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-protective 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 metastases in syngeneic mice with a recombinant antibody-IL-2 fusion protein (huKS1/4-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 transfer of CD8+ 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 carcinoma cells in BALB/c mice. This memory immune response was confirmed by flow cytometric analyses of CD8+ T cells isolated from secondary lymphoid tissue that revealed a phenotypic profile typical of early memory T cells. This long-lived protective tumor immunity was successfully boosted to become optimally effective in all experimental animals by injections of noncurative doses of IL-2 fusion protein 4 days after challenge with tumor cells. Taken together, our results indicate that the huKS1/4-IL-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.
Xiang
R
R
The Scripps Research Institute, Department of Immunology, La Jolla, California 92037, USA.
Lode
H N
HN
Dreier
T
T
Gillies
S D
SD
Reisfeld
R A
RA
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000276:immunology*; D005260:Female; D006801:Humans; D007156:Immunologic Memory; D007376:Interleukin-2 / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000556:secondary; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins