CONCOMITANT TREATMENT OF MBT-2 BLADDER-TUMOR BY TUMOR-NECROSIS-FACTOR-ALPHA AND INTERFERON-ALPHA IN CONJUNCTION WITH DELAYED-TYPE HYPERSENSITIVITY IMMUNOTHERAPY

In our previous study [9], we reported the anti-tumour effect of TNF on mouse bladder tumour (MBT-2) both in vivo and in vitro. Inoculation of a single dose of TNF alone caused significant but transient tumour growth inhibition. Subsequent repeated doses of TNF did not sustain or augment the anti-tumour effect. The current experiments were undertaken to assess the anti-tumour activity of (i)-concomitant treatment of TNF-A and IFN-A against MBT-2 bladder tumour and (ii)-concomitant TNF + IFN-A treatment in conjunction with T-DTH (delayed-type hypersensitivity) immunotherapy. Systemic administration of multiple doses of TNF + IFN-A in vivo caused initial partial tumour regression followed by tumour growth inhibition up to 14 days following treatment. This combined treatment showed an enhanced anti-tumour effect compared to TNF-A treatment alone. Immunotherapy of MBT-2 tumour-bearing mice with T-DTH "immune" effector cells alone did not cause significant tumour growth inhibition. In contrast, concomitant administration of both T-DTH effector cells and TNF + IFN-A in MBT-2 tumour-bearing mice resulted in significant tumour growth inhibition for up to 16 days. The immune effector cells conferring immunotherapy were isolated from the spleens of tumour-immunized, "DTH-primed" animals and were characterized as Lyt 1+2- helper/DTH T cells (CD4+ phenotype). These cells mediate both DTH response to MBT-2 tumour antigens as well as anti-MBT-2 tumour protection. In vitro treatment of the "immune" cells with TNF-A resulted predominantly in the proliferation of Lyt 1+ T cells versus Lyt 2+ cells. The anti-tumour effect of TNF + IFN-A can be augmented by immunotherapy possibly via the immune capacity of tumour sensitized T-DTH effector cells.