Adoptive immunotherapy with T lymphocytes appears clinically effective for therapy of several malignant and infectious disorders, and transduction of T cells with artificial T cell receptors (cTcR) can potentially expand the approach by redirecting the cellular immune response to almost any surface target antigen. However, recent efforts using chimeric receptor-expressing T cells have failed to demonstrate persistence or functionality of the infused T cells. This is likely because the tumor target cells do not express the costimulator molecules required to reactivate and sustain T cells. We have devised two means to overcome this problem. First, we will incorporated the cTcR in Epstein Barr Virus-specific cytotoxic T lymphocytes (CTL). These CTL maintain the activity of their native receptors, so that EBV-infected B cells continue to transfer costimulatory signals, ensuring sustained activation and proliferation for these CTL to be cytolytic when they encounter their tumor through the cTcR. Second, we will incorporate the endodomains of costimulatory molecules as part of the cTcR, so that encounter with the target antigen alone imparts sufficient costimulation to induce activation and proliferation. Using the Hodgkin Disease model and T cells redirected against the CD30 molecule that is specifically expressed by this tumor we compare in a pre-clinical human model the anti-tumor efficacy, growth and survival of redirected EBV-CTLs with the effectiveness of mitogen-activated T cells expressing cTcR linked to costimulatory endodomins (Aim 1). The in vivo efficacy and safety of these strategies will be compared in a xenograft mice model (Aim2). At the end of this study we should have clear evidence of the feasibility of using cTcR+ T cells directed against the CD30 antigen for the treatment of patients with HD and data to support or refute the use of modified chimeric receptors or viral antigen-specific CTL to augment the functionality of chimeric receptor bearing T cells - information of value not only for HD disease, but for any disease amenable to adoptive immunotherapy including virus-associated diseases. The data produced by this project will be crucial to develop appropriate clinical trails with redirected T cells.
