Induction of Persistent Tumor-protective Immunity in Mice Cured of Established Colon Carcinoma Métastases1

The induction of tumor-specific T-cell responses that are effective in eradicating disseminated tumors and in mounting a persistent tumorprotective immunity is one of the major goals of tumor immunotherapy. Here, we demonstrate that we achieved this goal by directing interleukin 2 (IL-2) to the tumor microenvironment of colon carcinoma métastases in syngeneic mice with a recombinant antibody-IL-2 fusion protein ilinKSl/ 4-IL-2). Eradication of established pulmonary métastasesis induced by a CDS' T cell-mediated immune response, which can be transmitted to naive syngeneic severe combined immunodeficient mice by adoptive trans fer of ( I)S ' T cells from immune animals. This immune response was followed by the induction of a long-lived immunity against challenge up 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 con firmed by flow cytometric analyses of CD8+ T cells isolated from second ary lymphoid tissue that revealed a phenotypic profile typical of early memory T cells. This long-lived protective tumor immunity was success fully boosted to become optimally effective in all experimental animals by injections of noncurative doses of IL-2 fusion protein 4 days after chal lenge with tumor cells. Taken together, our results indicate that the liiikSI/4-II -2 fusion protein elicits a long-lived cellular memory immune 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 patients with minimal residual disease.