The Clone Ranger?
Authors: Helen E Heslop, Malcolm K Brenner
Journal: Molecular Therapy (2008)

A recent article describing a T-lymphocyte cell clone that eliminated melanoma in a patient with advanced metastatic disease1Hunder NN Wallen H Cao J Hendricks DW Reilly JZ Rodmyre R et al.Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1.N Engl J Med. 2008; 358: 2698-2703Crossref PubMed Scopus (713) Google Scholar excited an exceptionally high level of publicity worldwide. An accompanying Perspective in the New England Journal of Medicine breathlessly concluded that for cell therapy of cancer, “the endgame has begun.”2Weiner LM Cancer immunotherapy—the endgame begins.N Engl J Med. 2008; 358: 2664-2665Crossref PubMed Scopus (33) Google Scholar Such broad enthusiasm for an article on a T-cell clone seems largely based on a hoped-for analogy to the development of monoclonal antibodies, which clearly opened a new era in immunotherapy. This may be an unwise comparison. Eradication of melanoma using a single T-lymphocyte clone is indeed of considerable interest and value, but as Cassian Yee (the report's senior author) himself points out, we need to be careful about assuming broader benefits for the approach.3Fred Hutchinson Cancer Research Center Patient's own infection-fighting T cells put late-stage melanoma into long-term remission—without chemotherapy or radiation http://www.fhcrc.org/about/ne/news/2008/06/18/T_cells.html18 June 2008Google Scholar In practical terms, cloned T cells of the desired specificities and phenotype are hard to consistently manufacture in large numbers, whereas biologically, the T-cell component of the immune system is designed to operate as a phenotypically and functionally diverse cellular network, and an individual clone may only rarely possess all the necessary characteristics for safe and effective activity. Notably, the single success reported was unique among the nine patients who received tumor-specific clones in the study. But even if we ignore the more hyperbolic assessments, the report of Hunder et al.1Hunder NN Wallen H Cao J Hendricks DW Reilly JZ Rodmyre R et al.Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1.N Engl J Med. 2008; 358: 2698-2703Crossref PubMed Scopus (713) Google Scholar nonetheless contains several critical insights that help to resolve important controversies in cancer immunotherapy. Their report also suggests ways in which gene transfer will undoubtedly be able to further advance this approach. One of the first points of interest is the use of a tumor antigen (NY-ESO)–specific clone derived from the CD4 T-cell subset. Until recently, CD8 T cells were assumed to have the greatest antitumor activity because they were the most obviously cytotoxic. As a consequence, most adoptive immunotherapy approaches tested in the clinic focused on transferring CD8 cytotoxic effector T cells.4Yee C Thompson JA Byrd D Riddell SR Roche P Celis E 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.Proc Natl Acad Sci USA. 2002; 99: 16168-16173Crossref PubMed Scopus (1006) Google Scholar Studies in murine models, however, have increasingly demonstrated the importance of the CD4 subset, showing that they play a crucial role in providing a “helper” function to more immediately cytotoxic effector cells, and ensuring long term persistence.5Pulendran B Ahmed R Translating innate immunity into immunological memory: implications for vaccine development.Cell. 2006; 124: 849-863Abstract Full Text Full Text PDF PubMed Scopus (494) Google Scholar Studies administering polyclonal Epstein-Barr virus (EBV)–specific cytotoxic T lymphocytes to treat EBV-associated malignancies have suggested that the same phenomena occur in humans,6Rooney 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: 1549-1555PubMed Google Scholar,7Bollard CM Gottschalk S Leen AM Weiss H Straathof KC Carrum G et al.Complete responses of relapsed lymphoma following genetic modification of tumor-antigen presenting cells and T-lymphocyte transfer.Blood. 2007; 110: 2838-2845Crossref PubMed Scopus (247) Google Scholar,8Straathof KC Bollard CM Popat U Huls MH Lopez T Morriss MC et al.Treatment of nasopharyngeal carcinoma with Epstein-Barr virus-specific T lymphocytes.Blood. 2005; 105: 1898-1904Crossref PubMed Scopus (303) Google Scholar and the effectiveness of the CD4+ cell clone in the current report helps to make the point unequivocally. Equally interesting is that the complete and sustained tumor response was observed even though the NY-ESO antigen was expressed by only 50% to 75% of tumor cells. Several model systems have shown the phenomenon of “epitope spreading,” in which an initial narrow immune response directed to a single epitope or antigen is subsequently followed by a broader immune response directed to a multiplicity of other antigens. It is hypothesized that immune destruction of the cell is followed by uptake and presentation of additional cellular antigens and the formation of a secondary immune response to these antigens in an immunological ripple effect. Alternatively, initial CD4+ cells of one specificity may provide nonspecific helper activities to expand T-effector cells directed to other antigens. Results from Hunder et al. unequivocally show this type of expansion of the immune response, in that the initial and clonal NY-ESO-specific immune response was followed by increased immune activity directed to at least two other antigens expressed on the patient's tumor cells: MAGE-3 and MART-1.1Hunder NN Wallen H Cao J Hendricks DW Reilly JZ Rodmyre R et al.Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1.N Engl J Med. 2008; 358: 2698-2703Crossref PubMed Scopus (713) Google Scholar Hence, infusion of CD4+ T lymphocytes may lead both directly and indirectly to activity against the targeted tumor cells, ensuring broad recognition even when antigen expression is heterogeneous. This characteristic allowed Hunder et al. to overcome the problem observed in earlier preclinical and clinical studies of cloned T cells for cancer therapy, whereby infusion of a product with specificity for a single-peptide epitope was followed by tumor evasion of the adoptively transferred immune response by a mutation affecting the antigen or epitope.9Gottschalk S Ng CY Perez M Smith CA Sample C Brenner MK et al.An Epstein-Barr virus deletion mutant that causes fatal lymphoproliferative disease unresponsive to virus-specific T cell therapy.Blood. 2001; 97: 835-843Crossref PubMed Scopus (221) Google Scholar Finally, it is noteworthy that the prolonged culture necessary for large-scale cloning did not, as previously, generate a product containing only differentiated effector cells and lacking the memory subset needed for long-term persistence. The clone used by Hunder et al. could be tracked for longer than 80 days—by detection of the unique T-cell receptor (TCR)—and it will be of interest to discover the characteristics that are associated with prolongation of clone survival, because a separate clinical study that began by infusing T-cell clones to treat malignancy subsequently switched to bulk cultures so as to increase persistence.10Till BG Jensen MC Wang J Chen EY Wood BL Greisman HA et al.Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells.Blood. 2008; (e-pub ahead of print 28 May 2008)PubMed Google Scholar Despite the undoubted scientific interest of the group's results, broader applicability of T-cell clones to cancer therapy will be dependent on the demonstration that they are more effective or safer than bulk populations of cells, and that they can be used for malignancies other than melanoma. Because the patient reported was the only one of nine treated to show such a response, it will be important to learn to predict which melanomas will be susceptible and to which CD4 clones, and to discover whether response rates to clones really will be higher than those already observed in melanoma using other T-cell products such as tumor-infiltrating lymphocytes.11Dudley 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 (2403) Google Scholar Thus far, only melanoma and EBV-associated malignancies have consistently shown susceptibility to T cell–based adoptive immunotherapy, and it will be a challenge over the next decade to escape from this therapeutic ghetto and thereby justify dedicating the necessary resources to the approach. Genetic manipulation of T cells is a means by which the range of T-cell immunotherapy could be increased and its effectiveness strengthened. For example, it is possible to isolate T-cell antigen receptors from clones that have mediated beneficial effects in vivo12Morgan RA Dudley ME Wunderlich JR Hughes MS Yang JC Sherry RM et al.Cancer regression in patients after transfer of genetically engineered lymphocytes.Science. 2006; 314: 126-129Crossref PubMed Scopus (2126) Google Scholar or to transfer chimeric antigen receptors that recognize (unprocessed) surface antigens on tumor cells. Transfer of TCRs specific for the melanoma antigen MART to autologous lymphocytes has produced successful clinical results12Morgan RA Dudley ME Wunderlich JR Hughes MS Yang JC Sherry RM et al.Cancer regression in patients after transfer of genetically engineered lymphocytes.Science. 2006; 314: 126-129Crossref PubMed Scopus (2126) Google Scholar but is challenged by the problem of cross-pairing of the transgenic and endogenous TCRs. Similarly, chimeric antigen receptor transfer has been tested clinically but has so far proved to be of limited benefit because of the brief persistence of transferred T cells. It may be possible to reduce cross-pairing and prolong persistence by introducing transgenic receptors into cells of guaranteed effector function. This strategy is being explored in the clinic using EBV-specific cytotoxic T lymphocytes as the target cell13Rossig C Bollard CM Nuchtern JG Rooney CM Brenner MK Epstein-Barr virus–specific human T lymphocytes expressing antitumor chimeric T-cell receptors: potential for improved immunotherapy.Blood. 2002; 99: 2009-2016Crossref PubMed Scopus (180) Google Scholar and could also be extended to the CD4-specific T-cell clones described by Hunder et al. Introduction of genetic countermeasures to the many identified tumor immune evasion strategies may also help increase the effectiveness of T-cell clones and lines.14Rabinovich GA Gabrilovich D Sotomayor EM Immunosuppressive strategies that are mediated by tumor cells.Annu Rev Immunol. 2007; 25: 267-296Crossref PubMed Scopus (1298) Google Scholar So is it true that the endgame has begun2Weiner LM Cancer immunotherapy—the endgame begins.N Engl J Med. 2008; 358: 2664-2665Crossref PubMed Scopus (33) Google Scholar and that we can anticipate seeing “clone rangers” widely used to vanquish tumors before riding off into their apoptotic sunset? We prefer to conclude that the battle for successful cancer immunotherapy is not at the end—or even at the beginning of the end—but that it is, perhaps, at the end of the beginning.15Churchill WS Speech delivered at Lord Mayor's Luncheon, Mansion House following the victory at El Alamein, North Africa, London, 10 November. 1942; Google Scholar