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Adoptive T-cell therapy for CMV
Cytotherapy (2002) Vol. 4, No. 1, 1
Martin Dunitz
Taylor&Francis healthsciences
Editorial
Adoptive T-cell therapy for CMV John Barrett Co-Editor
Over millions of years of evolution, human CMV has reached a comfortable accommodation with its host. Its acquisition early in life, at the cost of a brief upper respiratory infection, ensures the virus the opportunity of a safe haven in the BM for the life-span of the individual, with opportunities for salivary export and infection of new hosts, based upon the reliable behavior of humans, young or old, to get friendly. This apparently harmonious situation is not, however, all it seems. The virus first gains its foothold in the tissues by flying beneath the radar screen of the immune system. It does this by blocking the presentation of its early Ags through MHC Class I molecules of its host, thus blindfolding T cells to its presence. Thereafter, although never eradicated, CMV is kept firmly under control by a standing army of T cells, which kill cells harboring replicating virus by recognizing two major Ags: the matrix phosphor protein 65 and the intermediate early-1 protein. For most of us, this well-equilibrated cold war is good enough to prevent problems. Only serious damage to the memory T-cell compartment can upset the balance — but we regularly cause just that with stem-cell transplantation and immunosuppressive drugs. The result is the reactivation of CMV and the risk of fatal CMV pneumonia, aside from debilitating viral retinitis and gastroenteritis. Until recently, the only remedy was treatment with CMV-specific Ab and antiviral drugs, with some effect, but with many disadvantages and much cost. The alternative is to prevent viral reactivation by restoring the standing T-cell army in the immune-deficient host. Allogeneic stem-cell transplantation makes available a reservoir of such cells in a CMV-exposed donor. Required is a system to collect lymphocytes from the donor, rechallenge them with CMV Ag, expand and select Ag-specific T cells, and infuse sufficient
© 2002 ISCT
cells into the recipient to prevent viral reactivation. This may seem like a tall order, but the proof of principle that adoptive transfer of CMV-specific CD8 T cells could protect patients from CMV disease was clearly shown in a brilliant paper from Stanley Riddell and his group in Seattle in 1995 [1]. Since then, there has been much progress and great inventiveness in developing practical strategies to protect the recipient with CMV-specific T cells. In this issue of Cytotherapy, we present a collection of research papers and reviews that illustrate the diversity of approaches used to bring CMV-specific T-cell therapy to the clinic. In five papers, experts from the USA and Europe describe the process of generating CMV Ag-specific T cells — their induction, expansion and selection, as well as the in vivo monitoring of the immune response. The goal is to make the procedure routine, not an exotic extra, practical only in highly sophisticated and well-funded centers. With its well-characterized immune responses, CMV is the perfect proving ground for technical development in the whole field of adoptive immunotherapy. These contributions, therefore, point the way to practical ways to use adoptive T-cell therapy for other viruses and microorganisms, as well as for Ags on leukemia and tumor cells. As ever, the development of good manufacturing techniques for realizing our cell-therapy dreams are just as challenging as the first demonstration of principle. Cytotherapy aims to remain at the center of this unfolding story.
Reference 1
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 1995;333:1038–44.
1
Martin Dunitz
Taylor&Francis healthsciences
Editorial
Adoptive T-cell therapy for CMV John Barrett Co-Editor
Over millions of years of evolution, human CMV has reached a comfortable accommodation with its host. Its acquisition early in life, at the cost of a brief upper respiratory infection, ensures the virus the opportunity of a safe haven in the BM for the life-span of the individual, with opportunities for salivary export and infection of new hosts, based upon the reliable behavior of humans, young or old, to get friendly. This apparently harmonious situation is not, however, all it seems. The virus first gains its foothold in the tissues by flying beneath the radar screen of the immune system. It does this by blocking the presentation of its early Ags through MHC Class I molecules of its host, thus blindfolding T cells to its presence. Thereafter, although never eradicated, CMV is kept firmly under control by a standing army of T cells, which kill cells harboring replicating virus by recognizing two major Ags: the matrix phosphor protein 65 and the intermediate early-1 protein. For most of us, this well-equilibrated cold war is good enough to prevent problems. Only serious damage to the memory T-cell compartment can upset the balance — but we regularly cause just that with stem-cell transplantation and immunosuppressive drugs. The result is the reactivation of CMV and the risk of fatal CMV pneumonia, aside from debilitating viral retinitis and gastroenteritis. Until recently, the only remedy was treatment with CMV-specific Ab and antiviral drugs, with some effect, but with many disadvantages and much cost. The alternative is to prevent viral reactivation by restoring the standing T-cell army in the immune-deficient host. Allogeneic stem-cell transplantation makes available a reservoir of such cells in a CMV-exposed donor. Required is a system to collect lymphocytes from the donor, rechallenge them with CMV Ag, expand and select Ag-specific T cells, and infuse sufficient
© 2002 ISCT
cells into the recipient to prevent viral reactivation. This may seem like a tall order, but the proof of principle that adoptive transfer of CMV-specific CD8 T cells could protect patients from CMV disease was clearly shown in a brilliant paper from Stanley Riddell and his group in Seattle in 1995 [1]. Since then, there has been much progress and great inventiveness in developing practical strategies to protect the recipient with CMV-specific T cells. In this issue of Cytotherapy, we present a collection of research papers and reviews that illustrate the diversity of approaches used to bring CMV-specific T-cell therapy to the clinic. In five papers, experts from the USA and Europe describe the process of generating CMV Ag-specific T cells — their induction, expansion and selection, as well as the in vivo monitoring of the immune response. The goal is to make the procedure routine, not an exotic extra, practical only in highly sophisticated and well-funded centers. With its well-characterized immune responses, CMV is the perfect proving ground for technical development in the whole field of adoptive immunotherapy. These contributions, therefore, point the way to practical ways to use adoptive T-cell therapy for other viruses and microorganisms, as well as for Ags on leukemia and tumor cells. As ever, the development of good manufacturing techniques for realizing our cell-therapy dreams are just as challenging as the first demonstration of principle. Cytotherapy aims to remain at the center of this unfolding story.
Reference 1
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 1995;333:1038–44.
1