High doses of thymosin alpha 1 enhance the anti-tumor efficacy of combination chemo-immunotherapy for murine B16 melanoma

Background: We have reported previously that combined chemo-immunotherapy w ith cyclophosphamide (CY), thymosin alpha 1 (T alpha 1) and low dose interf eron alpha,beta (IFN alpha beta) has significant anti- tumour effects. Here , using mouse B16 melanoma as a model, we tested whether increasing the dos e of Tal could increase the anti-tumour activity of triple combination chem o-immunotherapy. Materials and Methods: C57BL/6 mice were challenged subcut aneously with B16 melanoma cells and injected intraperitoneally with saline , CY (200 mg/kg, day 7), or CY with Tal (200, 600 or 6000 mu g/kg/day, days 10-13) and IFN alpha beta (30,000 I.U., day 13). Results: Chemo-immunother apy with high dose (HD)-T alpha 1 caused complete tumour regression for 27. 5 days after tumour cell injection (3.9 times longer than untreated control s) and delayed tumour relapse compared to all other groups. Moreover, it si gnificantly increased the median survival time of treated mice, and cured a n average of 23% of animals, while none was cured in any other group. Splen ocytes from HD-Tal-treated mice showed markedly increased cytotoxic activit ies against both YAC-I and autologous B16 tumour cells. HD-T alpha 1 treatm ent reversed the tumour-induced reduction in percentages of CD3 and CD4-pos itive splenocytes to non- tumour levels, and it increased percentages of CD 8, B220 and IL-2R beta-positive cells to well beyond non-tumour controls. C onclusions: High doses of Tal improve antitumour efficacy of tnple chemo-im munotherapy against B16 melanoma. These effects appear to be mediated by st imulation of the host immune response.