Annals of Surgical Oncology

, Volume 11, Issue 2, pp 147–156 | Cite as

Intratumoral IL-12 and TNF-α–Loaded Microspheres Lead To Regression of Breast Cancer and Systemic Antitumor Immunity

  • Michael S. Sabel
  • Joseph Skitzki
  • Lloyd Stoolman
  • Nejat K. Egilmez
  • Edith Mathiowitz
  • Nicola Bailey
  • Wen-Jian Chang
  • Alfred E. Chang
Original Articles

Abstract

Background: Local, sustained delivery of cytokines at a tumor can enhance induction of antitumor immunity and may be a feasible neoadjuvant immunotherapy for breast cancer. We evaluated the ability of intratumoral poly-lactic-acid-encapsulated microspheres (PLAM) containing interleukin 12 (IL-12), tumor necrosis factor α (TNF-α), and granulocyte-macrophage colony stimulating factor (GM-CSF) in a murine model of breast cancer to generate a specific antitumor response.

Methods: BALB/c mice with established MT-901 tumors underwent resection or treatment with a single intratumoral injection of PLAM containing IL-12, TNF-α, or GM-CSF, alone or in combination. Two weeks later, lymph nodes and spleens were harvested, activated with anti-CD3 monoclonal antibodies (mAb) and rhIL-2, and assessed for antitumor reactivity by an interferon γ (IFNγ) release assay. Tumor-infiltrating lymphocyte (TIL) analysis was performed on days 2 and 5 after treatment by mechanically processing the tumors to create a single cell suspension, followed by three-color fluorescence-activated cell sorter (FACS) analysis.

Results: Intratumoral injection of cytokine-loaded PLAM significantly suppressed tumor growth, with the combination of IL-12 and TNF-α leading to increased infiltration by polymorphonuclear cells and CD8+ T-cells in comparison with controls. The induction of tumor-specific reactive T-cells in the nodes and spleens, as measured by IFN-γ production, was highest with IL-12 and TNF-α. This treatment resulted in resistance to tumor rechallenge.

Conclusions: A single intratumoral injection of IL-12 and TNF-α–loaded PLAM into a breast tumor leads to infiltration by polymorphonuclear cells and CD8+ T-cells with subsequent tumor regression. In addition, this local therapy induces specific antitumor T-cells in the lymph nodes and spleens, resulting in memory immune response.

Key Words

Breast cancer IL-12 Immunotherapy Microspheres TNF-α 

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Copyright information

© The Society of Surgical Oncology, Inc. 2004

Authors and Affiliations

  • Michael S. Sabel
    • 1
    • 5
  • Joseph Skitzki
    • 1
  • Lloyd Stoolman
    • 2
  • Nejat K. Egilmez
    • 3
  • Edith Mathiowitz
    • 4
  • Nicola Bailey
    • 4
  • Wen-Jian Chang
    • 1
  • Alfred E. Chang
    • 1
  1. 1.Division of Surgical OncologyUniversity of MichiganAnn Arbor
  2. 2.Department of PathologyUniversity of MichiganAnn Arbor
  3. 3.SUNY at BuffaloBuffaloNew York
  4. 4.Brown UniversityProvidenceIsland
  5. 5.Division of Surgical OncologyUniversity of Michigan Comprehensive Cancer CenterAnn Arbor

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