T cell-based gene therapy of cancer.

Adoptive immunotherapy using gene engineered T cells is a promising and rapidly evolving field, and the ability to engineer T cells to manifest desired phenotypes and functions has become a practical reality. In this review, we describe and summarize current thought about gene engineering of T cells. We focus on the identified requirements for the successful application of T cell based immunotherapy and discuss gene-therapy based strategies that address these requirements and have the potential to enhance the successful implementation of this promising approach to treat cancer.

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

[2]  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.

[3]  D. Venzon,et al.  Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets , 2008, The Journal of experimental medicine.

[4]  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.

[5]  J. Buckner,et al.  Optimization of Human T-Cell Expansion Ex Vivo Using Magnetic Beads Conjugated with Anti-CD3 and Anti-CD28 Antibodies , 2004, Journal of immunotherapy.

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

[7]  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.

[8]  M. Betts,et al.  The cytolytic enzymes granyzme A, granzyme B, and perforin: expression patterns, cell distribution, and their relationship to cell maturity and bright CD57 expression , 2008, Journal of leukocyte biology.

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

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

[11]  J. Wolchok,et al.  The heterogeneity of the kinetics of response to ipilimumab in metastatic melanoma: patient cases. , 2008, Cancer immunity.

[12]  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.

[13]  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.

[14]  G. Parmiani,et al.  A listing of human tumor antigens recognized by T cells: March 2004 update , 2005, Cancer Immunology, Immunotherapy.

[15]  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.

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

[17]  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.

[18]  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.

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

[20]  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.

[21]  S. Rosenberg,et al.  Telomere Length of Transferred Lymphocytes Correlates with In Vivo Persistence and Tumor Regression in Melanoma Patients Receiving Cell Transfer Therapy1 , 2005, The Journal of Immunology.

[22]  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.

[23]  M. Kalos.  Muscle CARs and TcRs: turbo-charged technologies for the (T cell) masses , 2011, Cancer Immunology, Immunotherapy.

[24]  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.

[25]  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.

[26]  Ping Jin,et al.  Global transcriptional analysis for biomarker discovery and validation in cellular therapies. , 2009, Molecular diagnosis & therapy.

[27]  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.

[28]  H. Heslop,et al.  Co-expression of cytokine and suicide genes to enhance the activity and safety of tumor-specific cytotoxic T lymphocytes. , 2007, Blood.

[29]  Pedro Romero,et al.  Exhaustion of tumor-specific CD8⁺ T cells in metastases from melanoma patients. , 2011, The Journal of clinical investigation.

[30]  R. Collins,et al.  transplantation with unrelated donor leukocyte infusions Treatment of relapsed leukemia after unrelated donor marrow , 2013 .

[31]  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.

[32]  P. Kantoff,et al.  Sipuleucel-T immunotherapy for castration-resistant prostate cancer. , 2010, The New England journal of medicine.

[33]  T. Waldmann,et al.  Transient and persistent effects of IL-15 on lymphocyte homeostasis in nonhuman primates. , 2010, Blood.

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

[35]  R. Hohlfeld,et al.  Reconstitution of paired T cell receptor α- and β-chains from microdissected single cells of human inflammatory tissues , 2006, Proceedings of the National Academy of Sciences.

[36]  P. Robbins,et al.  A listing of human tumor antigens recognized by T cells , 2001, Cancer Immunology, Immunotherapy.

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

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

[39]  Harjeet Singh,et al.  Chimeric Antigen Receptor (CAR)-Specific Monoclonal Antibody to Detect CD19-Specific T Cells in Clinical Trials , 2013, PloS one.

[40]  J. Lustgarten,et al.  The CD8+ T cell repertoire against Her‐2/neu antigens in neu transgenic mice is of low avidity with antitumor activity , 2004, European journal of immunology.

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

[42]  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.

[43]  T. Harrer,et al.  A fast and robust method to clone and functionally validate T-cell receptors. , 2009, Journal of immunological methods.

[44]  P. Hanley,et al.  Derivation of human T lymphocytes from cord blood and peripheral blood with antiviral and antileukemic specificity from a single culture as protection against infection and relapse after stem cell transplantation. , 2010, Blood.

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

[46]  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.

[47]  Richard A. Morgan,et al.  A Simplified Method for the Clinical-scale Generation of Central Memory-like CD8+ T Cells After Transduction With Lentiviral Vectors Encoding Antitumor Antigen T-cell Receptors , 2010, Journal of immunotherapy.

[48]  K. Cornetta,et al.  Cytokine-independent growth and clonal expansion of a primary human CD8+ T-cell clone following retroviral transduction with the IL-15 gene. , 2007, Blood.

