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The introduction and expression of genes in somatic cells is an innovative therapy for correcting genetic deficiency diseases and augmenting immune function. A potential obstacle to gene therapy is the elimination of such gene-modified cells by an immune response to novel protein products of the introduced genes. We are conducting an immunotherapy trial in which individuals seropositive for human immunodeficiency virus (HIV) receive CD8+ HIV-specific cytotoxic T cells modified by retroviral transduction to express a gene permitting positive and negative selection. However, five of six subjects developed cytotoxic T-lymphocyte responses specific for the novel protein and eliminated the transduced cytotoxic T cells. The rejection of genetically modified cells by these immunocompromised hosts suggests that strategies to render gene-modified cells less susceptible to host immune surveillance will be required for successful gene therapy of immunocompetent hosts.

Background: Cytomegalovirus (CMV) disease in immunocompromised patients correlates with a deficiency of CD8+ cytotoxic T lymphocytes specific for CMV. We evaluated the safety and immunologic effects of immunotherapy with clones of these lymphocytes in recipients of allogeneic bone marrow transplants., Methods: Clones of CD8+ cytotoxic T cells specific for CMV proteins were isolated from the blood of bone marrow donors. Fourteen patients each received four intravenous infusions of these clones from their donors beginning 30 to 40 days after marrow transplantation. The reconstitution of cellular immunity against CMV was monitored before and during the period of infusions and for up to 12 weeks after the final infusion. The rearranged genes encoding the T-cell receptor served as markers in evaluating the persistence of the transferred T cells., Results: No toxic effects related to the infusions were observed. Cytotoxic T cells specific for CMV were reconstituted in all patients. In vitro measurements showed that cytotoxic activity against CMV was significantly increased (P < 0.001) after the infusions in 11 patients who were deficient in such activity before therapy. The level of activity achieved after the infusions was similar to that measured in the donors. Analysis of rearranged T-cell-receptor genes in T cells obtained from two recipients indicated that the transferred clones persisted for at least 12 weeks. Cytotoxic-T-cell activity declined in patients deficient in CD4+ T-helper cells specific for CMV, suggesting that helper-T-cell function is needed for the persistence of transferred CD8+ T cells. Neither CMV viremia nor CMV disease developed in any of the 14 patients., Conclusions: The transfer of CMV-specific clones of CD8+ T cells derived from the bone marrow donor is a safe and effective way to reconstitute cellular immunity against CMV after allogeneic marrow transplantation.

The adoptive transfer of T cells specific for antigens encoded by pathogens and tumors has been an effective treatment for infections and malignancies in animal models and is potentially applicable for infections occurring in immunodeficient bone marrow transplant recipients. This article reviews recent insights derived from studies of the immunobiology of human cytomegalovirus (CMV) infection in healthy and immunodeficient hosts and the development of adoptive immunotherapy as prophylaxis for CMV infection in recipients of allogeneic bone marrow transplants.

The development of CD8+ cytotoxic T cell responses to viral pathogens is crucial for the prompt resolution of acute infections and for the control of viruses which persist in the host. Thus, cytomegalovirus often causes life threatening disease in immunosuppressed humans who fail to develop or maintain CD8+ cytotoxic T cells. Similarly, the loss of CD8+ cytotoxic T cell responses to HIV correlates with the development of AIDS. Recent investigations in the immunobiology of cytomegalovirus and HIV have resulted in the application of immunotherapeutic strategies designed to reconstitute or augment deficient CD8+ cytotoxic T cell responses to these human pathogens.