INDUCTION OF PERSISTENT TUMOR-PROTECTIVE IMMUNITY IN MICE CURED OF ESTABLISHED COLON-CARCINOMA METASTASES

The induction of tumor-specific T-cell responses that are effective in eradicating disseminated tumors and in mounting a persistent tumor-pr otective immunity is one of the major goals of tumor immunotherapy, He re, we demonstrate that we achieved this goal by directing interleukin 2 (IL-2) to the tumor microenvironment of colon carcinoma metastases in syngeneic mice with a recombinant antibody-IL-2 fusion protein (huK S1/4-IL-2), Eradication of established pulmonary metastases is induced by a CD8(+) T cell-mediated immune response, which can be transmitted to naive syngeneic severe combined immunodeficient mice by adoptive t ransfer of CD8+ T cells from immune animals. This immune response was followed by the induction of a long-lived immunity against challenge u p to 5 months later with CT26-KSA or wild-type CT26 murine colon carci noma cells in BALB/c mice. This memory immune response was confirmed b y flow cytometric analyses of CD8(+) T cells isolated from secondary l ymphoid tissue that revealed a phenotypic profile typical of early mem ory T cells. This long-lived protective tumor immunity was successfull y boosted to become optimally effective in all experimental animals by injections of noncurative doses of IL-2 fusion protein 4 days after c hallenge with tumor cells. Taken together, our results indicate that t he huKS1/4-IL-2 fusion protein elicits a long-lived cellular memory im mune response that can be amplified by additional applications of IL-2 fusion proteins. This approach could become useful for the treatment of colorectal carcinoma in an adjuvant setting, particularly in patien ts with minimal residual disease.