Induction of anti-tumor immunity by trifunctional antibodies in patients with peritoneal carcinomatosis

Peritoneal carcinomatosis (PC) from epithelial tumors is a fatal
diagnosis without efficient treatment. Trifunctional antibodies
(trAb) are novel therapeutic approaches leading to a concerted
anti-tumor activity resulting in tumor cell destruction. In
addition, preclinical data in mouse tumor models demonstrated the
induction of long lasting tumor immunity after treatment with trAb.
We describe the induction of anti-tumor specific T-lymphocytes
after intraperitoneal administration of trAb in patients with PC. 9
patients with progressive PC from gastric (n = 6) and ovarian
cancer (n = 2), and cancer of unknown primary (n = 1) received 3
escalating doses of trAb after surgery and/or ineffective
chemotherapy. The trAb EpCAM x CD3 (10, 20, 40 mu g) or HER2/neu x
CD3 (10, 40, 80 mu g)were applicated by intraperitoneal infusion.
Four weeks after the last trAb application, all patients were
restimulated by subdermal injection of trAb + autologous PBMC +
irradiated autologous tumor cells. Immunological reactivity was
tested by analyzing PBMC for specific tumor reactive CD4+/CD8+ T
lymphocytes using an IFN-gamma secretion assay. In 5 of 9 patients,
tumor reactive CD4+/CD8+T-lymphocytes increased significantly,
indicating specific anti-tumor immunity. A clinical response
(stable disease, partial regression) has been observed in 5 of 9
patients, with a mean time to progression of 3.6 months. Follow-up
showed a mean survival of 11.8 months (median 8.0 months) after
trAb therapy. TrAb are able to induce anti-tumor immunity after
intraperitoneal application and restimulation. The induction of
long-lasting anti-tumor immunity may provide an additional benefit
of the intraperitoneal therapy with trAb and should be further
elevated in larger clinical trials.