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Methods for treating renal cell carcinomaRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Lymphokine, InterleukinMethods for treating renal cell carcinoma description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070014765, Methods for treating renal cell carcinoma. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims benefit under 35 U.S.C. .sctn. 119(e) of provisional application 60/647,496, filed Jan. 27, 2005, which application is hereby incorporated by reference in its entirety. TECHNICAL FIELD [0002] The present invention pertains generally to methods for treating renal cell carcinoma with IL-2. In particular, the invention relates to methods of treating renal cell carcinoma in patients who are renally impaired or intolerant of high-dose IL-2 therapy. BACKGROUND [0003] Interleukin-2 (IL-2) is a potent stimulator of natural killer (NK) and T-cell proliferation and function (Morgan et al. (1976) Science 193:1007-1011). This naturally occurring lymphokine has been shown to have anti-tumor activity against a variety of malignancies either alone or when combined with lymphokine-activated killer (LAK) cells or tumor-infiltrating lymphocytes (TIL) (see, for example, Rosenberg et al., N. Engl. J. Med. (1987) 316:889-897; Rosenberg, Ann. Surg. (1988) 208:121-135; Topalian et al., J. Clin. Oncol. (1988) 6:839-853; Rosenberg et al., N. Engl. J. Med. (1988) 319:1676-1680; and Weber et al., J. Clin. Oncol. (1992) 10:33-40). The anti-tumor activity of IL-2 has best been described in patients with metastatic melanoma and renal cell carcinoma using Proleukin.RTM., a commercially available IL-2 formulation from Chiron Corporation, Emeryville, Calif. Other diseases, including lymphoma, also appear to respond to treatment with IL-2 (Gisselbrecht et al., Blood (1994) 83:2020-2022). However, high doses of IL-2 used to achieve positive therapeutic results with respect to tumor growth frequently cause severe side effects, including fever and chills, hypotension and capillary leak (vascular leak syndrome or VLS), and neurological changes (see, for example, Duggan et al., J. Immunotherapy (1992) 12:115-122; Gisselbrecht et al., Blood (1994) 83:2081-2085; and Sznol and Parkinson, Blood (1994) 83:2020-2022). [0004] Metastatic renal cell carcinoma (RCC) is generally resistant to chemotherapy, either with single agents or with multiple agents in combination. Greater success has been seen with immunotherapy, particularly with the use of IL-2. Therapy with high dose intravenous IL-2 has resulted in objective tumor responses in approximately 15% of patients, some with long durability. However, the administration of high dose IL-2 is associated with capillary leak syndrome, which results in hypotension and reduced organ perfusion, which can be severe and sometimes fatal. These toxicities have generally restricted the use of IL-2 to a highly selected group of patients administered by physicians with significant experience in its administration. The use of lower-dose and subcutaneously administered regimens of IL-2 alone or in combination with other biologic agents, such as interferon-.alpha., has been explored in an effort to develop a more broadly applicable therapy for this disease (see, for example, Nieken et al., Cancer Biother. Radiopharm. (1996) 11:289-295; Sleijfer et al., J. Clin. Oncol. (1992) 10:1119-1123; Lessoni et al., Anticancer Res. (2002) 22:1061-1-1064; Tourani et al., J. Clin. Oncol. (1998) 16:2505; and Schiller et al. Cancer Res. (1993) 53:1286-1292). [0005] There remains a need for an improved therapy for treating patients having renal cell carcinoma that would reduce toxicity and improve therapeutic efficacy. SUMMARY OF THE INVENTION [0006] The present invention provides an efficacious method for treating renal cell carcinoma with IL-2. The method utilizes a relatively low dose of IL-2 compared to dosages used previously in high dose IL-2 therapies in order to reduce toxicity. As shown in the examples herein, this therapeutic regimen significantly inhibits tumor growth with reduced adverse side effects and provides an alternative treatment for patients who cannot tolerate high dose IL-2 therapy. [0007] In one aspect, the invention provides a method for treating a human patient having renal cell carcinoma. In certain embodiments, the patient is renally impaired. In certain embodiments, the renal cell carcinoma is metastatic. In certain embodiments, the patient is intolerant of high dose IL-2 treatment. [0008] In one embodiment, the method comprises: a) administering a dose of 1-52 MIU of IL-2 per day, in 1-3 doses a day, for 3-6 days a week, repeated for 1-24 weeks; and b) administering no IL-2 for 1-4 weeks. [0009] In another embodiment, the