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Plasma sIl-2R and sCD8 levels of 12 patients with renal cell carcinoma were determined before and during subcutaneous rIl-2 therapy. Patients with a complete/partial remission showed a significantly stronger initial increase of sCD8 compared to patients with stable disease or tumour progression.

We report the immunomodulatory effects of an intravenous treatment with F(ab')2 fragments of the bispecific monoclonal antibody BIS-1 during subcutaneous recombinant interleukin 2 (rIL-2) therapy of renal cell cancer (RCC) patients. BIS-1 is directed against both the CD3 antigen on T cells and the EGP-2 molecule on carcinoma cells and some normal epithelia. The amount of BIS-1 F(ab')2 bound to peripheral blood lymphocytes (PBLs) increased dose-dependently. This occupation degree was highest at the end of the 2 h infusion and rapidly decreased subsequently. During the first hour of BIS-1 F(ab')2 infusion the number of PBLs decreased slowly. This was followed by an increase in serum tumour necrosis factor alpha (TNF-alpha) concentrations and a rapid decrease in the numbers of peripheral blood lymphocytes, monocytes and eosinophils. In our view, the most likely explanation for the observed decrease in occupation degree of BIS-1 F(ab')2 and the rise in TNF-alpha levels is based on the assumption that BIS-1-carrying T cells leave the circulation. The CD3 antigens on these extravasated T cells become cross-linked by EGP-2 antigens, inducing TNF-alpha secretion. This results in an enhanced decrease in the numbers of PBLs, monocytes and eosinophils. These preliminary results suggest that BIS-1 F(ab')2 treatment during IL-2 therapy may induce local T-cell activation.

In a phase I trial the toxicity and immunomodulatory effects of combined treatment with intravenous (i.v.) bispecific monoclonal antibody BIS-1 and subcutaneous (s.c.) interleukin 2 (IL-2) was studied in renal cell cancer patients. BIS-1 combines a specificity against CD3 on T lymphocytes with a specificity against a 40 kDa pancarcinoma-associated antigen, EGP-2. Patients received BIS-1 F(ab')2 fragments intravenously at doses of 1, 3 and 5 micrograms kg-1 body weight during a concomitantly given standard s.c. IL-2 treatment. For each dose, four patients were treated with a 2 h BIS-1 infusion in the second and fourth week of IL-2 therapy. Acute BIS-1 F(ab')2-related toxicity with symptoms of chills, peripheral vasoconstriction and temporary dyspnoea was observed in 2/4 and 5/5 patients at the 3 and 5 micrograms kg-1 dose level respectively. The maximum tolerated dose (MTD) of BIS-1 F(ab')2 was 5 micrograms kg-1. Elevated plasma levels of tumour necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) were detected at the MTD. Flow cytometric analysis showed a dose-dependent binding of BIS-1 F(ab')2 to circulating T lymphocytes. Peripheral blood mononuclear cells (PBMCs), isolated after treatment with 3 and 5 micrograms kg-1 BIS-1, showed increased specific cytolytic capacity against EGP-2+ tumour cells as tested in an ex vivo performed assay. Maximal killing capacity of the PBMCs, as assessed by adding excess BIS-1 to the assay, was shown to be decreased after BIS-1 infusion at 5 micrograms kg-1 BIS-1 F(ab')2. A BIS-1 F(ab')2 dose-dependent disappearance of circulating mononuclear cells from the peripheral blood was observed. Within the circulating CD3+ CD8+ lymphocyte population. LFA-1 alpha-bright and HLA-DR+ T-cell numbers decreased preferentially. It is concluded that i.v. BIS-1 F(ab')2, when combined with s.c. IL-2, has a MTD of 5 micrograms kg-1. The treatment endows the T lymphocytes with a specific anti-EGP-2-directed cytotoxic potential.

The phenotype of peripheral blood lymphocytes of 27 renal cell carcinoma patients before and at the end of subcutaneously given rIL-2 therapy was determined by two colour flow cytometry. Therapy induced changes in peripheral blood leucocyte composition and phenotypes were comparable to those reported for intravenously given rIL-2. The present paper shows a correlation between the 'activation status' of the patient before therapy and eventual response.

RECOMBINANT INTERLEIJKIN 2 (IL-2) has opened a new approach in the treatment of renal cell carcinoma [ 11. Because of the severe toxicity related to intravenous IL-2, this therapy appears only suitable for fit patients in which special attention is given to renal, cardiovascular and pulmonary function. Many patients with renal cell carcinoma are therefore not eligible for intravenous IL-2 treatment. Subcutaneously administered IL-2 alone, or combined with interferon alfa on an outpatient basis, can induce tumour regression in up to 20% [2-6]. Toxicity consists of fever and chills, local inflammation, anorexia, nausea, vomiting and hypotension. None of these side-effects requires hospitalisation, and are acceptable even in patients with major organ disfunction. We describe here the application of a subcutaneous IL-2 regimen in two patients on haemodialysis, with special emphasis on toxicity and immunological parameters. The first patient, male, born in 1934, underwent a nephrectomy of the right kidney (1965) for nephrolithiasis and of the left kidney for a renal cell carcinoma (1989), followed by dialysis, which was complicated by ventricular and supraventricular ectopic arrhythmias. The second patient, male, born in 1915, underwent a nephrectomy for a renal cell cancer of the left (1980) and of the right kidney (1986). Subcutaneous IL-2 (EuroCetus) was started for progressive lung metastases in both patients in a 5-day cycle, every week for 6 weeks, at a dose of 18x IO6 I.U. daily in the first cycle, while the dose in the first 2 days of the following cycles was reduced to 9x lo6 U; both patients received paracetamol. Toxicity of IL-2 consisted of transient inflammation and local induration at the injection sites, fever and chills WHO grade II, anorexia, nausea, vomiting and diarrhoea grade I, an increase in serum levels of alkaline phosphatase to 409 and 179 U/l, respectively (n 5 120), lactate dehydrogenase to 416 and 327 U/l (n 5 235) and gammaglutamyl transferase to 300 and 158 U/l (n 5 65). The leucocyte count rose to a maximum of 16.2 and 27.3 x 109/1, respectively (n = 4.0-11.0). Blood pressure decreased to a lowest value of 90/60 and 75/50 mmHg, respectively. No vasopressors were used. Fluid retention, weight gain and nephrotoxicity could not be evaluated because of the haemodialysis, which was continued two times a week in both patients and later, three times a week