177Lu-immunotherapy of experimental peritoneal carcinomatosis shows comparable effectiveness to 213Bi-immunotherapy, but causes toxicity not observed with 213Bi

Bi-213-d9MAb-immunoconjugates targeting gastric cancer cells have effectively cured peritoneal carcinomatosis in a nude mouse model following intraperitoneal injection. Because the beta-emitter Lu-177 has proven to be beneficial in targeted therapy, Lu-177-d9MAb was investigated in this study in order to compare its therapeutic efficacy and toxicity with those of Bi-213-d9MAb. Nude mice were inoculated intraperitoneally with HSC45-M2 gastric cancer cells expressing d9-E-cadherin and were treated intraperitoneally 1 or 8 days later with different activities of specific Lu-177-d9MAb immunoconjugates targeting d9-E-cadherin or with nonspecific Lu-177-d8MAb. Therapeutic efficacy was evaluated by monitoring survival for up to 250 days. For evaluation of toxicity, both biodistribution of Lu-177-d9MAb and blood cell counts were determined at different time points and organs were examined histopathologically. Treatment with Lu-177-immunoconjugates (1.85, 7.4, 14.8 MBq) significantly prolonged survival. As expected, treatment on day 1 after tumour cell inoculation was more effective than treatment on day 8, and specific Lu-177-d9MAb conjugates were superior to nonspecific Lu-177-d8MAb. Treatment with 7.4 MBq of Lu-177-d9MAb was most successful, with 90% of the animals surviving longer than 250 days. However, treatment with therapeutically effective activities of Lu-177-d9MAb was not free of toxic side effects. In some animals lymphoblastic lymphoma, proliferative glomerulonephritis and hepatocarcinoma were seen but were not observed after treatment with Bi-213-d9MAb at comparable therapeutic efficacy. The therapeutic efficacy of Lu-177-d9MAb conjugates in peritoneal carcinomatosis is impaired by toxic side effects. Because previous therapy with Bi-213-d9MAb revealed comparable therapeutic efficacy without toxicity it should be preferred for the treatment of peritoneal carcinomatosis.