Low-dose intravenous bolus interleukin-2 with interferon-alpha therapy for metastatic melanoma and renal cell carcinoma.
Department of Surgery, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Canada.
High-dose therapy with interleukin-2 (IL-2) can produce significant responses in patients with metastatic melanoma (MM) and renal cell carcinoma (RCC). Several studies have shown the benefit of low-dose IL-2 in patients with RCC, but few studies have evaluated low-dose IL-2 in MM. We have used the following regimen: Interferon-alpha 10 million units subcutaneously on days 1, 3, 5, 8, 10, 12, 22, 24, and 26; and IL-2 60,000 IU/kg i.v. every 8 h on days 8-12 and 22-26. Patients had measurable MM or RCC and were excluded for ECOG status > 3, brain metastases, or significant cardiopulmonary or renal dysfunction. Between January 1993 and April 1996, 38 patients with MM and 14 with RCC were treated. In MM, there were six responses (15.7%; 95% confidence interval 4.1-27.3%) (i.e., one complete response and five partial responses). Responses were seen in visceral and nodal disease. Responses were of good duration: 40+, 26+, 13, 6, 4, and 3 months. One response was seen in the 14 RCC patients. Treatment was considerably less toxic than with high-dose IL-2. All treatment was given in a medical or surgical ward with intensive care necessary in only two patients. More than 80% of patients received > 80% of the predicted dose of IL-2. Dose-limiting toxicity consisted mainly of mild confusion or fatigue. In summary, this regimen is better tolerated and produces response rates within the range reported for high-dose IL-2 for patients with MM.
Effects of total parental nutrition (TPN) during high-dose interleukin-2 treatment for metastatic cancer.
Samlowski WE. Wiebke G. McMurry M. Mori M. Ward JH.
Department of Internal Medicine (Hematology/Onocology), Huntsman Cancer Institute, Salt Lake City, Utah, USA.
Patients treated with high doses of interleukin-2 (IL-2) develop profound anorexia, malaise, loss of energy, mucositis, nausea, and vomiting, which may contribute to poor nutrition. We hypothesized that total parenteral nutrition (TPN) administration would ameliorate these changes and could improve fluid and electrolyte balance. A retrospective analysis of protein and energy intake was performed in 21 sequential patients who received a normal diet (controls) and 16 subsequent patients who received TPN during IL-2 treatment. The effect of TPN on laboratory abnormalities induced by IL-2 was also evaluated. Within 24 h of starting IL-2, mean energy intake declined to 2.5-2.8 kcal/kg in controls in contrast to the energy intake of 25-29 kcal/kg in patients receiving TPN. Protein nutrition was affected in a similar fashion, with a markedly lower protein intake in controls (0.08-0.12 g/kg) than in the TPN group (1.02-1.10 g/kg). TPN improved serum calcium and potassium concentrations, particularly during spontaneous diuresis after completion of IL-2 treatment. Unexpectedly, TPN decreased the frequency and severity of cholestatic jaundice caused by IL-2. Patients receiving TPN had an increased propensity for hyperglycemia and hypophosphatemia. High-dose intravenous bolus IL-2 therapy resulted in a markedly negative nutritional balance in control patients. A brief period of TPN during IL-2 treatment was well tolerated and corrected calorie and protein malnutrition. TPN administration also improved control of serum electrolytes. TPN did not adversely affect tumor progression or patient survival.
Functional and molecular analysis of T cell receptors used by pancreatic- and breast tumor- (mucin-) specific cytotoxic T cells.
Kirii Y. Magarian-Blander J. Alter MD. Kotera Y. Finn OJ.
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pennsylvania 15261, USA.
We have previously reported that tumor-specific cytotoxic T lymphocytes (CTLs) derived from pancreatic and breast cancer patients recognize specific epitopes on the mucin polypeptide core. These CTLs recognize breast and pancreatic tumor cells in a major histocompatibility complex (MHC)-unrestricted fashion, and the lytic activity of these T cells is mediated through the T cell receptor (TCR). To characterize the TCR-mediated MHC-unrestricted CTL function, we used semiquantitative polymerase chain reaction (PCR) and cytofluorometry to analyze the TCR repertoire in CTL lines established from cancer patients and specific for mucin-expressing tumors. We found three TCR Vbeta genes, Vbeta9, Vbeta13.1. and Vbeta17, predominantly expressed in these functional cell lines, established either from one patient by stimulation with various mucin-expressing targets or from different patients. Sequencing of these preferentially used TCR genes unveiled usage of distinct Jbeta and Cbeta but a potentially interesting conservation of certain amino acids in the CDR3 region.