574. Systemic IL-12 Eliminates Pre-Established Leukemia in a Murine Model of Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Abstract

Acute Lymphoblastic Leukemia (ALL) is the most frequent type of leukemia in children and represents roughly 30% of all childhood malignancies. With current chemotherapy protocols event-free survival in children with ALL has reached 75%. The 25% of patients who relapse can often be predicted based on certain prognostic factors including infants less than one year of age and/or the presence of the Philadelphia chromosome (Ph+). Our laboratory has established a murine model of Ph+ ALL utilizing a cell line, BM185, generated by the transformation of Balb/c bone marrow with the Bcr-Abl oncogene. Balb/c mice injected with as few as one thousand BM185 cells die within three to four weeks of challenge, with heavy tumor burdens in the blood, spleen, and bone marrow. Irradiated BM185 cells transduced with various immunomodulators including CD80, CD40 Ligand, and GM-CSF, are able to initiate anti-leukemic immune responses, and can prevent the development of leukemia in a portion of mice when given prior to challenge with live wild type leukemia. Recently our lab initiated experiments to determine if systemic recombinant murine IL-12 (rmIL-12) injections could be used as an adjuvant to enhance the effects of our tumor cell vaccine based approach. We found that rmIL-12 injections alone were able to eliminate disease in mice given lethal doses of leukemia on the same day as the initiation of treatment. This protection was mediated by CD4 T lymphocytes, CD8 T lymphocytes, and Natural Killer cells in combination, rather than by stimulating a single cell type alone as demonstrated by depletion studies and studies done in Nude mice. Mice surviving challenge as a result of concomitant treatment with rmIL-12 did not generate immunologic memory responses, as demonstrated by rechallenge with wild type BM185 cells in long term survivors. The combination of rmIL-12 treatments and cellular vaccines consisting of irradiated BM185 cells expressing CD80, CD40 Ligand, and GM-CSF was able to provide immediate protection as well as long term memory. Currently our lab is conducting experiments to compare the efficacy of rmIL-12 systemic treatments to IL-12 transduced BM185 cells in order to establish the best mode of immune system stimulation with the least amount of toxicity. The results of IL-12 in our murine model are encouraging as we were previously unable to eliminate pre-established disease in this aggressive model of Ph+ ALL. These studies validate the feasibility of a clinical trail to evaluate the ability of vaccinations in combination with IL-12 to eliminate minimal residual disease in Ph+ ALL patients in remission.