Therapy of advanced solid tumors in mice using chemotherapy in combination with interleukin-2 with and without lymphokine-activated killer cells.
Adoptive immunotherapy with LAK-cells in conjunction with high-dose IL-2 has recently been introduced in the treatment of patients with advanced cancer. This therapeutic modality has thus far proved to be of limited efficacy, severe toxicity and entails complicated logistics. Our present study is aimed at establishing a model system to test for increasing efficacy and reducing toxicity by using AIT cojointly with chemotherapy. Mice implanted i.v. or i.p. with weakly immunogenic tumors (M109 lung carcinoma, MCA-105 sarcoma) were treated 7 to 20 days after tumor inoculation with or without CTX, with and without recombinant human IL-2, and with and without syngeneic/allogeneic LAK-cells. Whereas IL-2 or IL-2 + LAK-cells without CTX was largely ineffective, and CTX alone cured 0 to 20% of the animals with an i.p. tumor and only slightly reduced pulmonary tumor mass, the combination of CTX + IL-2 cured 50 to 80% of the mice bearing i.p. tumors and reduced pulmonary tumor growth by greater than or equal to 80%. The combination of CTX + IL-2 + LAK-cells proved no more beneficial than CTX + IL-2 without LAK-cells. Also relevant were the observations that murine LAK-cells are transiently sensitive to moderate doses of CTX (greater than or equal to 100 mg/kg body weight) and X-irradiation (greater than equal to 400 rad), and that administration of IL-2 by the i.v. or i.p. route variously affects LAK-cell activation in different tissues and eradication of growths localized at different sites. With the regimens used, no signs of toxicity were detected. It is proposed that instillation of IL-2 (and perhaps of additional immunostimulating cytokines as well) as an adjunct to chemotherapy (or chemoradiotherapy), each given at a subtoxic dose, is both safe and effective in the treatment of metastatic advanced tumors, and that the additional administration of LAK-cells may not be required.
Kedar
E
E
Lautenberg Center for General and Tumor Immunology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Ben-Aziz
R
R
Shiloni
E
E
D000230:Adenocarcinoma / Q000188:drug therapy / Q000628:therapy*; D000818:Animals; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage*; D007376:Interleukin-2 / Q000008:administration & dosage*; D007694:Killer Cells, Natural; D008175:Lung Neoplasms / Q000188:drug therapy / Q000628:therapy*; D008214:Lymphocytes / Q000187:drug effects / Q000528:radiation effects; D008222:Lymphokines / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000628:therapy*
D007376:Interleukin-2; D008222:Lymphokines; D003520:Cyclophosphamide