Our laboratory has been investigating adoptive immunotherapy with unmodified and gene modified T cell clones to treat human immunodeficiency virus infection and to prevent cytomegalovirus (CMV) infection in allogeneic BMT recipients.

The persistence of HIV replication in infected individuals in part reflects an inadequate HIV-specific CD8+ cytotoxic T lymphocyte (CTL) response. The transfer of CD8+ HIV-specific CTL clones (>3.3 x 109/m²) provided high levels of CTL activity to HIV. Transferred CTL migrated to lymph nodes containing HIV infected cells and reduced HIV infected T cells in the blood. Efficacy was limited by a short in vivo survival of transferred effector cells. Thus, strategies to improve the persistence of transferred CD8+ CTL such as the administration of IL-2, the genetic modification of CTL to confer a helper independent phenotype, or the transfer of CD4+ Th cells which are resistant to HIV infection are being developed. A determinant of the outcome of cytomegalovirus infection in BMT recipients is the severity of the CMV-specific T cell immune deficiency. Both CD8+ CTL and CD4+ Th are important but CD8+ CTL appear to be critical. A phase 1 study was conducted in which CD8+ CMV-specific CTL clones were isolated from the immunocompetent HLA identical donor and adoptively transferred in escalating doses (3.3 x 107/m² - 1 x 109/m²) beginning 28-42 days after transplant. Fourteen patients were treated on this initial study and no serious toxicities were observed. Reconstitution of CD8+ CTL responses was observed in all patients and transferred immunity persisted for at least 12 weeks although responses declined in those individuals who were deficient in CD4+ CMV-specific Th responses. None of the 14 patients developed CMV viremia or disease. These results demonstrate that adoptive immunotherapy with CMV-specific T cell clones can restore protective levels of T cell immunity to CMV after BMT and a phase 2 study of the adoptive transfer of both CMV-specific CD8+ CTL and CD4+ Th clones is now in progress.