Intra-CSF administered recombinant adenovirus causes an immune response-mediated toxicity

High doses of adenotk were injected into the cerebrospinal fluid of rats an d nonhuman primates (Macaca mulatta). Vector administration was followed by ganciclovir administration for 14 days. Despite the absence of clinical sy mptoms, analysis of the cerebrospinal fluid (CSF) and histopathological exa mination of the central nervous system (CNS) of the monkeys (3 weeks after vector injection) were consistent with a viral meningitis. Immunohistochemi cal analysis of the inflammatory infiltrates in the monkeys revealed the pr esence of T and B lymphocytes, indicating a combined cellular and humoral i mmune response to the vector. This latter was supported by the finding of i ntrathecal anti-adenovirus antibody synthesis. Rats receiving high intrathe cal adenotk doses showed a transient and dose-dependent clinical toxicity c onsisting of lethargy, hyperemic eyes and weight lass. Histopathological ex amination of the meninges showed a shift from polymorphonuclear infiltrates during the first postinjection days to clusters of mononuclear cells after 7 days. Acute toxicity is probably related to the early, innate immune res ponse to the vector. In a separate experiment, high levels of IL-8 and IL-6 , were measured during the first 2-3 postinjection days in the CSF of two m onkeys which received intrathecal adenoLacZ. Therefore, these cytokines see m to play an important role in initiating the nonspecific immune response. In one monkey which received adenotk, recombinant adenovirus was cultured f rom serum samples obtained at the 7th post-injection day. At this time-poin t, no vector could be isolated from CSF samples. Based on these preclinical data, we recommend careful dose finding for clinical studies that aim to t reat patients with leptomeningeal metastases.