Monoclonal T-Cell Receptors: New Reagents for Cancer Therapy

Adoptive transfer of antigen-specific T lymphocytes is an effective form of immunotherapy for persistent virus infections and cancer. A major limitation of adoptive therapy is the inability to isolate antigen-specific T lymphocytes reproducibly. The demonstration that cloned T-cell receptor (TCR) genes can be used to produce T lymphocyte populations of desired specificity offers new opportunities for antigen-specific T-cell therapy. TCR gene-modified lymphocytes display antigen-specific function in vitro, and were shown to protect against virus infection and tumor growth in animal models. A recent trial in humans demonstrated that TCR gene-modified T cells persisted in all and reduced melanoma burden in 2/15 patients. In future trials, it may be possible to use TCR gene transfer to equip helper and cytotoxic T cells with new antigen-specificity, allowing both T-cell subsets to cooperate in achieving improved clinical responses. Sequence modifications of TCR genes are being explored to enhance TCR surface expression, while minimizing the risk of pairing between introduced and endogenous TCR chains. Current T-cell transduction protocols that trigger T-cell differentiation need to be modified to generate “undifferentiated” T cells, which, upon adoptive transfer, display improved in vivo expansion and survival. Both, expression of only the introduced TCR chains and the production of naïve T cells may be possible in the future by TCR gene transfer into stem cells. Adoptive transfer of antigen-specific T lymphocytes is an effective form of immunotherapy for persistent virus infections and cancer. A major limitation of adoptive therapy is the inability to isolate antigen-specific T lymphocytes reproducibly. The demonstration that cloned T-cell receptor (TCR) genes can be used to produce T lymphocyte populations of desired specificity offers new opportunities for antigen-specific T-cell therapy. TCR gene-modified lymphocytes display antigen-specific function in vitro, and were shown to protect against virus infection and tumor growth in animal models. A recent trial in humans demonstrated that TCR gene-modified T cells persisted in all and reduced melanoma burden in 2/15 patients. In future trials, it may be possible to use TCR gene transfer to equip helper and cytotoxic T cells with new antigen-specificity, allowing both T-cell subsets to cooperate in achieving improved clinical responses. Sequence modifications of TCR genes are being explored to enhance TCR surface expression, while minimizing the risk of pairing between introduced and endogenous TCR chains. Current T-cell transduction protocols that trigger T-cell differentiation need to be modified to generate “undifferentiated” T cells, which, upon adoptive transfer, display improved in vivo expansion and survival. Both, expression of only the introduced TCR chains and the production of naïve T cells may be possible in the future by TCR gene transfer into stem cells. Adoptive T-cell transfer can cure leukemia patients following allogeneic stem cell transplantation.1Kolb HJ Mittermuller J Clemm C Holler E Ledderose G Brehm G et al.Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients.Blood. 1990; 76: 2462-2465Crossref PubMed Google Scholar The infused donor-derived T lymphocytes recognize allo-antigens expressed by leukemia cells, resulting in T cell–mediated leukemia killing.2Horowitz MM Gale RP Sondel PM Goldman JM Kersey J Kolb HJ et al.Graft-versus-leukemia reactions after bone marrow transplantation.Blood. 1990; 75: 555-562Crossref PubMed Google Scholar Unfortunately, T cell recognized allo-antigens are also expressed in normal tissues which can lead to graft-versus-host disease, a condition where allo-reactive donor T cells attack and damage normal tissues such as gut, skin and liver. Hence, the lack of specificity for defined tumor antigens limits the usefulness of adoptive T-cell therapy for the management of leukemia. The adoptive transfer of tumor antigen-specific T cells has been used successfully in melanoma patients.3Rosenberg SA Packard BS Aebersold PM Solomon D Topalian SL Toy ST et al.Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report.N Engl J Med. 1988; 319: 1676-1680Crossref PubMed Scopus (1856) Google Scholar Although anti-melanoma effects were initially unimpressive, two recent developments substantially improved the clinical benefit of adoptive T-cell therapy in melanoma.4Dudley ME Wunderlich JR Robbins PF Yang JC Hwu P Schwartzentruber DJ et al.Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes.Science. 2002; 298: 850-854Crossref PubMed Scopus (2386) Google Scholar First, co-transfer of CD4+ T-helper lymphocytes together with CD8+ cytotoxic T lymphocytes (CTL) was found to be more effective than previous protocols using only CD8+ CTL. Second, conditioning of patients is now used to create a lymphopenic environment that favors the engraftment and expansion of adoptively transferred T cells. While T-cell transfer into normal recipients typically resulted in poor T-cell survival and persistence, transfer into lymphopenic hosts leads to substantial expansion and long-term survival of injected T cells. The combination of conditioning and transfer of CD4+ and CD8+ T cells resulted in disease control in approximately 50% of melanoma patients, an impressive clinical response rate that probably cannot be achieved with alternative therapy options.5Rosenberg SA Dudley ME Cancer regression in patients with metastatic melanoma after the transfer of autologous antitumor lymphocytes.Proc Natl Acad Sci USA. 2004; 101 (suppl 2): 14639-14645Crossref PubMed Scopus (315) Google Scholar Adoptive T-cell therapy is also effective in the management of latent infection by Epstein-Barr virus and cytomegalie virus in immuno-suppressed individuals.6Rooney CM Smith CA Ng CY Loftin S Li C Krance RA et al.Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr-virus-related lymphoproliferation.Lancet. 1995; 345: 9-13Abstract PubMed Scopus (990) Google Scholar,7Walter EA Greenberg PD Gilbert MJ Finch RJ Watanabe KS Thomas ED et al.Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor.N Engl J Med. 1995; 333: 1038-1044Crossref PubMed Scopus (1589) Google Scholar,8Rooney CM Smith CA Ng CY Loftin SK Sixbey JW Gan Y et al.Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients.Blood. 1998; 92: 1549-1555Crossref PubMed Google Scholar,9Haque T Taylor C Wilkie GM Murad P Amlot PL Beath S et al.Complete regression of posttransplant lymphoproliferative disease using partially HLA-matched Epstein Barr virus-specific cytotoxic T cells.Transplantation. 2001; 72: 1399-1402Crossref PubMed Scopus (79) Google Scholar,10Einsele H Roosnek E Rufer N Sinzger C Riegler S Loffler J et al.Infusion of cytomegalovirus (CMV)-specific T cells for the treatment of CMV infection not responding to antiviral chemotherapy.Blood. 2002; 99: 3916-3922Crossref PubMed Scopus (603) Google Scholar,11Peggs KS Verfuerth S Pizzey A Khan N Guiver M Moss PA et al.Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines.Lancet. 2003; 362: 1375-1377Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar,12Bollard CM Aguilar L Straathof KC Gahn B Huls MH Rousseau A et al.Cytotoxic T lymphocyte therapy for Epstein-Barr virus+ Hodgkin's disease.J Exp Med. 2004; 200: 1623-1633Crossref PubMed Scopus (334) Google Scholar,13Cobbold M Khan N Pourgheysari B Tauro S McDonald D Osman H et al.Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA-peptide tetramers.J Exp Med. 2005; 202: 379-386Crossref PubMed Scopus (428) Google Scholar In immuno-competent individuals, latent Epstein-Barr virus and cytomegalie virus infection is well tolerated as antigen-specific T cells efficiently control virus load. In contrast, the break down of T-cell surveillance, often seen after allogeneic stem cell or solid organ transplantation, is associated with a high risk of virus reactivation and the of clinical such as Epstein-Barr lymphoproliferative and cytomegalie virus In the transfer of of virus-specific donor T lymphocytes can disease and long-term The inability to generate antigen-specific T cells is a limitation of adoptive T-cell therapy of cancer. antigens are often and patients are as a of tumor burden or as a of treatment and In a adoptive T-cell therapy of Epstein-Barr virus and cytomegalie virus is typically the of virus-specific T cells from by transfer to patients. is to isolate virus-specific T cells from naïve individuals, as the is and the in of T-cell is T-cell receptor (TCR) gene transfer offers a to produce antigen-specific T cells of and the need for T-cell transfer of has been used as a to produce T cells with defined clinical PubMed Scopus Google Scholar the were to the of or to trigger T-cell T G and of cytotoxic lymphocytes chains of and the or of the and T-cell Natl Acad Sci USA. 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