| Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) is a highly malignant cancer refractory to current chemotherapy protocols. The presence of the Bcr-Abl oncogene in this type of leukemia makes it an attractive candidate for immunotherapy due to exclusive expression of the oncogene in the leukemia clone. Additionally, the oncogene results from the fusion of two cellular genes, BCR and abl, generating a unique junctional region not present in normal cells. It may, therefore, function as a tumor specific antigen and prime tumor specific immune responses if presented to the immune system with the appropriate stimulation. Several approaches have proved successful in the initiation of antitumor immune responses. These studies involve the investigation of two of these approaches for the treatment of Ph+ ALL.; In the first approach, we utilized a murine model of Ph+ ALL to look at the ability of gene-modified leukemia cells to initiate antileukemic immune responses. Leukemia cells engineered to express CD40 Ligand (CD40L), CD80, GM-CSF, or a combination of these genes demonstrated enhanced immunogenicity. Protection mediated by CD40L was dependent on Natural Killer cells, while CD80 expression led to T cell-mediated responses. Vaccination with leukemia cells expressing all three immunomodulators, along with the administration of systemic IL-12, led to the elimination of established disease. The ability of CD40L to act in a T cell-independent manner may be an important factor in tumor cell vaccines as patients have depressed cellular immunity following chemotherapy.; Experiments conducted in vitro were done with an alternative approach in which Bcr-Abl transduced dendritic cells were generated. Bcr-Abl expressing dendritic cells were analyzed for their ability to stimulate proliferation of autologous T lymphocytes. CD34+ hematopoietic progenitors from three of fifteen umbilical cord blood samples gave rise to Bcr-Abl positive dendritic cells which were able to stimulate proliferation of autologous T lymphocytes. This is supportive of the hypothesis that Bcr-Abl has the potential to initiate antileukemic immune responses. These studies demonstrate the feasibility of utilizing antileukemic immune responses in the design of novel therapies for Ph+ ALL. |
