This is a proposal to develop a model for immunotherapy of B-cell non-Hodgkin's lymphomas (B-NHL) in mice with severe combined immune deficiency (SCID mice) using in vitro-generated lymphoma-reactive T cell populations which will be engrafted into mice bearing human B-NHL. This model would help to define the principles necessary for immunotherapy of B-NHL with different populations of cultured human T cells. The proposal is based on previous data of others and ourselves showing that: 1) Human B-NHL can grow in SCID mice as localized or disseminated tumors, depending on route of administration. 2) Resting or in vitro-activated human T cells can engraft, proliferate and traffic to sites of lymphoma growth in SCID mice. 3) Human lymphoma-reactive T cell clones which appear to be specific for autologous or allogenic B-NHL can be generated and expanded in vitro to obtain sufficient numbers of cells for adoptive transfer into SCID mice.
The specific aims of this study are: 1) To establish human B-NHL lines with stable phenotypes and growth characteristics in SCID mice. We will inject B-NHL cell lines developed by us and others into SCID mice to characterize their growth, mode of spread, histological appearance, immunophenotype and karyotype. Tumor lines with stable phenotypes and reproducible growth characteristics in mice will be selected for further studies. 2) To generate and expand human B-NHL-reactive T cell populations in vitro. V(gamma)9/V(delta)2 T cell clones and bulk cultures of V(gamma)9/V(delta)2 T cells reactive against the Daudi Burkitt lymphoma will be generated from normal peripheral blood lymphocytes (PBL) or patients' PBL. B-NHL-reactive alpha-beta T cells will be generated from allogeneic and autologous PBL and from tumor infiltrating lymphocytes. Clones showing specific reactivity with B-NHL will be selected for in vivo studies. 3) To assess the effects of human B-NHL-reactive T cell populations on the growth of B-NHL in SCID mice. Initially, we will determine the effects of polyclonal and clonal V(gamma)9/V(delta)2 T cell populations on the engraftment and growth of Daudi lymphoma and other B-NHL recognized by this T cell subset. Subsequently, alpha-beta T cell clones that had been characterized in vitro will be tested for antitumor activity in SCID mice bearing the corresponding B-NHL. The in vivo anti-lymphoma activity of individual T cell clones or polyclonal populations will be correlated with the phenotype and in vitro functions as well as survival, migration patterns and requirements for exogenous interleukin 2 in SCID mice.
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