EBV-specific T-cell therapy

Cytotoxic T-cell therapy has been used to prevent and treat Epstein-Barr virus (EBV)–related posttransplantation lymphoproliferative disorder after allogeneic bone marrow transplantation. As reported in this issue of Blood, Haque and colleagues have extended such therapy to the wider range of lymphoproliferations encountered after solid organ transplantation by using partially human leukocyte antigen (HLA)–matched, EBV-specific, cytotoxic T lymphocytes (CTLs).

It has long been recognized that a proportion of cases of posttransplantation lymphoproliferative disease (PTLD) following organ transplantation will regress with reduction in immunosuppressives, presumably due to the recovery of EBV-specific immunocompetence. That approach is most likely to succeed with proliferations occurring early after transplantation, when PTLD is often polyclonal or oligoclonal in composition and manifests few, if any, detectable structural genetic alterations. That same pattern of disease is seen following allogeneic bone marrow transplantation, and EBV-specific T cells obtained from the marrow donor and expanded ex vivo have been effective as prophylaxis or treatment.¹  However, PTLD occurring late after organ transplantation often closely resembles non-Hodgkin lymphoma in morphology and clonal composition, manifests structural alterations, and is much less likely to respond to immunosuppressive reduction.²  It has therefore been unclear to what extent these EBV-directed strategies result in an antitumor response, as opposed to curtailing EBV-driven lymphoid expansion, akin to what occurs naturally during the resolution of infectious mononucleosis. A major obstacle to the use of T-cell therapy for PTLD after organ transplantation results from the fact that the vast majority of proliferations are of recipient, not donor, origin, whereas the opposite is true after bone marrow transplantation.³  CTLs must be HLA compatible with the tumor, making the organ donor, even if available, an unsuitable source of T cells.

Haque and colleagues prepared a bank of EBV-specific cytotoxic T-cell lines derived from EBV-seropositive blood donors, and used cells providing the best HLA matching to treat patients with PTLD that was unresponsive to prior therapies. Despite the daunting practical problems imposed by this approach and by the complexities of the clinical setting, the investigators have successfully conducted the trial, and report some remarkable conclusions. Durable tumor responses were seen in patients apparently refractory to immunosuppressive reduction. Furthermore, responses were also achieved in adult patients with monomorphic, monoclonal tumors presenting more than 2 years after transplantation. No major toxicity or evidence of graft-versus-host disease was encountered. Although rituximab is effective, has limited toxicity, is immediately available, and is easily administered, more than half of PTLD patients may relapse or fail to respond to that antibody.⁴  CTL therapy might therefore be an attractive alternative to chemotherapy for such patients. Significant uncertainties remain, in view of the many clinical variables in the trial and the unclear fate of the partially HLA-matched cells. Nonetheless, the results of this study can be seen as very encouraging for the concept of immunologically targeting EBV markers in the treatment of other EBV-associated tumors, such as Hodgkin disease, nasopharyngeal carcinoma, and a subset of the AIDS-related non-Hodgkin lymphomas.