[49]  C. Bordignon,et al.  HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. , 1997, Science.

[50]  Michael Milone,et al.  Genetic engineering of T cells for adoptive immunotherapy , 2008, Immunologic research.

[51]  B. Nelson,et al.  Expression of chimeric granulocyte-macrophage colony-stimulating factor/interleukin 2 receptors in human cytotoxic T lymphocyte clones results in granulocyte-macrophage colony-stimulating factor-dependent growth. , 1999, Human gene therapy.

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

[53]  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.

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

[55]  Wei-Ting Hwang,et al.  Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. , 2014, The New England journal of medicine.

[56]  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.

[57]  T. Barbui,et al.  Genetic modification of human T cells with CD20: a strategy to purify and lyse transduced cells with anti-CD20 antibodies. , 2000, Human gene therapy.

[58]  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.

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

[60]  V. Maino,et al.  Flow cytometric analysis of cell signaling proteins. , 2011, Methods in molecular biology.

[61]  L. G. Davis,et al.  Basic methods in molecular biology , 1986 .

[62]  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.

[63]  Michel Sadelain,et al.  The promise and potential pitfalls of chimeric antigen receptors. , 2009, Current Opinion in Immunology.

[64]  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.

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

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

[67]  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.

[68]  Yi Li,et al.  High-Affinity TCRs Generated by Phage Display Provide CD4+ T Cells with the Ability to Recognize and Kill Tumor Cell Lines1 , 2007, The Journal of Immunology.

[69]  D. Dolfi,et al.  Perforin and IL-2 Upregulation Define Qualitative Differences among Highly Functional Virus-Specific Human CD8+ T Cells , 2010, PLoS pathogens.

[70]  M. Bevan,et al.  CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection , 2004, Nature Immunology.

[71]  D. Campana,et al.  Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia , 2004, Leukemia.

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

[73]  S. Rosenberg,et al.  Adoptive cell therapy for the treatment of patients with metastatic melanoma. , 2009, Current opinion in immunology.

[74]  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.

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

[76]  D. Torigian,et al.  Mesothelin-Specific Chimeric Antigen Receptor mRNA-Engineered T Cells Induce Antitumor Activity in Solid Malignancies , 2013, Cancer Immunology Research.

[77]  T. Gajewski,et al.  Gene Signature in Melanoma Associated With Clinical Activity: A Potential Clue to Unlock Cancer Immunotherapy , 2010, Cancer journal.

[78]  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.

[79]  J. Ellis.  Silencing and variegation of gammaretrovirus and lentivirus vectors. , 2005, Human gene therapy.

[80]  Lieping Chen,et al.  Molecular mechanisms of T cell co-stimulation and co-inhibition , 2013, Nature Reviews Immunology.

[81]  C. June,et al.  Extensive Replicative Capacity of Human Central Memory T Cells1 , 2004, The Journal of Immunology.

[82]  S. Rosenberg,et al.  Transition of late-stage effector T cells to CD27+ CD28+ tumor-reactive effector memory T cells in humans after adoptive cell transfer therapy. , 2005, Blood.

[83]  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.

[84]  L. Old,et al.  Cancer vaccines: an overview. , 2008, Cancer immunity.

[85]  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.

[86]  M. Slovak,et al.  Human T lymphocyte genetic modification with naked DNA. , 2000, Molecular therapy : the journal of the American Society of Gene Therapy.

[87]  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.

[88]  P. Hanley,et al.  Cytotoxic T lymphocyte therapy with donor T cells prevents and treats adenovirus and Epstein-Barr virus infections after haploidentical and matched unrelated stem cell transplantation. , 2009, Blood.

[89]  M. Betts,et al.  Phenotype and function of protective T cell immune responses in HIV , 2008, Current opinion in HIV and AIDS.

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

[91]  S. Rosenberg,et al.  In vitro growth of cytotoxic human lymphocytes. II. Use of T cell growth factor (TCGF) to clone human T cells. , 1980, Journal of immunology.

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

[93]  F. Kern,et al.  Flow cytometric enumeration of antigen‐specific T lymphocytes , 2004, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[94]  F. Marincola,et al.  Global Transcriptional Analysis for Biomarker Discovery and Validation in Cellular Therapies , 2012, Molecular Diagnosis & Therapy.

[95]  C. Nabhan.  Sipuleucel-T immunotherapy for castration-resistant prostate cancer , 2015 .

[96]  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.

[97]  M. Roederer,et al.  T-cell quality in memory and protection: implications for vaccine design , 2008, Nature Reviews Immunology.

