Combination therapy of an orthotopic renal cell carcinoma model using intratumoral vector-mediated costimulation and systemic interleukin-2.
OBJECTIVE
Interleukin (IL)-2 therapy is currently used for therapy of renal cell carcinoma (RCC). However, it is only effective in approximately 10% to 15% of patients, showing a need for additional therapies. We have previously described a replication-defective fowlpox vector encoding three costimulatory molecules (B7-1, ICAM-1, and LFA-3), designated rF-TRICOM. Here, we show that intratumoral administration of rF-TRICOM in an orthotopic RCC model effectively enhances tumor immunogenicity and reduces tumor burden in mice and the combination of rF-TRICOM and IL-2 is more effective than either therapy alone.


METHODS
RCC cells were implanted under the capsule of the kidney, and mice were given rF-TRICOM intratumorally 14 days later. We compared the effect of rF-TRICOM, rF-granulocyte macrophage colony-stimulating factor (GM-CSF), and two doses of IL-2 and combinations of the above on antitumor efficacy and survival. Host CD4(+) and CD8(+) T-cell responses were also evaluated.


RESULTS
The results show that (a) systemic IL-2 therapy was moderately effective in the reduction of tumor burden in an orthotopic RCC model; (b) a single intratumoral injection of rF-TRICOM and rF-GM-CSF significantly reduced tumor burden; (c) the addition of systemic IL-2 to intratumoral rF-TRICOM/rF-GM-CSF administration resulted in further reduction of tumor burden, decrease in the incidence of metastasis, and extended survival in tumor-bearing mice above that seen with either treatment alone; and (d) CD8(+) T cells played a critical role in the antitumor effect seen with rF-TRICOM/rF-GM-CSF + IL-2 therapy. Finally, the addition of systemic recombinant IL-15 or intratumoral vector-delivered IL-15 to intratumoral rF-TRICOM/rF-GM-CSF administration resulted in substantially more tumor-free mice than either therapy alone.


CONCLUSIONS
These studies show that intratumoral administration of rF-TRICOM admixed with rF-GM-CSF is effective at reducing tumor burden in mice and the addition of IL-2 further contributes to this effect. These studies thus form the rationale for combination immunotherapy clinical trials in patients with RCC.
Kudo-Saito
Chie
C
Laboratories of Tumor Immunology and Biology and Experimental Immunology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Wansley
Elizabeth K
EK
Gruys
M Eilene
ME
Wiltrout
Robert
R
Schlom
Jeffrey
J
Hodge
James W
JW
D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics; D018968:CD58 Antigens / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D007167:Immunotherapy / Q000379:methods*; D015552:Injections, Intralesional; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007376:Interleukin-2 / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000401:mortality / Q000628:therapy; D047368:Tumor Burden; D014407:Tumor Cells, Cultured
D018122:B7-1 Antigen; D018968:CD58 Antigens; D007376:Interleukin-2; D018799:Intercellular Adhesion Molecule-1