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• W2023555552 abstract "ImmunotherapyVol. 3, No. 2 EditorialFree AccessIn vitro or in vivo expansion before adoptive T-cell therapy?Michael Uhlin & Jonas MattssonMichael UhlinDivision of Clinical Immunology, Karolinska Institutet, SE-141 86 Stockholm, SwedenSearch for more papers by this author & Jonas Mattsson† Author for correspondenceCenter for Allogeneic Stem Cell Transplantation, B87, Karolinska University Hospital Huddinge, SE-141 52 Stockholm, Sweden. Search for more papers by this authorEmail the corresponding author at jonas.mattsson@ki.sePublished Online:15 Feb 2011https://doi.org/10.2217/imt.10.106AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: allogeneic stem cell transplantationCTL therapyEBVimmune therapypentamerOver the past decade, there has been a considerable evolution in the field of immune therapy, including the use of specific T cells as a treatment modality for various infectious agents and cancers. As early as two decades ago, Riddell et al. successfully documented the first use of donor-derived T cells to treat life-threatening cytomegalovirus (CMV) disease following allogeneic stem cell transplantation (ASCT) [1]. This approach was also quickly adopted to treat Epstein–Barr virus (EBV)-associated post-transplantation lymphoproliferative disease (PTLD) [2]. It was common practice in those days to use a laborious protocol for the expansion of T cells over several weeks, including restimulations with either EBV-immortalized cell lines or donor-derived cells pulsed with the relevant antigens [3,4]. This approach, with modifications, is still used successfully today by several groups to counteract both cancer and virus diseases [5,6].However, there are drawbacks associated with this methodology. If the disease progression is rapid, it will often be too late for successful administration of cells. In addition, after implementation of more rigorous good manufacturing practice (GMP) regulations (adopted also for hospital routines), the cost has increased to prohibitive levels. Therefore, integration of these cell therapies into common hospital routines as prophylaxis or off-the-shelf treatment would be close to impossible, or at least only available to very well-founded university hospitals or patients with private means. Some attempts have also been made to create specific cell banks in order to overcome the time consumption associated with the methodology [7,8]. The expansion has yet to be carried out in a GMP environment for a prolonged period. In addition, the cytotoxic T-lymphocyte products may not be fully HLA compatible, thus increasing the risk of complications such as graft-versus-host disease where, instead of attacking the virus target specifically, the adopted T cells attack other tissues of the recipient.Fortunately, with the new techniques and tools of today and a broader knowledge of T-cell epitopes, faster and more cost–effective approaches have emerged. The invention of combining several recombinant HLA/peptide molecules with streptavidin and a fluorochrome created a revolutionary tool to both study and separate specific T cells of interest [9]. Cobbold et al. successfully used this labeling technique, combined with magnetic separation, to infuse CMV-specific T cells from the donor following transplantation [10]. In this case, the numbers of cells infused are obviously much smaller and trust must be put in the capacity of an in vivo antigen-driven expansion. This separation has also been modified by our group for EBV in a haploidentical setting, to rapidly treat life-threatening PTLD [11]. The EBV-specific T cells from the patient’s mother apparently expanded in vivo and were detected over a prolonged period of time following infusion. The clinical effect was dramatic, despite widespread tumors, and the patient is presently alive, 3 years after treatment. In the last few years, the clinically adapted IFN-γ capture assay (Miltenyi Biotec, Germany) has been tested in several Phase I and II studies with promising results [12]. This approach requires a 6-h step for activation of the blood product with relevant antigens before separation of specific T cells based on the production of IFN.So what is preferable – a time-consuming in vitro expansion creating a massive amount of cells, or direct separation and infusion of only a few cells?There are certainly advantages and disadvantages to both options. The in vitro expansion, which is dependent on antigen source, generally gives a wider range of T-cell specificities and cell numbers often over 107/kg. Therefore, it may be more efficacious clinically. In addition, it may be the only alternative when dealing with naive donors, cord blood or tumor antigens [13]. However, as mentioned previously, the main disadvantages are the duration and high costs associated with it. Since the method is time consuming, expansion must be started prior to transplantation in all patients at risk. However, only a minor proportion of the patients will actually need viral immunotherapy following ASCT. Thus, in the majority of patients, the expansion and the costs would have been unnecessary. In addition, it must be taken into account that the expansion per se might give either skewing, increased differentiation, or susceptibility to apoptosis [14].Use of direct ex vivo separation and in vivo expansion usually includes the problem of low cell doses: less than 1 × 105/kg. In healthy individuals, this should not pose a serious problem since the in vivo ‘culture conditions’ should be more optimized than the artificial products available on the market. However, if the individual is seriously immunosuppressed