ELIMINATION OF ESTABLISHED MURINE COLON-CARCINOMA METASTASES BY ANTIBODY-INTERLEUKIN-2 FUSION PROTEIN THERAPY

A recombinant humanized antibody-interleukin 2 fusion protein (huKS1/4 -IL-2) was used to direct IL-2 to the tumor microenvironment and elici t a T cell-mediated eradication of established pulmonary and hepatic C T26-KSA colon carcinoma metastases in syngeneic BALB/c mice, This anti tumor effect was specific because a fusion protein, which was nonreact ive with these tumor cells, failed to exert any such effect, The effic acy of the huKS1/4-IL-2 fusion protein in eliminating metastases was d ocumented because mixtures of monoclonal antibody huKS1/4 with recombi nant human IL-2 were ineffective and, at best, only partially reduced tumor load. Two lines of evidence indicated the eradication of metasta ses and the absence of minimal residual disease in animals treated wit h the fusion protein: first, the lack of detection of CT26-KSA cells b y reverse transcription-PCR, which can detect one tumor cell in 10(6) liver cells; and second, the tripling of life span. The effector mecha nism involved in this tumor eradication is dependent on T cells becaus e the IL-2-directed therapy is ineffective in T cell-deficient SCID mi ce, The essential effector cells were further characterized as CD8(+) T cells by in vivo depiction studies. Such T cells, isolated from tumo r-bearing mice after fusion protein therapy, elicited MHC class I-rest ricted cytotoxicity in vitro against colon carcinoma target cells, Tak en together, these data indicate that fusion protein-directed IL-2 the rapy induces a T cell-dependent host immune response capable of eradic ating established colon cancer metastases in an animal tumor model.