Immune Response to Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Induced by Expression of CD80,Interleukin 2,and Granulocyte-Macrophage Colony-Stimulating Factor

We examined the potential of generating an immune response against Philadelphia chromosome-positive acute lymphoblastic leukemia. The immunostimulatory molecules chosen for this study were the cytokines IL-2 and GM-CSF and the costimulatory ligand CD80 (B7.1). We used a murine model based on a BALB/c pre-B cell line, BM185wt, in which leukemia is induced by the p185 BCR-ABL oncogenic product, which reproduces Philadelphia chromosome-positive ALL. BM185wt cells were transduced with retroviral vectors and the transduced clones expressing mIL-2, mGM-CSF, or mCD80 were used for challenge. Expression of the immunomodulators by BM185 cells was correlated with delay in leukemia development in immunocompetent mice, but not in immunodeficient mice, indicating an immune response against the modified leukemia cells. Expression of CD80 caused leukemia rejection in 50% of the cohort, which was associated with the CD4⁺ and CD8⁺ T cell-dependent development of anti-leukemia cytotoxic T lymphocytes. Furthermore, mice surviving the BM185/CD80 challenge or preimmunized with irradiated BM185/CD80 cells developed an immune response against subsequent challenge with the parental leukemia. These studies provide evidence that immunotherapeutic approaches can be developed for the treatment of ALL.

Overview summary

Patients presenting with high-risk acute lymphoblastic leukemia (ALL) have a 30% (or lower) chance of long-term survival; alternative treatments such as immunotherapy could improve the survival rate. In this article we examine a novel murine model for Philadelphia-positive ALL that can be thoroughly explored for gene therapy studies. On the basis of that model, we evaluated the feasibility of cell vaccines expressing IL-2, GM-CSF, and CD80 in promoting an immune response against leukemia. Expression of CD80 promoted the strongest response, which was mediated by CD4⁺ and CD8⁺ T lymphocytes. In summary, this preclinical study supports the potential of engineered ALL cells to elicit an anti-leukemia immune response.