method comprises: a) administering a dose of 1-52 MIU of IL-2 every 5 days to 1 month, repeated for 1-24 weeks, wherein the IL-2 is covalently conjugated to polyethylene glycol or polyoxyethylated polyol; and b) administering no IL-2 for 1-4 weeks. [0010] In a further embodiment, the method comprises: a) administering a dose of 9-18 MII of IL-2 per day, in 1-3 doses a day, for 3-6 days a week, repeated for 1-24 weeks; b) administering no IL-2 for 1-4 weeks; c) administering a dose of 9 MIU of IL-2 per day, in 1-3 doses a day, for 3-6 days a week, repeated for 1-24 weeks; and d) administering no IL-2 for 1-4 weeks. [0011] In yet another embodiment, the method comprises: a) first, administering a dose of 18 MIU of IL-2 per day for 5 days during one week; b) second, administering a dose of 9 MIU of IL-2 per day for 2 days followed by administering a dose of 18 MIU of IL-2 per day for 3 days during each week, repeated for 5 weeks; c) third, administering no IL-2 for 3 weeks; d) fourth, administering a dose of 9 MIU of IL-2 per day for 5 days of each week, repeated for 6 weeks; and e) fifth, administering no IL-2 for 3 weeks. [0012] In any of the methods described herein, the IL-2 can be recombinantly produced IL-2. The IL-2 can include human IL-2 or variants thereof comprising a sequence having at least about 70-100% sequence identity to the sequence of human IL-2 (SEQ ID NO:1), including any percent identity within these ranges, such as 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100% sequence identity thereto. In certain embodiments, the IL-2 is an IL-2 mutein, for example, but not limited to, Ala.sub.104 Ser.sub.125 IL-2; des-Ala.sub.1 des-Pro.sub.2 des-Thr.sub.3 des-Ser.sub.4 Ala.sub.104 Ser.sub.125 IL-2; and des-Ala.sub.1 des-Pro.sub.2 des-Thr.sub.3 des-Ser.sub.4 des-Ser.sub.5 des-Ser.sub.6 IL-2. In a preferred embodiment, the IL-2 mutein is des-alanyl-1, serine-125 human interleukin-2 (aldesleukin). [0013] In certain embodiments, the IL-2 is conjugated to a polyethylene glycol. Exemplary polyethylene glycols include, but are not limited to, a polyethylene glycol having an average molecular weight of 1,000 to 40,000 daltons, a polyethylene glycol having an average molecular weight of 2,000 to 20,000 daltons, and a polyethylene glycol having an average molecular weight of 3,000 to 12,000 daltons. [0014] In other embodiments, the IL-2 is covalently conjugated to a polyoxyethylated polyol. Exemplary polyoxyethylated polyols include, but are not limited to, polyoxyethylated sorbitol, polyoxyethylated glucose and polyoxyethylated glycerol. In certain embodiments, the polyoxyethylated polyol is a polyoxyethylated glycerol having an average molecular weight of 1,000 to 40,000. [0015] In any of the methods described herein, multiple cycles of the method of treatment can be administered to the subject for a time period sufficient to effect at least a partial tumor response. In certain embodiments, the time period is at least 6 months. In certain embodiments, the time period is at least 12 months. In certain embodiments, the time period is sufficient to effect a complete tumor response. [0016] In certain embodiments, the method of treatment further comprises multiple cycles of a treatment comprising: a) administering a dose of 9 MIU of IL-2 per day, in 1-3 doses a day, for 3-6 days a week, repeated for 1-24 weeks; and b) administering no IL-2 for 1-4 weeks; administered to said subject for a time period sufficient to effect at least a partial tumor response. [0017] In any of the methods described herein, the IL-2 can be administered by subcutaneous, intraperitoneal, intramuscular, intravenous, oral, pulmonary, nasal, topical, or transdermal administration, or by infusion or suppositories. In a preferred embodiment, the IL-2 is administered subcutaneously. [0018] These and other embodiments of the subject invention will readily occur to those of skill in the art in view of the disclosure herein. BRIEF DESCRIPTION OF THE FIGURES [0019] FIG. 1 compares the relative efficacy of low dose IL-2 in patients with metastatic renal cell carcinoma having normal (serum creatinine (SCr) 1.5 mg/dL) and impaired renal function (SCr>1.5 mg/dL) following the administration regimen described in Example 3. FIG. 1 shows a plot of the percentage of subjects exhibiting progression free survival (PFS) versus time in years and a plot of the percentage of surviving subjects versus time in years. Continue reading about Methods for treating renal cell carcinoma... Full patent description for Methods for treating renal cell carcinoma Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Methods for treating renal cell carcinoma patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. 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