The long term goal of this proposal is to study the role of cytotoxic T cells (CTL) in the therapy of B cell lymphomas (BCL) associated with immunodeficiency states. BCL are seen with increasing frequency in patients with Human Immunodeficiency Virus (HIV) infection, which is often characterized by chronic antigen stimulation and immunodysfunction. Epstein Barr virus (EBV) infection has been implicated in subsets of HIV associated BCL (HIV-BCL) as a significant proportion of HIV-BCL contain EBV. HIV associated BCL often respond to chemotherapy, but the overall prognosis is poor with a median survival of less than one year. Treatment options in patients with profound defects in cellular immunity are even more restricted as many chemotherapeutic agents exacerbate immunosuppression and recurrent or unresponsive tumors occurring in this population have a dismal prognosis. An alternative to traditional chemotherapeutic agents include adoptive immunotherapy with cytotoxic T lymphocytes (CTL). We postulate that restoration of cellular immunity against the EBV expressed proteins in the lymphoma cells may have profound anti-lymphoma activity. Clinical evidence that cellular immunity may control the development of BCL exists in solid organ transplant recipients in which the incidence of BCL increases with the degree of immune impairment. In 23 per cent of transplant patients who develop BCL, cessation of the immunosuppressive agents leads to BCL regression without other specific treatment. Besides these clinical observations, we now have in vitro data demonstrating that BCL are susceptible to CTL lysis. We isolated a B cell lymphoma from an immunodeficient patient and have documented latent EBV gene expression. HLA restricted EBV specific CTL (EBV-CTL) generated by in vitro stimulation are able to lyse these cells in vitro. Furthermore, adoptive transfer of EBV-CTL leads to abrogation of tumor in immunodeficient SCID mice engrafted with EBV infected cells. Because adoptive transfer of EBV specific CTL can lead to tumor regression in an animal model, we propose to evaluate the role of adoptive therapy of ex vivo expanded EBV-CTL for the treatment of refractory or recurrent EBV expressing B cell lymphoma in the immunosuppressed HlV infected patient.
