Research Project
6172096
DESCRIPTION: (Applicant's Abstract) Leukemia and lymphoma usually do not recur in patients who develop graft-vs.-host disease (GVHD) following allogeneic bone marrow transplantation (BMT). Donor T cell populations that mediate GVHD can also mediate a graft-vs.-leukemia (GVL) effect that is commonly curative. Unfortunately, GVHD is difficult to control and often fatal. This application proposes to determine whether polymorphic segments of abundant hematopoietic differentiation antigens can serve as GVL targets. Leukemia therapy with T cells specific for antigens expressed only by hematopoietic cells might be curative without GVHD toxicity. The applicant's preliminary data show that T cells specific for polymorphic segments of CD45, and abundant differentiation antigen on all hematopoietic cells, can be elicited by immunization to peptides derived from polymorphic segments and can mediate vigorous responses against host lymphocytes and leukemia cells. The proposed experiments will determine whether T cells specific for polymorphic segments of CD45 and other abundant polymorphic hematopoietic differentiation antigens can mediate T cell therapy of leukemia and lymphoma without GVHD. The focus will be on therapy of B cell malignancies. The Specific Aims are: 1) To target T cell therapy against polymorphic segments of CD45; 2) To target T cell therapy against polymorphic segments of CD22; 3) To target T cell therapy against polymorphic segments of CD72; 4) To determine whether CD45, CD22, and CD72 are polymorphic in humans; 5) To compare therapy directed against the B cell differentiation antigens expressed by all B cells (CD22 and CD72) to antigens expressed by only subsets of B cells (polymorphic segments of the constant region of Ig heavy chain) and 6) To treat B cell malignancy in autologous hosts using autologous T cells transfected with T cell receptor (TCR) alpha and beta chains specific for polymorphic hematopoietic differentiation antigens.
