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Intratumoral delivery of encapsulated IL-12, IL-18 and TNF-α in a model of metastatic breast cancer

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Abstract

Intratumoral (i.t.) cytokine release through the use of poly-lactic acid microspheres (PLAM) holds tremendous potential for the immunotherapy of breast cancer as it harnesses the immunologic potential of autologous tumor in a clinically feasible and minimally toxic manner. We examined the potential of combinations of i.t. IL-12, IL-18 and TNF-α PLAM to generate a tumor-specific immune response and improve outcome in a model of metastatic breast cancer. Balb/c mice with established 4T1 mammary carcinomas were treated with a single injection of BSA, IL-12, IL-18 or TNF-α-loaded PLAM alone or in combination after spontaneous metastases occurred. Combined treatment with IL-12 and TNF-α PLAM was superior to all other treatments, including the triple combination of IL-12, IL-18 and TNF-α in ablation of the primary tumor, eradicating distant disease and enhancing survival. Simultaneous delivery of IL-12 and TNF-α was superior to sequential delivery of IL-12 followed by TNF-α, but not TNF-α followed by IL-12. In vivo lymphocyte depletion studies established that the effects of IL-12 alone are mediated primarily by NK cells, while the combination of IL-12 and TNF-α is dependent upon CD8+ T-cells. Only the combination of IL-12 and TNF-α results in an increase in both CD4+ and CD8+ T-cells and a reduction in CD4+CD25+ cells. While there was no change in the dendritic cell population, IL-12 and TNF-α resulted in a dramatic increase in DC maturation and antigen presentation. Neoadjuvant immunotherapy with simultaneous intratumoral delivery of IL-12 and TNF-α PLAM augments DC antigen presentation and increases cytotoxic T-cells without increasing regulatory T-cells, resulting in a T-cell based anti-tumor immune response capable of eradicating disseminated disease. The addition of IL-18 did not improve the efficacy.

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Acknowledgments

This work was in part funded by NIH Grant CA102602-01.

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Authors and Affiliations

  1. Division of Surgical Oncology, University of Michigan, Ann Arbor, MI, USA

    Michael S. Sabel, Gang Su & Alfred E. Chang

  2. Department of Biostatistics, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA

    Kent A. Griffith

  3. 3304 Cancer Center, 1500 East Medical Center Drive, Ann Arbor, MI, 48109-0932, USA

    Michael S. Sabel

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  1. Michael S. Sabel
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  2. Gang Su
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  4. Alfred E. Chang
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Correspondence to Michael S. Sabel.

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Sabel, M.S., Su, G., Griffith, K.A. et al. Intratumoral delivery of encapsulated IL-12, IL-18 and TNF-α in a model of metastatic breast cancer. Breast Cancer Res Treat 122, 325–336 (2010). https://doi.org/10.1007/s10549-009-0570-3

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  • DOI: https://doi.org/10.1007/s10549-009-0570-3

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