Project: Research project

Project Details


DESCRIPTION: (Applicant's Abstract) Graft versus leukemia effect observed after
allogeneic bone marrow transplant for chronic myelogenous leukemia (CML)
demonstrates that CML can be recognized by the immune system. Nonetheless, the
disease does not elicit a spontaneous effective immune response. The applicant
postulates that CML-associated antigens do not stimulate immunity because they
are not presented in the proper cellular and molecular context. He hypothesizes
that ex vivo matured dendritic cells (DC) provide proper presentation of
CML-associated antigens and that such DC are effective in stimulating
CML-specific immunity in patients. In this translational project, he proposes
to prime the immune response against CML by ex vivo matured reinfused
autologous leukemic dendritic cells and to define methods to further enhance
the effectiveness of priming and boosting the immune response. In Specific Aim
1, he will maximize expression and presentation of endogenous CML-associated
antigens by mature autologous leukemic dendritic cells and stimulate a
CML-specific immune response in a Phase I/II clinical trial. He will measure
immunization-induced changes in CML-specific immune effector cells and
correlate the changes with the status of disease; immunotherapy protocols often
involve boosting with dendritic cells, yet the effects on the dynamics of T
cell response are not fully understood. In Specific Aim 2, he will compare the
effectiveness of cells presenting bcr-abl in the presence and in the absence of
costimulatory molecules for boosting the immune response. In Specific Aim 3, he
will express in dendritic cells the human IL-2 gene introduced by infection
with recombinant adenovirus and test the cells for efficacy of expanding the
CML-specific T cell response in vitro. The clinical study will provide
information on: 1. the safety of autologous ex vivo matured dendritic cells
derived from CD14-selected cells; 2. efficacy of mature leukemic dendritic
cells in controlling CML, and 3. the relationship between the level of T-cell
response and tumor burden in CML patients. Laboratory studies will 1) identify
the cells optimal for boosting immunity in vitro and 2) maximize CML-specific
T-cell responses using CML-DC genetically modified to express and secrete IL-2.
The combined data will provide a comprehensive understanding of the interaction
of the immune system and CML and will yield information required for the
rational design of more effective clinical protocols in the future.
StatusNot started


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