Dissecting the mechanistic basis of effective anti-leukemic immunityagainst chronic lymphocytic leukemia

• Applicant: Dr. Ute Elisabeth Burkhardt
• Subject Area: Hematology, Oncology
• Term: from 2013 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 246488301

For many patients with advanced B cell malignancies, allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides the only potentially curative treatment option. The crucial anti-leukemic principle of allo-HSCT is a graft-versus-leukemia effect (GvL), in which the donors immune cells target malignant cells of the patient. As relapse is the primary cause for treatment failure, the development of strategies for inducing more robust GvL responses remains a high priority.In this proposal, I seek to dissect the mechanistic basis for effective tumor immunity in patients with advanced chronic lymphocytic leukemia (CLL) who developed durable GvL effects without damage of normal tissues by graft-versus-host disease following early post-transplant tumor cell vaccination. My preliminary studies reveal that vaccination with a mixture of autologous, irradiated CLL cells and GM-CSF-producing bystander cells early after allo-HSCT is associated with induction of CLL-specific T cell responses and promising clinical activity.I hypothesize this intervention shapes the reconstituting donor T cell repertoire. Mature T cells contained within the allograft have the potential to immediately initiate proliferation and to replenish the T cell compartment of the lymphopenic host. These T cells may encounter antigens provided by the vaccine, leading to clonal expansion of antigen-specific T cell clones. I propose that tumor-specific T cell clones may be able to eliminate residual tumor cells in the bone marrow, and that this may in turn lead to improved T cell neogenesis from hematopoietic precursor cells that are transferred with the allograft. One way to gain insight into the regulation of T cell immune recovery in the vaccinated or control patients is to analyze their T cell receptor (TCR) repertoire diversity using recently developed methodologies that apply deep sequencing techniques for the analysis of the highly variable CDR3 region of the TCR beta-chains. I propose that a detailed analysis of T cell clonal dynamics will enable discernment of whether the hypothesized processes in fact are active in patients receiving autologous tumor cell vaccination following HSCT. The TCRb CDR3 repertoire measures will be integrated with the assessment of minimal residual disease, immunophenotyping and TCR excision circle analysis.With the proposed studies I expect to learn about (1) the mechanisms that underlie effective GvL responses that are associated with tumor rejection and (2) the kinetics and diversity of T cell repertoire recovery in transplant patients which in turn determines immune competence. Furthermore, these studies provide me with (3) molecular tags that will enable tracking of specific T cell populations, such as tumor-specific T cells, over time. The results of the herein proposed studies are anticipated to provide valuable information for the design and optimization of future leukemia cancer vaccine trials and for improving allo-HSCT procedures.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Dr. Catherine J. Wu