High Risk Non-Hodgkin's Lymphoma Clinical Trial
Official title:
Phase II Study of IL-2 and Rituximab Maintenance in High Risk B Cell Non-Hodgkin's Lymphoma
This is a study to see if maintenance therapy with low dose interleukin-2 (IL-2) and rituximab can delay or prevent recurrences in patients with high risk Non-Hodgkin's Lymphoma (NHL). IL-2 is a naturally occurring cytokine in our immune system which may enhance the activity of a known therapeutic agent rituximab, a monoclonal antibody against CD-20, in the setting of NHL.
Interleukin 2 (IL-2) is a naturally circulating cytokine produced by immune cells including T
cells, dendritic cells and thymic cells. IL-2 is an integral part of T cell proliferation,
autoimmunity and self-tolerance. Low dose IL-2 has been studied as maintenance therapy
following autologous stem cell transplantation in Non-Hodgkin's Lymphoma. One early study
showed that low dose IL-2 at dose of 3 million units per m2 twice a week for one year
increased the activity and absolute number of natural killer (NK) cells which are a type of
cytotoxic lymphocyte that is a major component of our innate immune system. More importantly,
this dose of IL-2 prolonged time to progression in 9 patients with residual disease after
autologous transplant and induced sustained complete remissions in two more patients. NK
cells are involved in tumor killing via antibody dependent cell cytotoxicity, release of
cytotoxic granules causing direct tumor killing and expression of ligands that trigger
apoptosis or programmed cell death. In that study, no changes were seen in regulatory T cells
which have been recently found to exert an inhibitory effect on NK cell function and hence
limit the NK cell's ability to exert an anti-tumor effect.2,5 Because both regulatory T cells
and NK cells express the IL-2 receptor, higher doses of IL-2 administration (14MIU SQ thrice
weekly) would expand both populations of cells which may explain the lack of benefit seen in
other clinical studies. At lower doses of 3MIU SQ twice weekly used in the earlier study, we
anticipate selective upregulation of NK cells without effecting regulatory T cells.
Rituximab is a monoclonal antibody against CD20 antigen that is expressed in most B cell
lymphomas. It is commonly used in the treatment of B cell lymphomas either alone or in
combination with other therapy. It has been used as part of initial treatment after diagnosis
as well as re-treatment if lymphoma recurred. It has also been studied as maintenance therapy
in relapsed or resistant follicular lymphoma showing that rituximab delayed disease
progression compared to the group who did not receive maintenance rituximab.11 The mechanism
of action of rituximab includes complement mediated cytotoxicity, antibody dependent cellular
cytotoxicity, induction of apoptosis and sensitization of cancer cells to cytotoxic
chemotherapy. Antibody dependent cellular cytotoxicity is mediated by NK cells, macrophages
and monocytes.13 The purpose of this study is to determine if the combination of low dose
IL-2 plus rituximab is more effective than low dose IL-2 alone after primary or salvage
therapy.
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