[CANCER RESEARCH 50. 6708-6715. October 15. 1990] Subcutaneous Recombinant Interleukin 2 in a Dose Escalating Regimen in Patients with Metastatic Renal Cell Adenocarcinoma1 Robert P. Whitehead,2 Dave Ward, Lucy Hemingway, George P. Hemstreet III, Edward Bradley, and Michael Konrad Departments of Medicine [R. P. W.] and Urology [D. W., L. H., G. P. HJ, University of Oklahoma, Oklahoma City, Oklahoma 73190, and Cetus Corporation [E. B., M. K.J, Emeryville, California 94608 ABSTRACT Recombinant human interleukin 2 (rIL-2) was administered by s.c. injection daily, 5 days/week to patients with metastatic renal cell carci noma in an escalating dose regimen. Fifteen patients were entered in this study and are évaluable for toxicity with one patient not évaluable for response because of lack of measurable disease. The patient population had a median age of 63 years with initial performance status (Southwest Oncology Group criteria) of 0 in one patient, 1 in eight patients, and 2 in six patients. The starting dose was 5 x 10s Cetus units/m2/day with dose escalation to 1 x IO6, 2 x 10', 4 x IO6, and 5 x 10' Cetus units/m2/day scheduled at 2-week intervals if no significant toxicity or response was noted. Six patients were treated with drug doses of 2 x 10' Cetus units/ in-'/day or higher with a maximum daily dose achieved of 2 x 10' units/ nr in two patients, 4 x 10' units/m2 in two patients, and 5 x 10' units/ nr in two patients. Fatigue with decrease in performance status and elevations in serum creatinine were the most common reasons for limiting the dose or removing a patient from the study. Only one minor anti- tumor response was seen. Subcutaneously administered rIL-2 was able to alter immunological parameters. In two of the three patients tested, development of lympho- kine-activated killer cell activity in vivo was seen, and statistically significant enhancement of natural killer cell activity compared to values from a concurrently run normal control was demonstrated. With treat ment, there was a trend toward increased numbers of circulating total lymphocytes, OKT 8+, OKT 11+, Leu 7+, and Leu lla+ cells and decreased numbers of circulating OKT 3+ and OKT 4+ cells. However, for the heterogeneous group of six patients monitored, results were not statistically significant compared to pretreatment values. The levels of rIL-2-speciiîc antibodies were followed in the sera of 10 patients. Six of the 10 developed rIL-2-specific IgG during treatment with five of the six patients also developing neutralizing activity. Recombinant human interleukin 2 given by the s.c. route in the doses and schedule used in this trial can safely be given as an outpatient regimen with manageable toxicity. It may result in enhanced immune function in some patients but also results in a high incidence of antibody formation. INTRODUCTION Renal cell adenocarcinomas are relatively uncommon neo plasms, making up about 3% of all malignant tumors in adults. However, both the incidence and mortality of this tumor have been increasing since the 1930s (1). For localized disease, surgery for cure is the appropriate treatment. As many as one- half of patients may already have metastatic disease at the time of presentation, with the most common sites of métastases being the lungs, bones, liver, and lymph nodes (1,2). Hormonal therapy and chemotherapy are minimally effective for control ling metastatic disease with incomplete and usually brief re- Received2/1/89;accepted7/11/90. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. ' This research was supported in part by funds from Cetus Corporation, Emeryville, CA. 2 To whom requests for reprints should be addressed, at University of New Mexico Cancer Center, 900 Camino de Salud N.E., Albuquerque, NM 87131. sponses (3). Because of the spontaneous regressions rarely observed in renal cell carcinoma patients and the documented immune responses to these tumors (4), a number of immunoth- erapeutic trials have been initiated (5). Interferons, which have both growth inhibitory and immunomodulatory properties, have been tested in several routes and schedules with data from four different trials showing an overall response rate of 14% in 84 patients (6). IL-2,3 a lymphokine produced by helper T-lymphocytes, is a nonspecific immunopotentiator of cell-mediated immunity. In terleukin 2 corrects the immune deficiency of nude mice in vivo (7) and augments the generation of alloreactive cytolytic T- lymphocytes in alloimmunized mice and NK cells in nonim- munized mice (8). In addition, cancer patients' lymphocytes incubated in vitro with interleukin 2 lyse fresh or cultured tumor cells (9). Initial studies in mice demonstrated that these LAK cells can be generated in vivo by the administration of rIL-2 and the tumor burden can be reduced in treated animals (10). Treatment of renal cell carcinoma and melanoma patients with high dose i.v. rIL-2 alone or rIL-2 plus LAK cells generated in vitro has resulted in objective tumor regression (11-13). This trial was undertaken to determine the effects of s.c. adminis tered rIL-2 in renal cell carcinoma patients. The following measurements were monitored: serum drug levels at various times after treatment, serum antibody development, and deter mination of absolute numbers of lymphocyte subsets by FACS analysis, as well as in vitro lymphocyte lytic activity against natural killer cell-sensitive and -resistant tumor cell lines. MATERIALS AND METHODS Patient Selection. Eligible patients were 18 years of age or older with a histologically confirmed diagnosis of renal cell carcinoma and meas urable or évaluable metastatic disease that could not be cured surgically or with radiation therapy. Untreated patients and patients treated previously with hormonal therapy and/or chemotherapy, radiation therapy, or immunotherapy were eligible as long as a minimum of 3 weeks had elapsed since completion of the previous treatment and, if necessary, there had been progression of disease outside of previous radiation fields. Additional qualifications required for eligibility in cluded a performance status of <2 as defined by Southwest Oncology Group criteria (thus ambulatory >50% of the day), a WBC count of >4000/mm3 with 21500 granulocytes/mm3, a platelet count of >100,000/mm\ and a serum creatinine of <2.5 mg/dl, a serum aspar- tate aminotransferase <50/IU/liter, and a total bilirubin <1.5 mg/dl. Patients had to be fully recovered from any prior surgery, with no evidence of severe symptomatic cardiovascular disease, i.e.. New York Heart Association class III or IV, or serious active infections. Pregnant or lactating women were not eligible, nor were patients with organ allografts or symptomatic central nervous system metastasis or other primary' neoplasm (except for skin basal cell carcinoma or surgically 3The abbreviations used are: IL-2, interleukin 2; rIL-2. recombinant human interleukin 2; LAK, lymphokine-activated killer cell: I'llM. peripheral blood mononuclear cell; FACS, fluorescence-activated cell sorter; NK, natural killer; ELISA, enzyme-linked immunosorbent assay; PS, performance status. 6708 on May 3, 2017. © 1990 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from