There is abundant of evidence to suggest that chronic myeloid leukemia (CML) can be modulated by the effector cells in the immune system, suggesting the potential for the use of immunotherapy for patients with CML, either as a therapy following standard treatment to maintain disease remission or as part of leukemia-specific donor lymphocyte infusion to reduce the risk of leukemia relapse after allogeneic stem cell transplant. Unfortunately the antigens suitable for this purpose are yet to be defined. We have recently found that the testicular-specific antigen, SPAN-Xb, is aberrantly expressed by leukemia cells from CML patients. We have also found that in these patients, high IgG directing at SPAN-Xb protein could be detected in the serum. We have generated a recombinant SPAN-Xb protein and murine MoAbs against the protein. We have also demonstrated that SPAN-Xb recombinant protein could be used to induce HLA-A2-restricted CTLs from a healthy donor. These CTLs are not only SPAN-Xb-specific; they also killed fresh HLA-A2+ CML cells, providing the rationale for the present proposal. In this application, we hypothesize that SPAN-Xb is a target for immunotherapy of CML. To test this hypothesis, we will: 1. Use a combination of real time PCR and immunocytochemistry to determine the frequency and levels of SPAN-Xb gene and protein expression in CML. We will determine if there is any correlation between gene and protein expression in the CML population and also between the levels of gene and protein expression within individual patients. 2. We will serially determine any correlation between the de novo SPAN-Xb immunity and disease status of the patients. We will study HLA-A2+ SPAN-Xb+ CML patients and correlate the intensity of B- and T-cell immunity to the response to treatment. 3. We will determine the feasibility of generating SPAN-Xb-specific CTLs from healthy donors and SPAN-Xb+ CML patients with common HLA-class I phenotypes. We will characterize these CTLs in types of their phenotypes, cytokine profiles, activities against CML cells and inhibitory effect on CML colony formation. Successful completion of the proposal will therefore provide the basis for the clinical translation of SPAN-Xb. ? ?
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