ANTITUMOR MECHANISMS OF ATTENUATED SALMONELLA-TYPHIMURIUM CONTAINING THE GENE FOR HUMAN INTERLEUKIN-2 - A NOVEL ANTITUMOR AGENT

Currently, there is no long-term effective treatment for unresectable hepatic malignancies. Salmonella species are known to naturally track to the liver during active infection. To develop a biological vector f or delivery of interleukin-2 (IL-2) to the liver for antitumor purpose s, the (chi)4550 attenuated strain of Salmonella typhimurium was used as a vector for IL-2. The gene for human IL-2 was cloned into plasmid pYA292 and inserted into the attenuated S typhimurium and renamed [(ch i)4550(pIL-2)]: MCA-38 murine adenocarcinoma cells were injected intra splenically into C57BL/6 mice to produce hepatic metastases that were subsequently enumerated after 12 days. Wi previously have demonstrated that the (chi)4550(plL-2) produces biologically active IL-2 and that a single gavage feeding of 10(7) (chi)4550(plL-2) significantly reduce d the number of hepatic metastases' when compared with animals fed sal monella lacking the IL-2 gene or nontreated controls. The aims of the current studies were to determine which host effector cell populations were responsible for the antitumor effect seen with (chi)4550(plL-2) by depletion of natural killer (NK), cytotoxic T lymphocytes (CD8(+)), T helper (CD4(+)) cells, and Kupffer cells. Multiple experiments were conducted for each host effector cell population depleted. We found a consistent reduction in the mean number of hepatic: metastases in ani mals fed (chi)4550(pIL-2) (55.6 metastases; n = 54) when compared with controls (162.3 metastases; n = 53) (P <.0001). Depletion of NK cells and CD8(+) T cells significantly inhibited the antitumor effect of (c hi)4550(pIL-2) (analysis of variance [ANOVA], P <.01). Elimination of CD4(+) T cells and Kupffer cells had no significant impact on the anti tumor effect of (chi)4550(pIL-2) (ANOVA, P value was not significant). Salmonella IL-2 may represent a novel form of in vivo biotherapy for unresectable hepatic malignancies that employs the oral route of admin istration. Furthermore, both NK cells or CD8(+) cells are required for the antitumor effect seen while CD4(+) T cells and Kupffer cells do n ot appear to be as essential. Copyright (C) 1997 by W.B. Saunders Comp any.