This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We propose to develop and test an innovative approach to adoptive immunotherapy for Hodgkin disease (HD). Approximately 50% of cases of HD in immunocompetent individuals are associated with expression of a number of Epstein-Barr virus (EBV) derived antigens in the malignant Reed-Sternberg cells and their variants. Of these, the LMP1 and 2 antigens, represent a verifiable and unique tumor antigen and can be used as a target for cytotoxic T lymphocyte (CTL)-mediated immunotherapy. We have previously used the adoptive transfer of CTL successfully to prevent and treat EBV-related immunoblastic lymphoma post bone marrow transplant. By genetically marking the CTL before infusion, we were able to track them in vivo and analyze their safety, function and longevity. Having shown that the EBV-positive cells in post-transplant lymphoproliferation (LPD) are susceptible to immunotherapy, we hypothesize that the malignant cells in Hodgkin disease, which express a more restricted repertoire of EBV encoded antigens, are also suitable targets for immunotherapy.
In Specific Aim 1 we will generate gene-marked EBV-specific CTL from patients with relapsed Hodgkin disease, using autologous EBV-transformed B cells lines as stimulator cells. By tracking the marker gene, we will test the hypotheses that infused CTL survive and expand in vivo, are safe and contain sufficient LMP-1/2 specific effector cells to generate anti-tumor activity.
In specific Aim 2, we will test the hypotheses that CD4+ and CD8+ LMP1 and LMP2a-specific CTL lines can be prepared from patients, using autologous dendritic cells modified to express the appropriate stimulator antigens. CTL lines with defined specificity against LMP1 and or LMP2a (monospecific CTL) may be more effective than polyspecific lines, and in Specific Aim 3, we will test the hypotheses that gene-marked LMP1- and LMP2a-specific CTL lines from patients with relapsed Hodgkin disease, survive and persist in vivo, are safe, increase patient immune responses to LMP1 and LMP2a and have anti-tumor effects. The studies will provide information applicable to similar therapy for a variety of human malignancies of viral and non-viral origin.
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