[98]  J. Harty,et al.  Naive, effector and memory CD8 T-cell trafficking: parallels and distinctions. , 2011, Immunotherapy.

[99]  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.

[100]  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.

[101]  L. Zitvogel,et al.  Calreticulin exposure dictates the immunogenicity of cancer cell death , 2007, Nature Medicine.

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

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

[104]  David A Largaespada,et al.  Evaluating risks of insertional mutagenesis by DNA transposons in gene therapy. , 2013, Translational research : the journal of laboratory and clinical medicine.

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

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

[107]  C. June,et al.  The CD28 family: a T-cell rheostat for therapeutic control of T-cell activation. , 2005, Blood.

[108]  S. Rosenberg,et al.  Development of Human Anti-Murine T-Cell Receptor Antibodies in Both Responding and Nonresponding Patients Enrolled in TCR Gene Therapy Trials , 2010, Clinical Cancer Research.

[109]  D. Largaespada,et al.  Mammalian mutagenesis using a highly mobile somatic Sleeping Beauty transposon system , 2005, Nature.

[110]  S. Rosenberg,et al.  Minimally Cultured Tumor-infiltrating Lymphocytes Display Optimal Characteristics for Adoptive Cell Therapy , 2008, Journal of immunotherapy.

[111]  C. June,et al.  4-1BB Is Superior to CD28 Costimulation for Generating CD8+ Cytotoxic Lymphocytes for Adoptive Immunotherapy1 , 2007, The Journal of Immunology.

[112]  S. Goff,et al.  Host restriction factors blocking retroviral replication. , 2008, Annual review of genetics.

[113]  S. Rosenberg,et al.  Efficient transfer of a tumor antigen-reactive TCR to human peripheral blood lymphocytes confers anti-tumor reactivity. , 1999, Journal of immunology.

[114]  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.

[115]  R. Strong,et al.  Increasing functional avidity of TCR-redirected T cells by removing defined N-glycosylation sites in the TCR constant domain , 2009, The Journal of experimental medicine.

[116]  D. Kranz,et al.  Engineering higher affinity T cell receptors using a T cell display system. , 2008, Journal of immunological methods.

[117]  V. Appay,et al.  CD8+ T cell efficacy in vaccination and disease , 2008, Nature Medicine.

[118]  S. Heimfeld,et al.  Pharmacologically regulated Fas-mediated death of adoptively transferred T cells in a nonhuman primate model. , 2004, Blood.

[119]  Mario Roederer,et al.  High avidity myeloid leukemia-associated antigen-specific CD8+ T cells preferentially reside in the bone marrow. , 2009, Blood.

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

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

[122]  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.

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

[124]  S. Rosenberg,et al.  Transfer Therapy Cancer Regression in Patients Receiving Cell Lymphocyte Clonotypes Correlates with Cutting Edge: Persistence of Transferred , 2022 .

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

[126]  S. Sleijfer,et al.  Gene-modified T cells for adoptive immunotherapy of renal cell cancer maintain transgene-specific immune functions in vivo , 2007, Cancer Immunology, Immunotherapy.

[127]  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.

[128]  M. Kalos.  Biomarkers in T cell therapy clinical trials , 2011, Journal of Translational Medicine.

[129]  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.

[130]  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.

[131]  S. Rosenberg,et al.  The Stoichiometric Production of IL-2 and IFN-γ mRNA Defines Memory T Cells That Can Self-Renew After Adoptive Transfer in Humans , 2012, Science Translational Medicine.

[132]  M. Kami,et al.  Sipuleucel-T immunotherapy for castration-resistant prostate cancer. , 2010 .

[133]  R. Phillips,et al.  Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor , 2008, Nature Medicine.

[134]  E. Pamer,et al.  CD8 T cell responses to infectious pathogens. , 2003, Annual review of immunology.

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

[136]  J. Wolchok,et al.  Optimization and validation of a robust human T-cell culture method for monitoring phenotypic and polyfunctional antigen-specific CD4 and CD8 T-cell responses. , 2009, Cytotherapy.

[137]  George Coukos,et al.  Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. , 2003, The New England journal of medicine.

[138]  M. Tretiakova,et al.  Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. , 2009, Cancer research.

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

[140]  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.

[141]  P. Burkett,et al.  Diverse functions of IL-2, IL-15, and IL-7 in lymphoid homeostasis. , 2006, Annual review of immunology.

[142]  M. Sadelain,et al.  Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

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

[144]  Egbert Oosterwijk,et al.  Immune responses to transgene and retroviral vector in patients treated with ex vivo-engineered T cells. , 2011, Blood.

