Abstract
Current intensive chemotherapy regimens have dramatically increased survival in acute lymphoblastic leukemia (ALL) patients compared to the 1950s when single agent chemotherapy was used. Despite this success certain subsets of patients have a high rate of relapse such as those with the Philadelphia chromosome (Ph+). Because the Bcr-Abl oncogene is a novel protein product and uniquely expressed in the leukemia clone, it has the potential to generate anti-leukemic immune responses. Our lab has been studying immunotheraputic approaches for Ph+ ALL using a murine model. Previous data have demonstrated that transduction of leukemia cells with the immunomodulators CD40Ligand, CD80, and GM-CSF generate T and NK cell immune responses. When irradiated and given as a vaccine these gene-modified cells are able to protect a portion of mice from an otherwise lethal dose of leukemia. We looked at the ability to systemic IL-12 treatments to potentiate this immune response and found that IL-12 alone was able to eliminate pre-existing disease in mice. IL-12 treatments, however, did not establish immunologic memory and did not protect mice from subsequent re-challenge with a lethal dose of leukemia. IL-12 protection was primarily mediated by CD4 and CD8 T cells as demonstrated by a decrease in survival in nude mice. When CD4 or CD8 T cells were depleted individually, however, protection was maintained indicating that one cell type can compensate for the other in its absence. Depletion of NK cells from Nude mice further decreased survival indicating a role for these cells in the protection. Thus protection was mediated in part by CD4 T lymphocytes, CD8 T lymphocytes, and Natural Killer cells. The ability of IL-12 to activate three different cell types may explain the efficacy seen in this model, where other cytokines alone have failed. In combination, IL-12 and our leukemia cell vaccine are effective in eliminating pre-established aggressive Philadelphia chromosome positive leukemia and establishing long lasting immunity from subsequent lethal doses of wild type leukemia. As expected, the immunologic memory generated by vaccination with gene modified leukemia cells was mediated by CD4 T cells as indicated by depletion studies. These studies demonstrate the feasibility of immunotheraputic approaches in the treatment of Ph+ ALL.
Recombinant murine interleukin-12 elicits potent antileukemic immune responses in a murine model of philadelphia chromosome-positive acute lymphoblastic leukemia