Phase I study of intraperitoneal MHC unrestricted adoptive cell therapy with TALL-104 cells in patients with peritoneal carcinosis

Background: TALL-104 is an irradiated human leukemic T cell line (CD3 + , CD4– CD8 + , CD56 + , CD16–) grown in IL-2-containing medium, that has the ability to kill tumor cells in preclinical models in a MHC unrestricted way. A phase I trial in metastatic breast cancer patients, has shown that multiple i.v. infusions (infs) of TALL-104 cells can be given safely. In order to optimise the tumor:effector cell ratio, we have designed a phase I study of intraperitoneal administrations of g-irradiated TALL-104 cells. Methods: Patients (pts) with peritoneal carcinosis from solid tumors resistant to standard treatment were eligible for the study. The treatment included 5 i.p. infs (day 1, 3, 5, 15, 30) and the study was designed to test three cell dose levels: 1 × 108, 5 × 108, 2.5 × 109. End points were: safety, kinetic of TALL-104 cells on ascites (if present) and peripheral blood (PB), levels of cytokines (TGF-b, GM-CSF, IL-2, IL-4, IL-10, IFN-g, TNF-a and -b, HGF, sIL-2R, sICAM-1) on ascites and serum, and immunological monitoring. Results: Fifteen pts have been treated: 8 with ovarian and 7 with GI cancer. Five pts have been treated at each dose level. No treatment-related adverse events were observed. TALL-104 cells were detected in ascites (100% of the pts) and PB (3.3% of the pts) up to 48 hrs after the infs. Cytotoxicity of autologous MNC showed an increase up to 5% at day 3 through 7 and it was still evident at day 30. HLA-DR + /CD14 + cells increased up to 21% and 30% in the serum and ascites respectively at day 7 through 15. GM-CSF, IL-2, IL-4, IL-10, IFN-g, TNF were not detectable neither in serum nor in ascitic fl uid. sIL-2R showed an increase up to 22% and 109% in serum and ascites respectively. IL-10 showed an increase up to 34% at 1st dose level and a decrease down to 20% and 40% in ascites and serum respectively at 2nd dose level. TGF-b1 and -b2 showed an increase both in serum and ascites at 1st and 2nd dose level. sICAM-1 showed an increase up to 22% at 1st dose level and a decrease down to 41% at 2nd dose level. Six patients had a confi rmed stable disease with a median duration of response of 5 months (3–7). Conclusion: These results show that the i.p. infusion of TALL- 104 is safe. Moreover, the increased autologous cell-mediated cytotoxicity and the levels of soluble cytokines after i.p. infs indicate that TALL-104 cells may elicit potential antitumor activity and deserve further evaluation in patients with a less severe stage of disease.