commentary
© The American Society of Gene Therapy
The Clone Ranger? Helen E Heslop1 and Malcolm K Brenner1 doi:10.1038/mt.2008.154
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recent article describing a T-lymphocyte cell clone that eliminated melanoma in a patient with advanced metastatic disease1 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.”2 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.3 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.1 nonetheless contains several critical insights that help to resolve important controversies in cancer immunotherapy. Their report also suggests ways in which 1 Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children’s Hospital, Houston, Texas, USA Correspondence: Malcolm K. Brenner, Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children’s Hospital, 6621 Fannin Street, Houston, Texas 77030, USA. E-mail:
[email protected]
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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.4 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.5 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,6–8 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-1.1 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.9 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.10 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 tumorinfiltrating lymphocytes.11 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. www.moleculartherapy.org vol. 16 no. 9 sep. 2008
© The American Society of Gene Therapy
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 vivo12 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 results12 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 cell13 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.14 So is it true that the endgame has begun2 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.15 References
1. Hunder, NN, Wallen, H, Cao, J, Hendricks, DW, Reilly, JZ, Rodmyre, R et al. (2008). Treatment of metastatic melanoma with autologous CD4+ T cells against NYESO-1. N Engl J Med 358: 2698–2703. 2. Weiner, LM (2008). Cancer immunotherapy—the endgame begins. N Engl J Med 358: 2664–2665. 3. Fred Hutchinson Cancer Research Center. Patient’s own infection-fighting T cells put late-stage melanoma into long-term remission—without chemotherapy or radiation (18 June 2008). 4. Yee, C, Thompson, JA, Byrd, D, Riddell, SR, Roche, P, Celis, E et al. (2002). 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 99: 16168–16173. 5. Pulendran, B and Ahmed, R (2006). Translating innate immunity into immunological memory: implications for vaccine development. Cell 124: 849–863. 6. Rooney, CM, Smith, CA, Ng, CY, Loftin, SK, Sixbey, JW, Gan, Y et al. (1998). Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus–induced lymphoma in allogeneic transplant
Molecular Therapy vol. 16 no. 9 sep. 2008
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recipients. Blood 92: 1549–1555. 7. Bollard, CM, Gottschalk, S, Leen, AM, Weiss, H, Straathof, KC, Carrum, G et al. (2007). Complete responses of relapsed lymphoma following genetic modification of tumor-antigen presenting cells and T-lymphocyte transfer. Blood 110: 2838–2845. 8. Straathof, KC, Bollard, CM, Popat, U, Huls, MH, Lopez, T, Morriss, MC et al. (2005). Treatment of nasopharyngeal carcinoma with Epstein-Barr virus-specific T lymphocytes. Blood 105: 1898–1904. 9. Gottschalk, S, Ng, CY, Perez, M, Smith, CA, Sample, C, Brenner, MK et al. (2001). An Epstein-Barr virus deletion mutant that causes fatal lymphoproliferative disease unresponsive to virus-specific T cell therapy. Blood 97: 835–843. 10. Till, BG, Jensen, MC, Wang, J, Chen, EY, Wood, BL, Greisman, HA et al. (2008). Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood, e-pub ahead of print 28 May 2008.
11. Dudley, ME, Wunderlich, JR, Robbins, PF, Yang, JC, Hwu, P, Schwartzentruber, DJ et al. (2002). Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298: 850–854. 12. Morgan, RA, Dudley, ME, Wunderlich, JR, Hughes, MS, Yang, JC, Sherry, RM et al. (2006). Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314: 126–129. 13. Rossig, C, Bollard, CM, Nuchtern, JG, Rooney, CM and Brenner MK (2002). Epstein-Barr virus–specific human T lymphocytes expressing antitumor chimeric T-cell receptors: potential for improved immunotherapy. Blood 99: 2009–2016. 14. Rabinovich, GA, Gabrilovich, D, Sotomayor, EM. (2007). Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol 25: 267–296. 15. Churchill, WS. Speech delivered at Lord Mayor’s Luncheon, Mansion House following the victory at El Alamein, North Africa, London, 10 November 1942.
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Fighting Fire With Fire: Effects of Oncolytic Virotherapy on Underlying Viral Hepatitis in Hepatocellular Carcinoma Tony Reid1 doi:10.1038/mt.2008.176
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epatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of cancer-related death.1 It arises in the context of cirrhosis, due most commonly to chronic alcohol exposure or chronic infection with either hepatitis B or hepatitis C virus.2 With the exception of a minority of patients who can undergo liver transplant, HCC is generally fatal within a short period of time.3,4 A critical factor for the high mortality is the underlying liver cirrhosis. This comorbidity not only limits treatment options owing to poor residual hepatic function but is often the cause of death among these patients. Thus, without an effective treatment for viral hepatitis, the long-term value of effective therapy for HCC will be limited. In this issue of Molecular Therapy, Liu et al.5 present provocative clinical find1 University of California, San Diego, La Jolla, California, USA Correspondence: Tony Reid, Department of Hematology/Oncology, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, California 92093, USA. E-mail:
[email protected]
ings arising out of the use of a molecularly targeted oncolytic vaccinia virus (JX-594) for the treatment of patients with advancedstage HCC. The article describes the evaluation of JX-594 in three patients with hepatitis B–related HCC. These three patients are a subset of 14 patients with advanced cancer treated in a phase I study with JX-594. The analysis of the three patients highlights several critical issues confronting the development of novel therapeutic agents as well as the complexity associated with treatment of HCC. Most importantly, the article describes the suppression of hepatitis B viral genomes associated with concurrent treatment with vaccinia virus. It further shows replication of JX-594 in the presence of high-titer neutralizing antibody to vaccinia and extensive tumor necrosis following treatment with an oncolytic virus. The incidence of HCC is highest in Asia and sub-Saharan Africa but has been rising rapidly in the United States and Europe.1,3 Hepatitis B infection, as discussed by Liu et al.,5 is the main risk factor in Asia and Africa, whereas hepatitis C infection 1521
