Journal
JOURNAL OF SURGICAL ONCOLOGY
Volume 94, Issue 5, Pages 403-412Publisher
WILEY
DOI: 10.1002/jso.20572
Keywords
melanoma; microspheres; immunotherapy; intralesional; intratumoral; interleukin-12 (IL-12); tumor necrosis factor alpha (TNF-alpha); granulocyte-macrophage colony stimulating factor (GM-CSF); in situ vaccination
Funding
- NCI NIH HHS [CA102602-01] Funding Source: Medline
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Background: Sustained intratumoral cytokine release using poly-lactic acid microspheres (PLAMs) can induce a systemic immune response, shifting immunotherapy to the neoadjuvant setting. Methods: C57BL6 mice with established B16 melanomas underwent a single intralesional injection of IL-12, TNF-alpha or GM-CSF PLAM, alone or in combination. Tumor draining lymph nodes (TDLN) and spleens were assessed for a specific antitumor response by IFN gamma release assay and ELISPOT. Results: Intralesional injection of TNF-alpha, alone or in combination, resulted in significant tumor ablation. The induction of tumor specific reactive T-cells in the TDLN was greatest with IL-12 and TNF-alpha. Only mice treated with IL-12 and TNF-alpha demonstrated a substantial T-cell response in cultured splenocytes. This combination resulted in a significant reduction in new tumors after re-challenge. Adjuvant therapy, using irradiated B 16 cells in combination with equivalent doses of IL-12 and TNF-alpha, failed to generate a similar T-cell response or prevent re-challenge. Conclusions: Intratumoral IL-12 and TNF-alpha loaded PLAM leads to both local eradication of tumor and the induction of specific anti-tumor T-cells in the lymph nodes and spleens, resulting in memory immune response. Neoadjuvant treatment was significantly superior to postoperative autologous cellular vaccines using IL-12 and TNF-alpha PLAM.
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