[145]  S. Rosenberg,et al.  Effective tumor treatment targeting a melanoma/melanocyte-associated antigen triggers severe ocular autoimmunity , 2008, Proceedings of the National Academy of Sciences.

[146]  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.

[147]  E. Jaffee,et al.  Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. , 2001, Cancer research.

[148]  I. Chen,et al.  Lentiviral Vectors--the Promise of Gene Therapy Within Reach? , 1999, Science.

[149]  Mark M. Davis,et al.  Melanocyte Destruction after Antigen-Specific Immunotherapy of Melanoma , 2000, The Journal of experimental medicine.

[150]  Bastian R. Angermann,et al.  Yellow fever vaccine induces integrated multilineage and polyfunctional immune responses , 2008, The Journal of experimental medicine.

[151]  Daniel T. Fisher,et al.  Hurdles to Lymphocyte Trafficking in the Tumor Microenvironment: Implications for Effective Immunotherapy , 2006, Immunological investigations.

[152]  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.

[153]  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.

[154]  Qing He,et al.  Efficacy and Toxicity Management of 19-28z CAR T Cell Therapy in B Cell Acute Lymphoblastic Leukemia , 2014, Science Translational Medicine.

[155]  Ximing J. Yang,et al.  Adoptive transfer of tumor-reactive transforming growth factor-beta-insensitive CD8+ T cells: eradication of autologous mouse prostate cancer. , 2005, Cancer research.

[156]  G. Dotti,et al.  Redirecting T-cell specificity by introducing a tumor-specific chimeric antigen receptor. , 2010, Blood.

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

[158]  D. Scheinberg,et al.  Adoptive transfer of unselected or leukemia-reactive T-cells in the treatment of relapse following allogeneic hematopoietic cell transplantation. , 2010, Seminars in immunology.

[159]  S. Mackinnon,et al.  Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: separation of graft-versus-leukemia responses from graft-versus-host disease. , 1995, Blood.

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

[161]  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.

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

[163]  S. Mackinnon,et al.  Dose-escalated donor lymphocyte infusions following reduced intensity transplantation: toxicity, chimerism, and disease responses. , 2004, Blood.

[164]  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.

[165]  H. Heslop,et al.  Assessing the Safety of Cytotoxic T Lymphocytes Transduced With a Dominant Negative Transforming Growth Factor-β Receptor , 2006, Journal of immunotherapy.

[166]  M. Bendandi.  Idiotype vaccines for lymphoma: proof-of-principles and clinical trial failures , 2009, Nature Reviews Cancer.

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

[168]  F. Bushman.  Retroviral integration and human gene therapy. , 2007, The Journal of clinical investigation.

[169]  S. Rosenberg,et al.  Bcl-2 overexpression enhances tumor-specific T-cell survival. , 2005, Cancer research.

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

[171]  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.

[172]  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.

[173]  M. Kalos.  An integrative paradigm to impart quality to correlative science , 2010, Journal of Translational Medicine.

[174]  J. Waxman,et al.  CD3 limits the efficacy of TCR gene therapy in vivo. , 2011, Blood.

[175]  P. Darcy,et al.  Autoimmunity associated with immunotherapy of cancer. , 2011, Blood.

[176]  S. Rosenberg,et al.  In vitro growth of cytotoxic human lymphocytes. I. Growth of cells sensitized in vitro to alloantigens. , 1978, Journal of immunology.

[177]  Carl June,et al.  Chemokine receptor 5 knockout strategies , 2011, Current opinion in HIV and AIDS.

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

[179]  Michael J. Bevan,et al.  CD8+ T Cells: Foot Soldiers of the Immune System , 2011, Immunity.

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

[181]  P. Muranski,et al.  Tumor-specific Th17-polarized cells eradicate large established melanoma. , 2008, Blood.

[182]  D. Lindemann,et al.  Foamy Virus Biology and Its Application for Vector Development , 2011, Viruses.

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

[184]  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.

[185]  M. Kalos,et al.  Transfer of Specificity for Human Immunodeficiency Virus Type 1 into Primary Human T Lymphocytes by Introduction of T-Cell Receptor Genes , 2000, Journal of Virology.

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

[187]  Cameron S. Osborne,et al.  LMO2-Associated Clonal T Cell Proliferation in Two Patients after Gene Therapy for SCID-X1 , 2003, Science.

[188]  Michel Sadelain,et al.  Manufacturing Validation of Biologically Functional T Cells Targeted to CD19 Antigen for Autologous Adoptive Cell Therapy , 2009, Journal of immunotherapy.

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