Chitra Hosing, M.D., Elizabeth Shpall, M.D., John Gribben, M.D., DSc University of Texas MD Anderson Cancer Center, Barts Cancer Center of Excellence/ The London School of Medicine (United Kingdom)

TRANSPLANTATION/IMMUNE RECONSTITUTION

Activating immune cells in CLL

Grant Awarded in 2008

Abstract:

Defects of the immune system have been described in CLL patients that make them highly susceptible to infections. Progressive dysfunction of the immune system often parallels disease progression. This CLL Alliance proposal includes two clinical trials with companion laboratory studies which will be performed by scientific teams in Houston and London, aimed at improving the clinical outcome of patients with CLL

In the first trial, immune cells (T-cells) will be harvested from patients with newly diagnosed CLL prior to the start of immunosuppressive chemotherapy. These cells will then be expanded and activated in our stem cell laboratory. The activated T-cells will then be infused back into the patients once the chemotherapy is completed. The hope is that the activated T-cells will reverse some of the immunological defects seen in CLL, thus reducing the risk of infections and potentially improve malignant disease control.

In the second trial, umbilical cord blood will be evaluated as a donor source of cells for CLL patients undergoing allogeneic stem cell transplantation who do not have an appropriately matched adult stem cell donor. A portion of the cord unit will be expanded and activated ex vivo (outside the body), and then will be trained to specifically kill CLL cells. These activated CLL-specific cells will be infused into the patient post-transplant. The hope is that the primary cord blood transplant and the subsequent activated T-cell infusion will eradicate the malignant CLL cells completely, leaving the patient with a normal immune system and long-term CLL-free survival.

Correlative laboratory studies will be performed to study the immune function of the patients before and after the T-cell therapy. We will determine how effective the activated T-cells are in fighting CLL and infections. Dr. John Gribben's laboratory has recently demonstrated that CLL cells interact directly with immune cells and decrease the ability of these cells to mount an effective immune response. His group now has data that CLL cells can also affect healthy immune cells, so there is the potential that CLL cells can decrease responses after allogeneic transplantation. They have developed evaluation tools to be able to assess the impact of CLL on immune cell responses.

A more important assessment will be whether new treatments, including expansion of these cells or use of alternative stem cell donor sources such as cord blood cells, are able to prevent or reverse the defects induced by CLL cells. As part of the Alliance grant, the experiment shall be refined and automated for use in the two clinical trials.