Amplified production of immunostimulatory molecules by tumor cells offers an attractive way to generate specific immune responses in vivo. The investigator has demonstrated the feasibility of this approach in neuroblastoma patients, using an adenoviral vector to transduce autologous tumor cells with IL-2. The research proposed here builds on that experience to test IL-2 and the costimulator molecule CD40 ligand in CD40+ blast cells from patients with ALL. Preliminary data in a murine model suggests that combined expression of CD40L and IL-2 does enhance the anti-tumor effect over results seen with either molecule alone. However, primary ALL blasts are difficult to transduce with adenoviral or other available vectors, leading the investigator to develop a herpes virus vector for this purpose. The subject of this project is a phase I clinical trial.
Aim 1 tests the safety and immunogenicity of herpes virus-IL-2 transduced autologous lymphoblasts, while Aim 2 tests cells transduced with a herpes-CD4OL vector.
In Aim 3, the goal will be to administer a fixed dose of IL-2 transduced cells with an escalating dose of CD4R0L-transduced cells to test the central hypothesis of this project, that in vivo immune responses against leukemia cells can be greatly enhanced by co-administering autologous blasts that express both stimulatory molecules. The results will permit a reliable assessment of the safety of this strategy, as well as the likelihood of amplifying human immune responses to putative leukemia specific antigens.
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