MIG (CXCL9) chemokine gene therapy combines with antibody-cytokine fusion protein to suppress growth and dissemination of murine colon carcinoma.
The induction of a CTL response capable of eradicating disseminated tumor metastases and the establishment of a persistent tumor-protective immunity remain major goals of cancer immunotherapy. Here, we demonstrate for the first time that the combination of interleukin 2 (IL-2) targeted to the tumor microenvironment by a recombinant antibody-IL-2 fusion protein (huKS1/4-IL-2) with gene therapy by the murine chemokine MIG (CXCL9) markedly reduced s.c. tumor burden and decisively suppressed dissemination of experimental lung metastases of CT26-KSA colon carcinoma in syngeneic BALB/c mice. This combined therapy significantly prolonged the life span of these mice 3-4-fold by concurrently delivering MIG and IL-2 to the tumor site and thereby achieving chemoattraction of T cells together with their activation. The antitumor effect obtained was mediated predominantly by MHC class I antigen-restricted CD8(+) T cells with help from MHC class II antigen-restricted CD4(+) T lymphocytes. In addition, the MIG chemokine also induced angiostatic effects in the tumor vasculature. Taken together, this combination of MIG chemokine gene therapy with tumor-targeted cytokine IL-2 provides an approach for the rational design of novel cancer immunotherapy modalities.
Ruehlmann
J M
JM
The Scripps Research Institute, Department of Immunology, La Jolla, California 92037, USA.
Xiang
R
R
Niethammer
A G
AG
Ba
Y
Y
Pertl
U
U
Dolman
C S
CS
Gillies
S D
SD
Reisfeld
R A
RA
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D019556:COS Cells; D015815:Cell Adhesion Molecules; D002455:Cell Division / Q000187:drug effects; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D003131:Combined Modality Therapy; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D000922:Immunotoxins / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins; D007376:Interleukin-2 / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000556:secondary / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*
D000951:Antigens, Neoplasm; C080810:CXCL9 protein, human; D015815:Cell Adhesion Molecules; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D000071858:Epithelial Cell Adhesion Molecule; D000922:Immunotoxins; D036341:Intercellular Signaling Peptides and Proteins; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins