The genetic modification of T lymphocytes is the basis for novel approaches to study and establish tumorimmunity. The genetic transfer of antigen receptors is indeed a powerful approach to rapidly generate tumorspecificT lymphocytes. However, while necessary, tumor antigen recognition is not sufficient to permit tumoreradication. To achieve this goal, primed CTLs must expand to sufficient numbers, migrate to tumor sites,mature into effector cells and carry out their cytolytic function unimpeded. The genetic strategies we arepursuing aim to increase recognition of tumor antigens, enhance anti-tumor functions and sustain T cellfunction in cancer patients. Most important for our understanding of human tumor immunology andtherapeutic goals, gene addition and knockdown strategies can be applied to human T lymphocytes, onwhich we focus in this project.
The specific aims are based on our published and preliminary data.
Aim 1 : Toinvestigate the biological properties and therapeutic potential of tumor specific CD8+ T cells co-stimulated byCD28 and 4-1BB. We hypothesize that concerted CD28 and 4-1BB signals sustain CD8+ T cell proliferationand survival, and may thus augment the therapeutic potency of genetically targeted T lymphocytes.
Aim 2 :To investigate the effect of ex vivo IL-15 on the proliferation, survival, differentiation and therapeutic potentialof adoptively transferred human primary T lymphocytes.
This aim builds on our recent finding that IL-15enhances the therapeutic potential of cultured 19z1-transduced PBLs upon adoptive transfer to tumorbearingmice. We hypothesize that IL15 increases therapeutic efficacy through several mechanisms, mostimportantly T cell survival.
Aim 3 : To establish an efficient protocol for T'cell transduction and expansion in aclosed system and perform a phase I clinical trial to assess the safety, persistence and therapeutic activity ofautologous 19-28z-transduced T lymphocytes in patients with relapsed, chemo-refractory chroniclymphocytic leukemia. We hypothesize that patient T cells expressing a CD28/ -like chimeric antigenreceptor will induce durable remissions, more so in cyclophosphamide-treated recipients. Our investigationcritically depends on the Gene Transfer and Somatic Cell Engineering Core, to genetically modify patient Tcells, the Imaging Core, to study T cell migration and persistence in vivo, and the Administrative Core, forbiostatistics and data management.
Showing the most recent 10 out of 186 publications
