Intrathecal therapy of leptomeningeal CEM T-cell lymphoma in nude rats with anti-CD7 ricin toxin A chain immunotoxin

Abstract

We have established a new xenogeneic animal model of leptomeningeal metastasis (LM) by intracisternal inoculation of human CEM T-cell lymphoma into nude rats, and used it to evaluate the anti-lymphoma efficacy of an anti-CD7 ricin A chain immunotoxin (DA7). In vitro incubation with 2 μg/ml DA7 for 72 h inhibited CEM cells by 90% in a trypan blue exclusion assay. To establish its anti-lymphoma activity, one and four days after cisternal inoculation of 106 CEM cells, eight animals each were treated cisternally with 10 μg DA7 in 50 μl PBS or sham-treated with 50 μl PBS. Histopathologically, all eight sham-treated and five of eight DA7 treated animals showed typical features of LM with multilayers of tumor cells along the whole subarachnoid space and the ventricular walls, as well as subependymal and diffuse parenchymal tumor cell infiltration. Three DA7 treated animals were free of tumor. Two of these animals were asymptomatic long-term survivors (> 90 days). The third tumor-free animal suddenly died on day 51. Histology revealed viral myocarditis. Median symptom-free survival was 51 days (range 29–90+ days) in DA7 treated and 34 days (range 29–87 days) in sham-treated animals (p=0.12, log-rank test). Histologically, no signs of neurotoxicity or systemic toxicity was found. However, DA7 treated animals showed a tendency to a slower weight increase on days 6–28 after tumor cell inoculation. Our results indicate that this model is useful in studying leptomeningeal seeding and intracisternal treatment of lymphoma. The demonstrated anti-tumor effect of DA7 treatment deserves further evaluation especially regarding the application of DA7 in early stages of LM from T-cell lymphoma.