PREDOMINANCE OF TH1 RESPONSE IN TUMOR-BEARING MICE AND CANCER-PATIENTS TREATED WITH AS101

Background Several studies have recently suggested that the immune res ponse to malignant growths is regulated by distinct patterns of type 2 cytokine production. These cytokines, regulating the cytotoxic T-lymp hocyte response in patients with advanced cancers, may be associated w ith disease progression, Evidence suggests that the T Helper 1 (TH1) a nd T Helper 2 (TH2) types of reaction are reciprocally regulated in vi vo. The immunomodulator AS101 (ammonium trichloro[dioxoethylene-O,O']t ellurate) was found to stimulate mouse and human cells to proliferate and secrete a variety of cytokines. Clinical trials using AS101 on can cer patients are now in progress, Purpose: The aim of this study was t o evaluate the ability of AS101 to modulate TH1 and TH2 responses in t umor-bearing mice and in patients with advanced cancer. In addition, w e investigated the association between the predominance of each type o f response with the antitumoral effects of AS101. Methods: Mice into, which Lewis lung carcinoma (3LL) had been transplanted (n = 221) and c ancer patients (n = 13) were treated with AS101 on alternate days, at 10 mu g/mouse intraperitoneally, or for the patients, at 3 mg/m(2) int ravenously, The types were sarcoma, melanoma, and colon, lung, ovarian , and renal cancers, Cytokine levels were determined by immunoassay hi ts and compared with the paired Student's t test: in mice, they were t ested in spleen cell supernatants; in humans, in sera and mononuclear cell supernatants, The chi-squared test was used to compare tumor volu mes, All P values represent two-sided tests of statistical significanc e. Results: Our results show that treatment of mice and patients with AS101 results im a clear predominance ire TH1 responses, with a concom itant decrease in the TH2-type response, This was reflected by a signi ficant enhancement in interleukin 2 (IL-2) and interferon gamma (IFN g amma) 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) ire AS101-treated patients who also showed enhanced levels of natural and lymphokine-activated killer cell-mediated cytoto xicity. 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 anatitumoral effects. In addition, systemic cotreatment of 3LL-transplanted mice with AS101 an d anti-IL-12 antibodies partly abrogated the antitumoral effect of AS1 01, Conclusions: Immunotherapy with AS101 enhances TR1 function while interfering with the TH2 response, This TH1 trend may he related to th e antitumor effects of AS101, Implications: Isolation and characteriza tion of a distinct cytokine pattern in patients with advanced cancer t reated with AS101 may contribute to the development of intervention st rategies using this compound.