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Intratumoral delivery of vector mediated IL-2 in combination with vaccine results in enhanced T cell avidity and anti-tumor activity

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Abstract

Systemic IL-2 is currently employed in the therapy of several tumor types, but at the price of often severe toxicities. Local vector mediated delivery of IL-2 at the tumor site may enhance local effector cell activity while reducing toxicity. To examine this, a model using CEA-transgenic mice bearing established CEA expressing tumors was employed. The vaccine regimen was a s.c. prime vaccination with recombinant vaccinia (rV) expressing transgenes for CEA and a triad of costimulatory molecules (TRICOM) followed by i.t. boosting with rF-CEA/TRICOM. The addition of intratumoral (i.t.) delivery of IL-2 via a recombinant fowlpox (rF) IL-2 vector greatly enhanced anti-tumor activity of a recombinant vaccine, resulting in complete tumor regression in 70–80% of mice. The anti-tumor activity was shown to be dependent on CD8+ cells and NK1.1+. Cellular immune assays revealed that the addition of rF-IL-2 to the vaccination therapy enhanced CEA-specific tetramer+ cell numbers, cytokine release and CTL lysis of CEA+ targets. Moreover, tumor-bearing mice vaccinated with the CEA/TRICOM displayed an antigen cascade, i.e., CD8+ T cell responses to two other antigens expressed on the tumor and not the vaccine: wild-type p53 and endogenous retroviral antigen gp70. Mice receiving rF-IL-2 during vaccination demonstrated higher avidity CEA-specific, as well as higher avidity gp70-specific, CD8+ T cells when compared with mice vaccinated without rF-IL-2. These studies demonstrate for the first time that the level and avidity of antigen specific CTL, as well as the therapeutic outcome can be improved with the use of i.t. rF-IL-2 with vaccine regimens.

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Abbreviations

rV:

Replication-competent recombinant vaccinia

FP-WT:

Fowlpox wild-type

rF:

Replication-defective recombinant fowlpox

TRICOM:

Triad of costimulatory molecules (B7-1, ICAM-1 and LFA-3)

IL-2:

Interleukin-2

CEA:

Carcinoembryonic antigen

GM-CSF:

Granulocyte macrophage colony-stimulating factor

TAA:

Tumor-associated antigen

TIL:

Tumor-infiltrating cell

i.t.:

Intratumoral (ly)

s.c.:

Subcutaneous (ly)

i.p.:

Intraperitoneal (ly)

APC:

Antigen-presenting cells

Tg:

Transgenic

CTL:

Cytotoxic T lymphocyte

DC:

Dendritic cells

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Acknowledgments

We thank Marion Taylor for excellent technical assistance. We thank Debra Weingarten for her editorial assistance in the preparation of this manuscript. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

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Authors and Affiliations

  1. Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Chie Kudo-Saito, Charlie T. Garnett, Elizabeth K. Wansley & James W. Hodge

  2. Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Building 10, Room 8B09, MSC 1750, Bethesda, MD, 20892-1750, USA

    Jeffrey Schlom

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  1. Chie Kudo-Saito
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  2. Charlie T. Garnett
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  3. Elizabeth K. Wansley
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  4. Jeffrey Schlom
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Correspondence to Jeffrey Schlom.

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Kudo-Saito, C., Garnett, C.T., Wansley, E.K. et al. Intratumoral delivery of vector mediated IL-2 in combination with vaccine results in enhanced T cell avidity and anti-tumor activity. Cancer Immunol Immunother 56, 1897–1910 (2007). https://doi.org/10.1007/s00262-007-0332-1

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