after ASCT, the potential expansion capacity becomes doubtful. When using recombinant HLA molecules, coupled to magnetic separation, the repertoire of the T-cell specificity infused is limited to one of a few peptide epitopes at most [10]. This might be troublesome if the virus, pathogen or cancer is prone to mutate [15], but when dealing with herpesviruses or adenoviruses, the issues might be of less importance. This problem can be totally circumvented by using the IFN-γ capture assay, with peptide mixtures or extracts from pathogens as antigens, for example [16].So what is to be preferred? These approaches are not mutually exclusive, but perhaps some strategies could be proposed. When the possibility exists to use a separation technique followed by an in vivo expansion, this should be preferred. Possible scenarios are viral or fungal infections after ASCT when a putative donor or haploidentical relative is available. This could then be done either by sorting with HLA molecules (if possible HLA/peptide combinations exist) or by the IFN-γ capture assay. If no putative donors exist or if the response is naive, an in vitro expansion technique should be attempted.Whichever method is used, the importance of specific immunotherapy against viral antigens and cancer after ASCT will continue to increase.Financial & competing interests disclosureThis work was supported by the Swedish Children’s Cancer Foundation, ALF Gothenburg, The Stockholm County Council and the Swedish Society for Medical Research. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Bibliography1 Riddell SR, Watanabe KS, Goodrich JM, Li CR, Agha ME, Greenberg PD: Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T-cell clones. Science257(5067),238–241 (1992).Crossref, Medline, CAS, Google Scholar2 Rooney CM, Smith CA, Ng CY et al.: Use of gene-modified virus-specific T lymphocytes to control Epstein–Barr-virus-related lymphoproliferation. Lancet345(8941),9–13 (1995).Crossref, Medline, CAS, Google Scholar3 Walter EA, Greenberg PD, Gilbert MJ 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.333(16),1038–1044 (1995).Crossref, Medline, CAS, Google Scholar4 Heslop HE, Ng CY, Li C et al.: Long-term restoration of immunity against Epstein–Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes. Nat. Med.2(5),551–555 (1996).Crossref, Medline, CAS, Google Scholar5 Dudley ME, Wunderlich JR, Shelton TE, Even J, Rosenberg SA: Generation of tumor-infiltrating lymphocyte cultures for use in adoptive transfer therapy for melanoma patients. J. Immunother.26(4),332–342 (2003).Crossref, Medline, Google Scholar6 Karlsson H, Brewin J, Kinnon C, Veys P, Amrolia PJ: Generation of trispecific cytotoxic T cells recognizing cytomegalovirus, adenovirus, and Epstein–Barr virus: an approach for adoptive immunotherapy of multiple pathogens. J. Immunother.30(5),544–556 (2007).Crossref, Medline, Google Scholar7 Wilkie GM, Taylor C, Jones MM et al.: Establishment and characterization of a bank of cytotoxic T lymphocytes for immunotherapy of Epstein–Barr virus-associated diseases. J. Immunother.27(4),309–316 (2004).Crossref, Medline, Google Scholar8 Haque T, Wilkie GM, Jones MM et al.: Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a Phase II multicenter clinical trial. Blood110(4),1123–1131(2007).Crossref, Medline, CAS, Google Scholar9 Altman JD, Moss PA, Goulder PJ et al.: Phenotypic analysis of antigen-specific T lymphocytes. Science274(5284),94–96 (1996).Crossref, Medline, CAS, Google Scholar10 Cobbold M, Khan N, Pourgheysari B et al.: Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA-peptide tetramers. J. Exp. Med.202(3),379–386 (2005).Crossref, Medline, CAS, Google Scholar11 Uhlin M, Okas M, Gertow J, Uzunel M, Brismar TB, Mattsson J: A novel haplo-identical adoptive CTL therapy as a treatment for EBV-associated lymphoma after stem cell transplantation. Cancer Immunol. Immunother.59(3),473–477 (2010).Crossref, Medline, Google Scholar12 Feuchtinger T, Opherk K, Bethge WA et al.: Adoptive transfer of pp-65 specific T-cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell transplantation. Blood116(20),4360–4367 (2010).Crossref, Medline, CAS, Google Scholar13 Hanley PJ, Cruz CR, Savoldo B et al.: Functionally active virus-specific T cells that target CMV, adenovirus, and EBV can be expanded from naive T-cell populations in cord blood and will target a range of viral epitopes. Blood114(9),1958–1967 (2009).Crossref, Medline, CAS, Google Scholar14 Okas M, Gertow J, Uzunel M et al.: Clinical expansion of cord blood-derived T cells for use as donor lymphocyte infusion after cord blood transplantation. J. Immunother.33(1),96–105 (2009).Crossref, Google Scholar15 Koenig S, Conley AJ, Brewah YA et al.: Transfer of HIV-1-specific cytotoxic T lymphocytes to an AIDS patient leads to selection for mutant HIV variants and subsequent disease progression. Nat. Med.1(4),330–336 (1995).Crossref, Medline, CAS, Google Scholar16 Moosmann A, Bigalke I, Tischer J et al.: Effective and long-term control of EBV PTLD after transfer of peptide-selected T cells. Blood115(14),2960–2970 (2010).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetails Vol. 3, No. 2 STAY CONNECTED Metrics History Published online 15 February 2011 Published in print February 2011 Information© Future Medicine LtdKeywordsallogeneic stem cell transplantationCTL therapyEBVimmune therapypentamerFinancial & competing interests disclosureThis work was supported by the Swedish Children’s Cancer Foundation, ALF Gothenburg, The Stockholm County Council and the Swedish Society for Medical Research. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download" @default.
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