Listeria monocytogenes (L. monocytogenes) is a promising candidate vaccine vector that naturally infects antigen-presenting cells, and targets antigen delivery to both the class I MHC pathway of endogenous antigen presentation and the class II pathway of exogenous antigen presentation. At the same time, L. monocytogenes stimulates the innate immune response to produce cytokines that enhance antigen-presenting function and induce a Th1-type cytokine profile associated with cell-mediated immune responses. Immune responses with these features are considered to be particularly important for clearance of viruses, tumors, and intracellular infections. In this review, we describe the development of methods to transform L. monocytogenes to express and secrete foreign antigens and the studies that have demonstrated that genetically engineered L. monocytogenes mutants are highly effective vectors for the induction of potent immune responses against viral antigens and tumor cells. In addition, we discuss the strengths and weaknesses of L. monocytogenes as a vaccine vector.

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We have previously shown that spleen cells from BALB/c mice that are in the process of eradicating a large MOPC-315 tumor following low-dose (2.5 mg/kg) melphalan (L-phenylalanine mustard) therapy are effective in preventing tumor progression upon adoptive transfer into BALB/c mice bearing a barely palpable tumor that had been treated with a subcurative dose of melphalan [Mokyr et al. (1989) Cancer Res 49:4597]. Here we show that such spleen cells in conjunction with a subcurative dose of drug (adoptive chemoimmunotherapy, ACIT) can cause the complete regression of a large (15-20 mm) s.c. MOPC-315 tumor in a large percentage of T-cell-deficient (athymic nude) tumor-bearing mice. Spleen cells that were effective in ACIT of athymic nude mice displayed in vitro a substantial direct lytic activity against MOPC-315 tumor cells, and the lytic activity was greatly enhanced when the spleen cells were cultured for 5 days with or without mitomycin-C-treated MOPC-315 stimulator tumor cells. The cells responsible for the therapeutic effectiveness of the spleen cells in ACIT of athymic nude mice, as well as the cells responsible for the direct in vitro anti-MOPC-315 lytic activity of the spleen cells, were of the Lyt 2 and not the L3T4 phenotype. Most of the athymic nude mice that completely eradicated a large MOPC-315 tumor as a consequence of ACIT were capable of rejecting a challenge with 30-100 times the minimal lethal tumor dose for 100% of normal BALB/c mice administered more than 1 month after the ACIT. The ability of these athymic nude mice to resist the tumor challenge was associated with the presence of a greatly elevated percentage of cells expressing T cell surface markers in their spleens. Thus, it is conceivable that splenic Lyt 2+T cells from melphalan-treated BALB/c mice bearing a large MOPC-315 tumor mediate their therapeutic effectiveness in ACIT of athymic nude mice bearing a large MOPC-315 tumor, at least in part, through direct cytotoxicity for MOPC-315 tumor cells. In addition, eradication of a large MOPC-315 tumor through cooperation between antitumor immunity and melphalan toxicity endues the athymic nude mice with an elevated percentage of T cells in their secondary lymphoid organs, and these T cells are probably responsible for the long-lasting protective antitumor immunity exhibited by these mice.

We have previously shown that treatment of mice bearing a large MOPC-315 plasmacytoma with a low dose of the anticancer drug melphalan (L-phenylalanine mustard; L-PAM) results in the acquisition of a potent CD8+ T-cell-mediated anti-MOPC-315 cytotoxic T lymphocyte (CTL) activity by the hitherto immunosuppressed tumor bearers, and this immunity contributes to complete tumor eradication. In the studies presented here, we sought to determine how the acquisition of this antitumor immunity following low-dose chemotherapy is possible, in light of the report that MOPC-315 tumor cells produce transforming growth factor-beta (TGF-beta), an immunosuppressive cytokine that can down-regulate the generation of CTL responses. We found that the acquisition of CTL activity following low-dose L-PAM therapy is not due to a chemotherapy-induced decrease in the sensitivity of MOPC-315 tumor bearer spleen cells to TGF-beta-mediated inhibition of CTL generation. Moreover, even spleen cells from MOPC-315 tumor-bearing mice, which had received L-PAM therapy 7 days earlier and had acquired CTL activity in vivo, were sensitive to the inhibitory activity of TGF-beta upon culture for as little as 1 day, with or without stimulator tumor cells. However, the production of TGF-beta by MOPC-315 tumors decreased drastically as a consequence of the low-dose chemotherapy. Thus, the curative effectiveness of low-dose L-PAM therapy for MOPC-315 tumor-bearing mice may be due, at least in part, to a reduction in TGF-beta production that enables the development of tumor-eradicating immunity.

We have previously shown that treatment of mice bearing a large MOPC-315 plasmacytoma with a low dose of the anticancer drug melphalan (L-phenylalanine mustard; L-PAM) results in the acquisition of a potent CD8+ T-cell-mediated anti-MOPC-315 cytotoxic T lymphocyte (CTL) activity by the hitherto immunosuppressed tumor bearers, and this immunity contributes to complete tumor eradication. In the studies presented here, we sought to determine how the acquisition of this antitumor immunity following low-dose chemotherapy is possible, in light of the report that MOPC-315 tumor cells produce transforming growth factor-beta (TGF-beta), an immunosuppressive cytokine that can down-regulate the generation of CTL responses. We found that the acquisition of CTL activity following low-dose L-PAM therapy is not due to a chemotherapy-induced decrease in the sensitivity of MOPC-315 tumor bearer spleen cells to TGF-beta-mediated inhibition of CTL generation. Moreover, even spleen cells from MOPC-315 tumor-bearing mice, which had received L-PAM therapy 7 days earlier and had acquired CTL activity in vivo, were sensitive to the inhibitory activity of TGF-beta upon culture for as little as 1 day, with or without stimulator tumor cells. However, the production of TGF-beta by MOPC-315 tumors decreased drastically as a consequence of the low-dose chemotherapy. Thus, the curative effectiveness of low-dose L-PAM therapy for MOPC-315 tumor-bearing mice may be due, at least in part, to a reduction in TGF-beta production that enables the development of tumor-eradicating immunity.