Many children and most adults with acute lymphoblastic leukemia (ALL) are not cured by conventional therapy. Moreover, the long-term effects of chemo-radiotherapy are now being manifest in survivors of childhood ALL. Immunotherapy may improve the therapeutic index of ALL treatment. We have shown that patients with B cell precursor ALL have tumor-specific T cells in their repertoire. This significant finding demonstrates that ALL cells express antigens which can be recognized by autologous T cells. Discovering the identity of these antigens is important because doing so will enable the characterization of host anti-tumor immunity in patients with ALL, and will offer new therapeutic targets. Tumor antigens can represent gene products overexpressed in tumor cells compared with non-malignant cells. We have developed a strategy that has identified successfully tumor antigens on the basis of their overexpression in cancer cells. However, in ALL, this approach has so far been limited by the small number of genes known to be overexpressed in leukemia cells. Gene expression profiling can identify genes that are overexpressed in B cell ALL relative to its normal counterpart, the B cell precursor, and relative to other normal tissues. These genes represent a pool of candidate tumor antigens that can be functionally validated. My hypothesis is therefore that GENOMIC APPROACHES TO TUMOR ANTIGEN DISCOVERY IN ACUTE LYMPHOBLASTIC LEUKEMIA WILL ADVANCE UNDERSTANDING OF HOST-TUMOR INTERACTIONS IN PATIENTS AND IDENTIFY NEW TARGETS FOR TREATMENT. To test this hypothesis I plan to: (1) define candidate tumor antigens bioinformatically using gene expression profiling; (2) validate candidate tumor antigens in vitro; and (3) credential tumor antigens in vivo. My career goal is to become an independent physician-scientist studying tumor immunology both in the laboratory and in the clinic. Specifically, I plan to study the biology of the host anti-tumor immune response in patients and determine how it contributes to disease outcome. Achieving this goal will require expertise in laboratory, translational and clinical research. To develop the necessary skills, I have the mentorship of co-sponsors with international reputations in laboratory research and translational medicine. I have also assembled a panel of advisors with great expertise in the field. My research environment is rich with opportunities for interaction and education, and I will enroll in didactic courses in biostatistics, study design and ethics to complement my research experience. This training will form the foundation of my career in translational research.
