caa a22 4500 397563647 CHVBK 20180308164822.0 cr unu---uuuuu 161202e19960918xx s 000 0 eng 10.1093/jnci/88.18.1276 doi (NATIONALLICENCE)oxford-10.1093/jnci/88.18.1276 Predominance of TH1 Response in Tumor-Bearing Mice and Cancer Patients Treated With AS 101 [Elektronische Daten] [Benjamin Sredni, Thomas Tichler, Adi Shani, Rafael Catane, Bella Kaufman, Gideon Strassmann, Michael Albeck, Yona Kalechman] Background Several studies have recently suggested that the immune response to malignant growths is regulated by distinct patterns of type 2 cytokine production. These cytokines, regulating the cytotoxic T-lymphocyte response in patients with advanced cancers, may be associated with disease progression. Evidence suggests that the T Helper 1 (TH1) and T Helper 2 (TH2) types of reaction are reciprocally regulated in vivo. The immunomodulator AS101 (ammonium trichloro [dioxoethylene-O,O'] tellurate) was found to stimulate mouse and human cells to proliferate and secrete a variety of cytokines. Clinical trials using AS101 on cancer patients are now in progress. Purpose The aim of this study was to evaluate the ability of AS101 to modulate TH1 and TH2 responses in tumor-bearing mice and in patients with advanced cancer. In addition, we investigated the association between the predominance of each type of response with the antitumoral effects of AS101. Methods Mice into which Lewis lung carcinoma (3LL) had been transplanted (n = 221) and cancer patients (n = 13) were treated with AS101 on alternate days, at 10μg/mouse intraperitoneally, or for the patients, at 3 mg/m2 intravenously. The types were sarcoma, melanoma, and colon, lung, ovarian, and renal cancers. Cytokine levels were determined by immunoassay kits and compared with the paired Student's t test: in mice, they were tested in spleen cell supernatants; in humans, in sera and mononuclear cell supernatants. The chi-squared test was used to compare tumor volumes. All P values represent two-sided tests of statistical significance. Results Our results show that treatment of mice and patients with AS101 results in a clear predominance in TH1 responses, with a concomitant decrease in the TH2-type response. This was reflected by a significant enhancement in interleukin 2 (IL-2) and interferon gamma (IFN γ) levels (P<.01) paralleled by a substantial decrease in IL-4 and IL-10 (P<.01). Moreover, the concentration of IL-12 was significantly increased (P<.01) in AS101-treated patients who also showed enhanced levels of natural and lymphokine-activated killer cell-mediated cytotoxicity. The statistically significant increases in IL-2 and IFN γ levels, paralleled by the pronounced decrease in IL-4 and IL-10 in the AS101-treated mice, were associated with its antitumoral effects. In addition, systemic contreatment of 3LL-transplanted mice with AS101 and anti-IL-12 antibodies partly abrogated the antitumoral effect of AS101. Conclusions Immunotherapy with AS101 enhances TH1 function while interfering with the TH2 response. This TH1 trend may be related to the antitumor effects of AS101. Implications Isolation and characterization of a distinct cytokine pattern in patients with advanced cancer treated with AS101 may contribute to the development of intervention strategies using this compound. [J Natl Cancer Inst 1996; 88: 1276-84] © Oxford University Press ARTICLES nationallicence Sredni Benjamin Cancer, AIDS, and Immunology Research Institute, Marilyn Finkler Cancer Research Center, Department of Life Sciences. Bar-Han University Ramat-Gan, Israel aut Tichler Thomas Department of Oncology, Shcba Medical Center Tel-Hashomer, Ramat Gan aut Shani Adi Department of Oncology, Kaplan Hospital Rehovot, Israel aut Catane Rafael Department of Oncology, Hadassah Hospital Jerusalem, Israel aut Kaufman Bella Department of Oncology, Hadassah Hospital Jerusalem, Israel aut Strassmann Gideon Otsuka-American Pharmaceutical Inc. Rockville, MD aut Albeck Michael Cancer, AIDS, and Immunology Research Institute, Marilyn Finkler Cancer Research Center, Department of Life Sciences. Bar-Han University Ramat-Gan, Israel aut Kalechman Yona Cancer, AIDS, and Immunology Research Institute, Marilyn Finkler Cancer Research Center, Department of Life Sciences. Bar-Han University Ramat-Gan, Israel aut JNCI: Journal of the National Cancer Institute Oxford University Press 88/18(1996-09-18), 1276-1284 0027-8874 88:18<1276 1996 88 jnci https://doi.org/10.1093/jnci/88.18.1276 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1093/jnci/88.18.1276 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Sredni Benjamin Cancer, AIDS, and Immunology Research Institute, Marilyn Finkler Cancer Research Center, Department of Life Sciences. Bar-Han University Ramat-Gan, Israel aut NATIONALLICENCE 700 1- Tichler Thomas Department of Oncology, Shcba Medical Center Tel-Hashomer, Ramat Gan aut NATIONALLICENCE 700 1- Shani Adi Department of Oncology, Kaplan Hospital Rehovot, Israel aut NATIONALLICENCE 700 1- Catane Rafael Department of Oncology, Hadassah Hospital Jerusalem, Israel aut NATIONALLICENCE 700 1- Kaufman Bella Department of Oncology, Hadassah Hospital Jerusalem, Israel aut NATIONALLICENCE 700 1- Strassmann Gideon Otsuka-American Pharmaceutical Inc. Rockville, MD aut NATIONALLICENCE 700 1- Albeck Michael Cancer, AIDS, and Immunology Research Institute, Marilyn Finkler Cancer Research Center, Department of Life Sciences. Bar-Han University Ramat-Gan, Israel aut NATIONALLICENCE 700 1- Kalechman Yona Cancer, AIDS, and Immunology Research Institute, Marilyn Finkler Cancer Research Center, Department of Life Sciences. Bar-Han University Ramat-Gan, Israel aut NATIONALLICENCE 773 0- JNCI: Journal of the National Cancer Institute Oxford University Press 88/18(1996-09-18), 1276-1284 0027-8874 88:18<1276 1996 88 jnci Metadata rights reserved CC BY-NC-4.0 http://creativecommons.org/licenses/by-nc/4.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-oxford