Optimizing adoptive polyclonal T cell immunotherapy of lymphomas, using a chimeric T cell receptor possessing CD28 and CD137 costimulatory domains.

We previously demonstrated the feasibility of generating therapeutic numbers of cytotoxic T lymphocyte (CTL) clones expressing a CD20-specific scFvFc:CD3zeta chimeric T cell receptor (cTCR), making them specifically cytotoxic for CD20+ B lymphoma cells. However, the process of generating and expanding he CTL clones was laborious, the CTL clones expressed the cTCR at low surface density, and they exhibited suboptimal proliferation and cytotoxicity. To improve the performance of the CTLs in vitro and in vivo, we engineered "second-generation'' plasmid constructs containing a translational enhancer (SP163) and CD28 and CD137 costimulatory domains in cis with the CD3zeta intracellular signaling domain of the cTCR gene. Furthermore, we verified the superiority of generating genetically modified polyclonal T cells expressing the second-generation cTCR rather than T cell clones. Our results demonstrate that SP163 enhances the surface expression of the cTCR; that the second-generation cTCR improves CTL activation, proliferation, and cytotoxicity; and that polyclonal T cells proliferate rapidly in vitro and mediate potent CD20-specific cytotoxicity. This study provides the preclinical basis for a clinical trial of adoptive T cell immunotherapy for patients with relapsed CD20+ mantle cell lymphoma and indolent lymphomas.

[1]  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.

[2]  K. Margolin.  Cytokine therapy in cancer , 2008, Expert opinion on biological therapy.

[3]  L. Cooper,et al.  Adoptive cellular immunotherapy for childhood malignancies , 2008, Bone Marrow Transplantation.

[4]  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.

[5]  David D. Smith,et al.  CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. , 2006, Cancer research.

[6]  T. Waldmann.  The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design , 2006, Nature Reviews Immunology.

[7]  S. Riddell,et al.  53. Preliminary Results of a Pilot Phase I Clinical Trial of Adoptive Immunotherapy for B Cell Lymphoma Using CD8+ T Cells Genetically Modified To Express a Chimeric T Cell Receptor Recognizing CD20 , 2006 .

[8]  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.

[9]  Michel Sadelain,et al.  Targeted elimination of prostate cancer by genetically directed human T lymphocytes. , 2005, Cancer research.

[10]  D. Friedmann-Morvinski,et al.  Redirected primary T cells harboring a chimeric receptor require costimulation for their antigen-specific activation. , 2005, Blood.

[11]  H. Heslop,et al.  Current status of genetic modification of T cells for cancer treatment. , 2005, Cytotherapy.

[12]  M. Kalos,et al.  T-cell genetic modification for re-directed tumor recognition. , 2005, Cancer chemotherapy and biological response modifiers.

[13]  M. Brenner,et al.  Genetic modification of T lymphocytes for adoptive immunotherapy. , 2004, Molecular therapy : the journal of the American Society of Gene Therapy.

[14]  M. Sadelain,et al.  Novel strategies for cancer therapy: the potential of genetically modified T lymphocytes. , 2004, Current hematology reports.

[15]  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.

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

[17]  G. Mufti,et al.  Role of 4-1BB:4-1BB ligand in cancer immunotherapy , 2004, Cancer Gene Therapy.

[18]  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.

[19]  P. Nguyen,et al.  Identification of a murine CD28 dileucine motif that suppresses single-chain chimeric T-cell receptor expression and function. , 2003, Blood.

[20]  W. Lindenmaier,et al.  Provision of 4-1BB Ligand Enhances Effector and Memory CTL Responses Generated by Immunization with Dendritic Cells Expressing a Human Tumor-Associated Antigen1 , 2003, The Journal of Immunology.

[21]  S. Larson,et al.  Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15 , 2003, Nature Medicine.

[22]  A. Wu,et al.  Engineered CD20-specific primary human cytotoxic T lymphocytes for targeting B-cell malignancy. , 2003, Cytotherapy.

[23]  Michel Sadelain,et al.  Targeting tumours with genetically enhanced T lymphocytes , 2003, Nature Reviews Cancer.

[24]  Richard A. Flavell,et al.  Targeting autoantigen-specific T cells and suppression of autoimmune encephalomyelitis with receptor-modified T lymphocytes , 2002, Nature Biotechnology.

[25]  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.

[26]  Sujung Park,et al.  4-1BB Promotes the Survival of CD8+ T Lymphocytes by Increasing Expression of Bcl-xL and Bfl-11 , 2002, The Journal of Immunology.

[27]  M. Jensen.  Targeting malignant B cells of lymphoma and leukemia with genetically engineered T-cell clones. , 2002, Cytotherapy.

[28]  C. Macken,et al.  A phase II randomized study of HIV-specific T-cell gene therapy in subjects with undetectable plasma viremia on combination antiretroviral therapy. , 2002, Molecular therapy : the journal of the American Society of Gene Therapy.

[29]  R. Kennedy,et al.  Direct costimulation of tumor-reactive CTL by helper T cells potentiate their proliferation, survival, and effector function. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[30]  Mary Collins,et al.  The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses. , 2002, Annual review of immunology.

[31]  Michel Sadelain,et al.  Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ /CD28 receptor , 2002, Nature Biotechnology.

[32]  T. Waldmann,et al.  Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy. , 2001, Immunity.

[33]  J. Metcalf,et al.  Long-term in vivo survival of receptor-modified syngeneic T cells in patients with human immunodeficiency virus infection. , 2000, Blood.

[34]  M. Gavin,et al.  Immunotherapy of human viral and malignant diseases with genetically modified T-cell clones. , 2000, Cancer journal.

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

[36]  M. Weijtens,et al.  Functional balance between T cell chimeric receptor density and tumor associated antigen density: CTL mediated cytolysis and lymphokine production , 2000, Gene Therapy.

[37]  M. Debenedette,et al.  T cell co-stimulatory molecules other than CD28. , 1999, Current opinion in immunology.

[38]  J. Allison,et al.  Costimulatory regulation of T cell function. , 1999, Current opinion in cell biology.

[39]  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.

[40]  P. Einat,et al.  Translation of Vascular Endothelial Growth Factor mRNA by Internal Ribosome Entry: Implications for Translation under Hypoxia , 1998, Molecular and Cellular Biology.

[41]  L. Zheng,et al.  T cell growth cytokines cause the superinduction of molecules mediating antigen-induced T lymphocyte death. , 1998, Journal of immunology.

[42]  A. Aruffo,et al.  4-1BB Costimulatory Signals Preferentially Induce CD8+ T Cell Proliferation and Lead to the Amplification In Vivo of Cytotoxic T Cell Responses , 1997, The Journal of experimental medicine.

[43]  C. Thompson,et al.  CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-XL. , 1995, Immunity.

[44]  Z. Eshhar,et al.  Endowing T cells with antibody specificity using chimeric T cell receptors , 1992, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.