The long term goal of this study is to develop successful immunotherapy for human renal cell carcinoma based on the adoptive transfer of autologous, mononuclear leukocytes (PBM) activated in a novel way (combined treatment with sodium periodate (IO-4) and recombinant IL2 (rIL2)) along with systemic administration of rIL2, with the goal of reducing toxicity and maintaining or enhancing efficacy of this therapeutic approach. Treatment of human PBM with IO4, induces the expression of IL2 receptors and enhances cytotoxicity for tumor targets induced by IL2.
The first aim of this study is to conduct a Phase II trial to determine response rates of patients with metastatic renal cell carcinoma receiving autologous PBM activated with IO-4 and IL2 along with continuous infusion of low dose IL2. The next major aim is to conduct a Phase III trial comparing response rates of patients treated with cells activated with IO-4 and IL2 with response rates of patients treated with cells activated with IL2 alone, keeping all other aspects of the protocol the same. We have shown in preliminary studies that the dose and route of administration of rIL2 that we propose to use (continuous infusion, 5 days/week, maximum dose 50,000 mu/kg/24 hrs) results in regression of renal cell carcinoma metastatic lesions when combined with adoptive transfer of cells activated by the combined action of IO-4 and rIL2. This protocol was not associated with severe fluid retention or life-threatening toxicity. The Phase II study will take approximately one year to complete treatment in a total of 40 patients. We will then study additional patients over a 2 year period to compare IO4/IL2 activated cells with cells activated with IL2 alone (LAK cells) in patients receiving systemic rIL2. The patients will have metatastic renal cell carcinoma (biopsy proven) and will be stratified and assigned to either arm of this protocol. Toxicity and effects on evaluable tumor will be evaluated. Homing patterns of activated cells will be studied using III Indium labelling and scanning with a gamma detector. We will monitor circulating IL2 levels, antibodies to IL2 (by an ELISA method) and cytotoxicity of patients PBM for a variety of tumor targets. These targets will include freshly prepared renal carcinoma cells, a renal cell cancer line, and an NK sensitive target. Methodology and feasibility for on-line activation of lymphoid cells for adoptive immunotherapy will be investigated using a murine tumor model.
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