D. Campana,et al.  Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[348]  M. Neuenhahn,et al.  CD8+ T cell differentiation in the aging immune system: until the last clone standing. , 2011, Current opinion in immunology.

[349]  A. Bagg,et al.  Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. , 2011, The New England journal of medicine.

[350]  L. Chicaybam,et al.  An Efficient Low Cost Method for Gene Transfer to T Lymphocytes , 2013, PloS one.

[351]  J. Moyer,et al.  Human TH17 Cells Are Long-Lived Effector Memory Cells , 2011, Science Translational Medicine.

[352]  I. Pastan,et al.  Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. , 2013, Blood.

[353]  J. Byrd,et al.  Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug. , 2008, The Journal of clinical investigation.

[354]  D. Largaespada,et al.  A transposon and transposase system for human application. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[355]  W. Wilmanns,et al.  Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. , 1990, Blood.

[356]  T. Schumacher,et al.  Selecting highly affine and well-expressed TCRs for gene therapy of melanoma. , 2007, Blood.

[357]  H. Heslop,et al.  Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety , 2010, Leukemia.