Local administration of IL-12-transfected dendritic cells induces antitumor immune responses to colon adenocarcinoma in the liver in mice.
Colorectal cancer is one of the most common fatal malignancies in the United States, with an incidence second only to lung cancer. The liver is the most common site of colorectal metastases and frequently the only affected organ once the primary tumor has been surgically removed. The only potentially curative treatment for metastatic colorectal cancer in the liver is surgery, although most patients are not eligible for resection. We have therefore, evaluated the therapeutic efficacy of dendritic cells (DCs) engineered to express IL-12 in a liver metastasis model. Direct administration of DCs into the portal vein significantly inhibited the growth of established MC38 colon carcinoma in the liver in C57BL/6 mice. This effect was accompanied by an intratumoral accumulation of CD4+, CD8+, and NLDC-145+ immune effector cells, and also resulted in a systemic immune response as determined by enhanced production of IFN-gamma by T lymphocytes isolated from both spleen and draining lymph nodes. Evaluation of homing of Cy3-labeled DCs following the portal vein injection confirmed their distribution in the liver and lymphoid tissue. Thus, a local delivery of DCs transduced with the IL-12 gene can not only inhibit colorectal tumor growth in vivo but also mount systemic antitumor immune responses. This approach is likely to improve the outcome of immunotherapy for metastatic colorectal cancer since high numbers of tumor-associated DCs positively correlate with a more favorable prognosis. Simultaneous local gene therapy with IL-12 will further improve clinical efficacy without placing the patient at risk for systemic toxicity.
Satoh
Yuji
Y
Biologic Therapeutics Program, University of Pittsburgh Cancer Institute, 5725 CHP-MT, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
Esche
Clemens
C
Gambotto
Andrea
A
Shurin
Galina V
GV
Yurkovetsky
Zoya R
ZR
Robbins
Paul D
PD
Watkins
Simon C
SC
Todo
Satoru
S
Herberman
Ronald B
RB
Lotze
Michael T
MT
Shurin
Michael R
MR
D000230:Adenocarcinoma / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002455:Cell Division / Q000502:physiology; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D006801:Humans; D007111:Immunity, Cellular; D016219:Immunotherapy, Adoptive; D018664:Interleukin-12 / Q000235:genetics* / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000276:immunology / Q000556:secondary / Q000628:therapy; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014161:Transduction, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000378:metabolism / Q000637:transplantation
D015703:Antigens, CD; D018664:Interleukin-12