Intraperitoneal lymphokine-activated killer-cell and interleukin-2 therapy for malignancies limited to the peritoneal cavity.

Abstract

Autologous lymphokine-activated killer (LAK) cells and recombinant human interleukin-2 (rIL-2) were administered intraperitoneally (IP) to 24 patients with malignancies limited to the peritoneal space. Ten patients had ovarian cancer, 12 had colorectal cancer, and one patient each had endometrial carcinoma and primary small-bowel adenocarcinoma. All ovarian cancer patients, three of twelve colorectal cancer patients, and one patient with endometrial carcinoma had received prior therapy. Patients received IL-2 100,000 U/kg every 8 hours intravenously (IV) for 3 days, and 2 days later underwent daily leukapheresis for 5 days. LAK cells were generated in vitro by incubating the peripheral blood mononuclear cells in IL-2 for 7 days and were then administered IP daily for 5 days through a Tenckhoff catheter (Davol, Inc, Cranston, RI) together with IL-2 25,000 U/kg IP every 8 hours. All but one patient completed at least one cycle of therapy. Toxic side effects included minor to moderate hypotension, fever, chills, rash, nausea, vomiting, abdominal pain and distension, diarrhea, oliguria, fluid retention, thrombocytopenia, and minor elevations of liver function tests; all of these rapidly improved after discontinuation of IL-2. One patient had a grand mal seizure, and one suffered a colonic perforation; these were felt to be treatment-related. IP fibrosis developed in 14 patients and limited repeated cyclic administration of this therapy in five patients. Two of 10 (20%) ovarian cancer patients and five of 12 (42%) colorectal cancer patients had laparoscopy- or laparotomy-documented partial responses. We conclude that LAK cells and rIL-2 can be administered IP to cancer patients, resulting in moderate to severe short-term toxicity and modest therapeutic efficacy. Further investigation of this form of adoptive immunotherapy modified to address the problem of IP fibrosis and with lower IP IL-2 doses is justified by these initial results.

Cellular therapy in combination with cytokines improves survival in a xenograft mouse model of ovarian cancer

“…Early investigations using tumor infiltrating lymphocytes (TIL) for the treatment of ovarian cancer failed to demonstrate effectiveness, likely because of the inability to expand an adequate population of therapeutic cells [1]. Furthermore, specifics of the interplay between tumor micro-environment and many aspects of the host immune response were poorly described at that time.…”

Interleukin-2 in cancer treatment: Disappointing or (still) promising? A review

“…At this time a series of clinical trials with IL-2 alone or IL-2 plus LAK cells have shown response rates in patients with renal cell cancer and melanoma varying from 3% to 56% [9,15,17,57,58,67]. Responses have also been reported in patients with lymphoma [1], ovarian cancer, or colorectal cancer [73]. In patients with brain tumors [49,86] or bladder cancer [29] IL-2 immunotherapy has been unsuccessful so far.…”

Optimal regimes for local IL-2 tumour therapy

“…Many studies have been performed to improve the results and/or reduce treatment-related toxicity. In both experimental tumour models and human cancer patients it has been shown that S.C. or regional IL-2 administration results in better tolerance of the treatment without apparent loss of therapeutic efficacy (Ottow et al, 1987;Steis et al, 1990;Vaage, 1991;Sleijfer et al, 1992;Ravaud et al, 1994;Sone and Ogura, 1994). Also, evidence is accumulating that doses of less than 10% of the maximum tolerated dose are therapeutically effective (Cortesina et Bruton and Koeller, 1994;Yang et al, 1994).…”