Intratumoral immunotherapy of established solid tumors with chitosan/il-12

David A. Zaharoff, Kenneth W. Hance, Connie Jo Rogers, Jeffrey Schlom, John W. Greiner

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

IL-12 is a potent antitumor cytokine that exhibits significant clinical toxicities after systemic administration. We hypothesized that intratumoral (i.t.) administration of IL-12 coformulated with the biodegradable polysaccharide chitosan could enhance the antitumor activity of IL-12 while limiting its systemic toxicity. Noninvasive imaging studies monitored local retention of IL-12, with and without chitosan coformulation, after i.t. injection. Antitumor efficacy of IL-12 alone and IL-12 coformulated with chitosan (chitosan/IL-12) was assessed in mice bearing established colorectal (MC32a) and pancreatic (Panc02) tumors. Additional studies involving depletion of immune cell subsets, tumor rechallenge, and CTL activity were designed to elucidate mechanisms of regression and tumor-specific immunity. Coformulation with chitosan increased local IL-12 retention from 1 to 2 days to 5 to 6 days. Weekly i.t. injections of IL-12 alone eradicated ≤10% of established MC32a and Panc02 tumors, while i.t. chitosan/IL-12 immunotherapy caused complete tumor regression in 80% to 100% of mice. Depletion of CD4 or Gr-1 cells had no impact on chitosan/IL-12-mediated tumor regression. However, CD8 or NK cell depletion completely abrogated antitumor activity. I.t. chitosan/IL-12 immunotherapy generated systemic tumor-specific immunity, as >80% of mice cured with i.t. chitosan/IL-12 immunotherapy were at least partially protected from tumor rechallenge. Furthermore, CTLs from spleens of cured mice lysed MC32a and gp70 peptide-loaded targets. Chitosan/IL-12 immunotherapy increased local retention of IL-12 in the tumor microenvironment, eradicated established, aggressive murine tumors, and generated systemic tumor-specific protective immunity. Chitosan/IL-12 is a well-tolerated, effective immunotherapy with considerable potential for clinical translation.

Original languageEnglish (US)
Pages (from-to)697-705
Number of pages9
JournalJournal of Immunotherapy
Volume33
Issue number7
DOIs
StatePublished - Sep 1 2010

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Chitosan
Interleukin-12
Immunotherapy
Neoplasms
Immunity
Injections
Tumor Microenvironment
Natural Killer Cells
Polysaccharides

All Science Journal Classification (ASJC) codes

  • Immunology
  • Immunology and Allergy
  • Cancer Research
  • Pharmacology

Cite this

Zaharoff, David A. ; Hance, Kenneth W. ; Rogers, Connie Jo ; Schlom, Jeffrey ; Greiner, John W. / Intratumoral immunotherapy of established solid tumors with chitosan/il-12. In: Journal of Immunotherapy. 2010 ; Vol. 33, No. 7. pp. 697-705.
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abstract = "IL-12 is a potent antitumor cytokine that exhibits significant clinical toxicities after systemic administration. We hypothesized that intratumoral (i.t.) administration of IL-12 coformulated with the biodegradable polysaccharide chitosan could enhance the antitumor activity of IL-12 while limiting its systemic toxicity. Noninvasive imaging studies monitored local retention of IL-12, with and without chitosan coformulation, after i.t. injection. Antitumor efficacy of IL-12 alone and IL-12 coformulated with chitosan (chitosan/IL-12) was assessed in mice bearing established colorectal (MC32a) and pancreatic (Panc02) tumors. Additional studies involving depletion of immune cell subsets, tumor rechallenge, and CTL activity were designed to elucidate mechanisms of regression and tumor-specific immunity. Coformulation with chitosan increased local IL-12 retention from 1 to 2 days to 5 to 6 days. Weekly i.t. injections of IL-12 alone eradicated ≤10{\%} of established MC32a and Panc02 tumors, while i.t. chitosan/IL-12 immunotherapy caused complete tumor regression in 80{\%} to 100{\%} of mice. Depletion of CD4 or Gr-1 cells had no impact on chitosan/IL-12-mediated tumor regression. However, CD8 or NK cell depletion completely abrogated antitumor activity. I.t. chitosan/IL-12 immunotherapy generated systemic tumor-specific immunity, as >80{\%} of mice cured with i.t. chitosan/IL-12 immunotherapy were at least partially protected from tumor rechallenge. Furthermore, CTLs from spleens of cured mice lysed MC32a and gp70 peptide-loaded targets. Chitosan/IL-12 immunotherapy increased local retention of IL-12 in the tumor microenvironment, eradicated established, aggressive murine tumors, and generated systemic tumor-specific protective immunity. Chitosan/IL-12 is a well-tolerated, effective immunotherapy with considerable potential for clinical translation.",
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Intratumoral immunotherapy of established solid tumors with chitosan/il-12. / Zaharoff, David A.; Hance, Kenneth W.; Rogers, Connie Jo; Schlom, Jeffrey; Greiner, John W.

In: Journal of Immunotherapy, Vol. 33, No. 7, 01.09.2010, p. 697-705.

Research output: Contribution to journalArticle

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