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Intratumoral immunotherapy of established solid tumors with chitosan/IL-12.

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Intratumoral immunotherapy of established solid tumors with chitosan/IL-12.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Zaharoff, David A. Hance, Kenneth W. Rogers, Connie J. Schlom, Jeffrey Greiner, John W.
Description	Country affiliation: United States Author Affiliation: Zaharoff DA ( Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. zaharoff@uark.edu)
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.
File Format	HTM / HTML
ISSN	15249557
e-ISSN	15374513
DOI	10.1097/CJI.0b013e3181eb826d
Journal	Journal of Immunotherapy
Issue Number	7
Volume Number	33
Language	English
Publisher	Lippincott Williams & Wilkins
Publisher Date	2010-09-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Immunology Discipline Therapeutics Adjuvants, Immunologic Administration & Dosage Chitosan Colorectal Neoplasms Therapy Immunotherapy Pancreatic Neoplasms Animals Carcinoembryonic Antigen Genetics Cells, Cultured Immunology Cytotoxicity, Immunologic Drug Effects Immunologic Memory Interleukin-12 Adverse Effects Lymphocyte Depletion Mice Mice, Inbred C57bl Mice, Transgenic Neoplasm Transplantation Remission Induction Tumor Burden
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Cancer Research Immunology Pharmacology

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