Immunology of CLL I--Active immunotherapy & autologous stem cell transplantation

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The central hypothesis of this proposal is that there exist leukemia- associated antigens that can induce host anti-leukemia immunity resulting in leukemia-cell clearance. Furthermore, we hypothesize that because of the leukemia cell phenotype, such leukemia-specific T cells exist in a state o f anergy, thereby precluding effective immune-mediated clearance of the leukemic clone. Finally, we hypothesize that methods that alter this phenotype, or that induce immunity against leukemia-associated antigens, will provide novel and effective therapeutic strategies for patients with this disease. To examine this, we have the following specific aims: (1) Evaluate the potential for immunotherapy using autologous leukemia cells that have been: (A) genetically-modified to express recombinant CD40- ligand (CD154); or (B) induced to express immune co-stimulatory molecules through CD40-ligation ex vivo; (2) Determine the capacity of professional antigen presenting cells (APCs) to present B-CLL Ig specific antigens to induce anti-B-CLL specific immunity in vitro and in vivo by: (A) cloning and expressing the leukemia specific Ig; (B) identifying the putative peptide sequences from the B-CLL specific Ig rearrangements; (C) pulsing APCs with B-CLL specific Ig and Ig peptides; and (D) attempting to generate Ig specific cytotoxic T cells (CTL) using professional APCs pulsed with B-CLL specific Ig and Ig peptides; (3) examine the expressed T cell receptor V beta repertoires of blood T cells, T cell subsets, anti-leukemia CTL cell lines, and CD4+ T cells, or CD4+ T cell subsets expanded via CD3/CD28 ligation in vitro; (4) Undertake autologous stem cell transplantation (SCT) to address the impact on clinical outcome of : (A) purging; or (B) high dose myeloablative therapy; and (5) Determine the feasibility, safety, and efficacy of treating minimal residual disease following conventional therapy and autologous SCT using: (A) genetically modified CLL cells to express recombinant CD154; (B) CLL cells activated via CDE40 ex vivo; or (C) professional APC pulsed with B-CLL specific Ig and/or peptides. Through these studies we will test the hypothesis that patients with CLL can develop cellular immune recognition of their leukemia cells that potentially may be effective in the treatment of this disease.