PMID- 14559827
OWN - NLM
STAT- MEDLINE
DCOM- 20031203
LR  - 20181130
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 63
IP  - 19
DP  - 2003 Oct 1
TI  - Intratumoral delivery of dendritic cells engineered to secrete both interleukin 
      (IL)-12 and IL-18 effectively treats local and distant disease in association 
      with broadly reactive Tc1-type immunity.
PG  - 6378-86
AB  - Dendritic cells (DCs) were adenovirally engineered to constitutively and durably 
      secrete the potent Th1-biasing cytokines interleukin (IL)-12 (AdIL12DC) and/or 
      IL-18 (AdIL18DC) and evaluated for their ability to promote therapeutic antitumor 
      immunity in murine sarcoma models. Injection of either AdIL12DC or AdIL18DC into 
      day 7 CMS4 or MethA tumors resulted in tumor rejection or slowed tumor growth 
      when compared with control cohorts. Importantly, intratumoral injection with DCs 
      engineered to secrete both IL-12 and IL-18 (AdIL12/IL18DC) resulted in complete 
      and the most acute rejection of any treatment group analyzed. This strategy was 
      also effective in promoting the regression of contralateral, untreated tumors. 
      Both CD4+ and CD8+ T cells were required for tumor rejection. CD8+ splenic T 
      cells from mice treated with AdIL12/IL18DC produced the highest levels of 
      IFN-gamma in response to tumor rechallenge in vitro and displayed the broadest 
      repertoire of Tc1-type reactivity to acid-eluted, tumor-derived peptides among 
      all treatment cohorts. This apparent enhancement in cross-presentation of 
      tumor-associated epitopes in vivo may result from the increased capacity of 
      engineered DCs to kill tumor cells, survive tumor-induced apoptosis, and present 
      immunogenic MHC/tumor peptide complexes to T cells after intratumoral injection. 
      In support of this hypothesis, cytokine gene-engineered DCs expressed higher 
      levels of MHC and costimulatory molecules, as well as Fas ligand and 
      membrane-bound tumor necrosis factor alpha, with the latter markers associated 
      with elevated tumoricidal activity in vitro. Cytokine gene-engineered DCs 
      appeared to have a survival advantage in situ when injected into tumor lesions, 
      to be found in approximation with regions of tumor apoptosis, and to have the 
      capacity to ingest apoptotic tumor bodies. These results support the ability of 
      combined cytokine gene transfer to enhance multiple effector functions mediated 
      by intralesionally injected DCs that may concertedly promote cross-priming and 
      the accelerated immune-mediated rejection of tumors.
FAU - Tatsumi, Tomohide
AU  - Tatsumi T
AD  - Department of Surgery, University of Pittsburgh School of Medicine, The Hillman 
      Cancer Center, 5117 Center Avenue, Pittsburgh, PA 15213, USA.
FAU - Huang, Jian
AU  - Huang J
FAU - Gooding, William E
AU  - Gooding WE
FAU - Gambotto, Andrea
AU  - Gambotto A
FAU - Robbins, Paul D
AU  - Robbins PD
FAU - Vujanovic, Nikola L
AU  - Vujanovic NL
FAU - Alber, Sean M
AU  - Alber SM
FAU - Watkins, Simon C
AU  - Watkins SC
FAU - Okada, Hideho
AU  - Okada H
FAU - Storkus, Walter J
AU  - Storkus WJ
LA  - eng
GR  - CA 63350/CA/NCI NIH HHS/United States
GR  - DE 14775/DE/NIDCR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (Epitopes, T-Lymphocyte)
RN  - 0 (Interleukin-18)
RN  - 0 (Lymphotoxin-alpha)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (Tnfsf10 protein, mouse)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 187348-17-0 (Interleukin-12)
SB  - IM
MH  - Adenoviridae/genetics
MH  - Animals
MH  - Apoptosis Regulatory Proteins
MH  - CD8-Positive T-Lymphocytes/immunology
MH  - Dendritic Cells/*immunology/metabolism/physiology/virology
MH  - Epitopes, T-Lymphocyte/immunology
MH  - Female
MH  - Immunotherapy, Adoptive/*methods
MH  - Interleukin-12/biosynthesis/genetics/*immunology/metabolism
MH  - Interleukin-18/biosynthesis/genetics/*immunology/metabolism
MH  - Lymphotoxin-alpha/biosynthesis
MH  - Membrane Glycoproteins/biosynthesis
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Sarcoma, Experimental/immunology/*therapy
MH  - TNF-Related Apoptosis-Inducing Ligand
MH  - Th1 Cells/*immunology/metabolism
MH  - Transduction, Genetic
MH  - Tumor Necrosis Factor-alpha/biosynthesis
EDAT- 2003/10/16 05:00
MHDA- 2003/12/04 05:00
CRDT- 2003/10/16 05:00
PHST- 2003/10/16 05:00 [pubmed]
PHST- 2003/12/04 05:00 [medline]
PHST- 2003/10/16 05:00 [entrez]
PST - ppublish
SO  - Cancer Res. 2003 Oct 1;63(19):6378-86.