Tumor immunotherapy using EBV-specific cytotoxic T lymphocytes (CTLs) has been successful for the treatment of EBV-associated lymphomas arising in the immunocompetent host. However, the majority of referred patients have EBV-negative lymphomas, precluding the use of virus-targeted T cells; also, CTLs do not eliminate tumors in all patients, likely because potentially immunogenic tumors arising in immunocompetent persons develop immune evasion strategies that subvert the effector function of the infused CTLs. These include downregulation of viral antigens, and the production of soluble immunomodulatory cytokines, such as 1L4, from malignant and infiltrating inhibitory cells, which limit the in vivo activity of adoptively transferred T cells. To extend T cell therapy to all patients with Hodgkin lymphoma (HL), regardless of tumor EBV status, we used the previous SPORE funding cycle to develop a strategy to reactivate and expand CTLs with specificity for the nonviral tumor-associated antigens (TAAs) Survivin SSX2, MAGE-A4, NY-ESO-1 and FRAME expressed by malignant cells. We reasoned that targeting multiple TAAs simultaneously would minimize tumor immune escape and therefore are assessing the safety and efficacy of these multiTAA-CTLs in vivo. We now propose, in Project 1, to address two remaining barriers to successful T cell therapy, namely (a) low target antigen expression, and (b) the immunosuppressive tumor microenvironment. Thus, our central hypotheses are that the efficacy ot immunotherapy for HL can be enhanced by combination with epigenetic drugs and by modifying infused T cells to retain Thi function in the Th2 cytokine milieu of the tumor. Hence, in Aim 1 of our renewal application, in a phase I clinical trial, we will generate and infuse multiTAA-targeted CTLs in combination with a hypomethylating agent known to upregulate T cell target antigen expression on malignant cells and sensitize them to immune-mediated destruction. The impact of this combination therapy on tumor immunogenicity, T cell antitumor activity and epitope spreading will be assessed in Aim 2. Finally, Aim 3 seeks to protect adoptively transferred multiTAA-targeted CTLs from the tumor microenvironment by engineering the T cells to express a chimeric cytokine receptor that can bind the Th2 cytokine 1L4 and convert its inhibitory signal to one that is activating. Although restricted to preclinical models initially. Aim 3 will be clinically developed in the future. In summary, this approach combining drug therapy with tumorspecific CTLs may enable T cell immunotherapy to become more broadly applied to all patients with cancer.