Safety and Efficacy Study of Immunotherapy With Rituximab and Interleukin-2 in Patients With Non-Hodgkin's Lymphoma

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.

Inclusion Criteria:

- Histologically confirmed CD20 B cell non-Hodgkin's lymphoma

- Karnofsky performance status scores of 70 or greater (ECOG performance status 0 to 2).

- Age greater than 18.

- Eligible patients will start treatment between D+30 and D+100 from end of prior
therapy

- Patients have obtained a complete remission after induction chemotherapy or salvage
chemotherapy who are not candidates for autologous stem cell transplantation or at
least a partial remission after autologous transplantation (Stem cell collection, if
indicated, should be collected prior to starting therapy)

- International Prognostic Index (IPI)* or Follicular Lymphoma IPI (FLIPI)of 3 or more

- Adequate organ function that has been determined within 2 weeks prior to the study
entry, defined as:

- Absolute neutrophil count (ANC) >/=1000/mm3, platelets >/=100,000/mm3, and hemoglobin
>/=8 g/dl.

- Serum bilirubin < 1.5 times ULN and serum albumin > 2.0 g/dl.

- If female, neither pregnant (negative pregnancy test) nor breast-feeding.

- If of child bearing potential (< one year post-menopausal), must agree to practice an
effective method of avoiding pregnancy (including oral or implanted contraceptives,
intrauterine device, condom, diaphragm with spermicidal, cervical cap, abstinence or
sterile sex partner) from the time informed consent is signed.

- No other concurrent active malignancy requiring treatment.

- Able to render informed consent and to follow protocol requirements.

Exclusion Criteria:

- CNS lymphoma

- Presence of any other medical complications which imply a survival of less than three
months.

- Prior IL-2 therapy

- HIV or Viral Hepatitis

- Karnofsky performance score less than 70.

- Pregnancy or breast-feeding.

- Unable or unwilling to utilize contraception if of childbearing potential.

- Severe cardiovascular disease within 12 months including myocardial infarction,
severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic
congestive heart failure, cerebrovascular accident or transient ischemic attach,
pulmonary embolism, life threatening arrhythmias, or uncontrollable hypertension.

- Autoimmune disorders

- Concurrent immunosuppressive medications

- Concurrent systemic corticosteroids at doses greater than replacement levels

- Prior history of intolerance to rituximab