Mesothelioma Legal Rights - Inhaling Asbestos Fibers
Substantial recent information suggests that immunotherapy might be a useful therapeutic option in MM, which is encouraging considering the frustrating failure of all standard treatment modalities to offer hope to patients with this disease. One of the most powerful experimental approaches used to date against tumors has been administration of the cytokine IL-12, which induces a number of antitumor effects, such as the induction of tumor-specific immune responses and antiangiogenic factors. In fact, we have previously shown that systemic administration of IL-12 reduces the incidence of murine MM tumors (11). Unfortunately, IL-12 in therapeutic doses, particularly those associated with systemic administration, can cause severe toxic side effects. Because of this we reasoned that local delivery of IL-12 may be of greater therapeutic value, and that gene transfer may be the most feasible and powerful way to achieve this. Indeed, the data presented here show that paracrine secretion of IL-12 induced both local and distal anti-MM responses without any associated toxicity.
That the antitumor effects in our study were the result of induction of systemic T-cell immunity was supported by four observations. First, AB1-IL-12 transfectant cells did not produce progressive tumors in normal mice but did so in nude mice, thus implicating T-cells in tumor rejection. Importantly, tumor rejection in our model correlated with the degree of T-cell infiltration. The transient tumors that developed in a proportion of mice challenged with AB1- IL-12 had large numbers of infiltrating CD4+ and CD8+ cells, in contrast to mice injected with parental AB1 tumor only, which had very few CD4+ or CD8+ cells infiltrating the tumor mass.
This is consistent with our previous finding that intratumoral injection of IL-12 was associated with large numbers of T-cells infiltrating the MM tumors, whereas progressively growing tumors had sparse T-cell infiltrates (11). This correlation between regression and cellular infiltration with IL-12 treatment has been reported in other systems (30, 32). Second, mice challenged with AB1-IL-12 were protected against rechallenge with parental AB1 tumor, indicating that a memory response had been established. Third, memory CD8+ effector cells generated by multiple priming with AB1-IL-12 completely prevented the growth of parental AB1 when coinoculated into naive recipients. We have not observed such memory responses using the irradiated parental AB1 cell line in a vaccine protocol. Moreover, we found evidence of systemic antitumor activity at a distal site.