TOXICOLOGICAL AND IMMUNOLOGICAL EVALUATION OF THE MHC-NON-RESTRICTED CYTOTOXIC T-CELL LINE TALL-104

The human MHC-non-restricted cytotoxic T cell line TALL-104 has been s hown to display potent antitumor effects in several animal models with spontaneous and induced malignancies. In view of its potential future use in cancer therapy, we investigated the tolerability and target-or gan toxicity of these cells in various animal species. The acute toxic ity of TALL-104 cell administrations was evaluated in: (a) healthy imm unocompetent mice and immunodeficient (SCID) mice bearing human tumors using multiple (up to 15) intraperitoneal (i.p.) injections, and (b) healthy dogs, tumor-bearing dogs, and healthy monkeys using multiple ( up to 17) intravenous (i.v.) injections. TALL-lO4 cells were gamma-irr adiated (40 Gy) prior to administration to mice and dogs, but administ ered without irradiation in monkeys. Cell doses ranged from 5x107/kg t o 10(10)/kg for each injection. All regimens were well tolerated, the main clinical signs observed being transient gastrointestinal effects. Moderate and transient increases in liver transaminase levels were ob served in all animal species, Discrete and transient leukocytosis with neutrophilia was also noted in dogs and monkeys after i.v injections of TALL-104 cells. Histological analysis revealed foci of hepatic necr osis with lympho-/mono-/granulocytic infiltration in immunocompetent m ice injected i.p. with 5x10(9)-10(10) cells/kg. In the same mice, the colon showed an increased number of muciparous cells and alterations i n the villi structure: these alterations were completely reversed by 7 2 h after the last injection, while liver alterations reversed more sl owly (I week). No delayed or chronic toxicity was observed in any of t he animals even when nonirradiated TALL-104 cells were administered: b oth immunocompetent mice and healthy dogs were found to be grossly and histopathologically normal when sacrificed (1 year and 1 month after the last TALL-104 injection respectively). TALL-104 cells did not pers ist in these hosts. In addition, monkeys showed no molecular signs of TALL-104-cell-induced leukemia in their blood 1 year after the last ce ll injection. Despite immunosuppression, most of the tumor-bearing dog s as well as the healthy dogs and monkeys developed both humoral and c ellular immune responses against TALL-104 cells. The data derived from these preclinical studies suggest that administration of high doses o f irradiated TALL-104 cells is well tolerated and would be unlikely to induce severe toxicity if applied in clinical trials to the treatment of patients with refractory cancer.