Neoadjuvant intratumoral cytokine-loaded microspheres are superior to postoperative autologous cellular vaccines in generating systemic anti-tumor immunity.
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 anti-tumor response by IFNgamma 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 B16 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.
Arora
Alisha
A
Division of Surgical Oncology, University of Michigan, Ann Arbor, Michigan 48109-0932, USA.
Su
Gang
G
Mathiowitz
Edith
E
Reineke
Joshua
J
Chang
Alfred E
AE
Sabel
Michael S
MS
D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage*; D016219:Immunotherapy, Adoptive; D015552:Injections, Intralesional; D018664:Interleukin-12 / Q000008:administration & dosage*; D019344:Lactic Acid; D008198:Lymph Nodes / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008863:Microspheres; D020360:Neoadjuvant Therapy; D011091:Polyesters; D011108:Polymers; D011184:Postoperative Period; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*
D019496:Cancer Vaccines; D011091:Polyesters; D011108:Polymers; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D019344:Lactic Acid; C033616:poly(lactide); D016178:Granulocyte-Macrophage Colony-Stimulating Factor