Combination therapy of an orthotopic renal cell carcinoma model using intratumoral vector-mediated costimulation and systemic interleukin-2

Chie Kudo-Saito, Elizabeth K. Wansley, M. Eilene Gruys, Robert Wiltrout, Jeffrey Schlom, James W. Hodge

Research output: Contribution to journalArticle

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Abstract

Purpose: 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. Experimental Design: 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+ Tcells 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.

Original languageEnglish
Pages (from-to)1936-1946
Number of pages11
JournalClinical Cancer Research
Volume13
Issue number6
DOIs
Publication statusPublished - 2007 Mar 15
Externally publishedYes

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Renal Cell Carcinoma
Granulocyte-Macrophage Colony-Stimulating Factor
Interleukin-2
Tumor Burden
Interleukin-15
Therapeutics
Fowlpox
CD80 Antigens
CD58 Antigens
Neoplasms
Survival
Intercellular Adhesion Molecule-1
Immunotherapy
Capsules
Research Design
Clinical Trials
Neoplasm Metastasis
T-Lymphocytes
Kidney
Injections

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Combination therapy of an orthotopic renal cell carcinoma model using intratumoral vector-mediated costimulation and systemic interleukin-2. / Kudo-Saito, Chie; Wansley, Elizabeth K.; Gruys, M. Eilene; Wiltrout, Robert; Schlom, Jeffrey; Hodge, James W.

In: Clinical Cancer Research, Vol. 13, No. 6, 15.03.2007, p. 1936-1946.

Research output: Contribution to journalArticle

Kudo-Saito, Chie ; Wansley, Elizabeth K. ; Gruys, M. Eilene ; Wiltrout, Robert ; Schlom, Jeffrey ; Hodge, James W. / Combination therapy of an orthotopic renal cell carcinoma model using intratumoral vector-mediated costimulation and systemic interleukin-2. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 6. pp. 1936-1946.
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AU - Wiltrout, Robert

AU - Schlom, Jeffrey

AU - Hodge, James W.

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