Predominance of TH1 response in tumor-bearing mice and cancer patients treated with AS101

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. Eviden...

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Published in:JNCI : Journal of the National Cancer Institute 1996-09, Vol.88 (18), p.1276-1284
Main Authors: Sredni, B, Tichler, T, Shani, A, Catane, R, Kaufman, B, Strassmann, G, Albeck, M, Kalechman, Y
Format: Article
Language:English
Subjects:
Adjuvants, Immunologic - therapeutic use
Animals
Antineoplastic Agents - therapeutic use
Cancer
Carcinoma, Lewis Lung - drug therapy
Carcinoma, Lewis Lung - immunology
Cell Division - drug effects
Cytokines - blood
Cytokines - drug effects
Drug therapy
Ethylenes - therapeutic use
Female
Humans
Interferon-gamma - blood
Interleukin-10 - blood
Interleukin-12 - blood
Interleukin-12 - physiology
Interleukin-2 - blood
Interleukin-4 - blood
Killer Cells, Lymphokine-Activated - drug effects
Killer Cells, Natural - drug effects
Male
Medical research
Mice
Mice, Inbred C57BL
Neoplasm Transplantation
Neoplasms - drug therapy
Neoplasms - immunology
Neoplasms - pathology
Neoplasms, Experimental - drug therapy
Neoplasms, Experimental - immunology
Rodents
Spleen - cytology
Spleen - metabolism
Tumors
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Summary: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. 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. 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 10 micrograms/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. 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 gamma) 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 gamma 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 cotreatment of 3LL-transplanted mice with AS101 and anti-IL-12 antibodies partly abrogated the antitumoral effect of AS101. Immunoth
ISSN:0027-8874
1460-2105
DOI:10.1093/jnci/88.18.1276