Immunomodulatory gene therapy with interleukin 12 and 4-1BB ligand: Long-term remission of liver metastases in a mouse model

被引:93
|
作者
Martinet, O
Ermekova, V
Qiao, JQ
Sauter, B
Mandeli, J
Chen, LP
Chen, SH
机构
[1] CUNY Mt Sinai Sch Med, Inst Gene Therapy & Mol Med, New York, NY 10029 USA
[2] CUNY Mt Sinai Sch Med, Dept Surg, New York, NY 10029 USA
[3] CUNY Mt Sinai Sch Med, Dept Biomath Sci, New York, NY 10029 USA
[4] Mayo Clin, Dept Immunol, Rochester, MN USA
关键词
D O I
10.1093/jnci/92.11.931
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: The success of immunomodulatory cancer therapy is frequently hampered by the transient nature of the antitumor immune response. We have shown previously in a mouse model that interleukin 12 (IL-12) generates a strong natural killer (NK) cell-mediated antitumor response and reduces liver metastases induced by a colon carcinoma cell line, However, only a small percentage of the treated animals developed the cytotoxic T-lymphocytic response required for a long-term systemic antitumor immunity, 4-1BB is a co-stimulatory molecule expressed on the surface of activated T cells. Interaction of 4-1BB with its natural ligand (4-1BBL) has been shown to amplify T-cell (especially CD8+)-mediated immunity, In this study, we investigated the effects of adenovirus-mediated gene therapy delivering both IL-12 and 4-1BBL genes on mice with hepatic metastases induced by colon cancer cells. Methods: Syngeneic BALB/c mice received intrahepatic injection of poorly immunogenic MCA26 colon cancer cells. Various combinations of replication-defective adenoviruses expressing IL-12 and 4-1BBL genes were injected into the established liver tumors. Changes in tumor size and animal survival were then monitored. All statistical tests were two-sided, Results: The long-term survival rate of mice treated with the combination of IL-12 and 4-1BBL was significantly improved over that of animals in the control group (P = .0001). In vivo depletion of NK cells or CD8+ T cells completely abolished the long-term survival advantage of the IL-12 plus 4-1BBL-treated animals (P<.002). Moreover, the systemic immunity induced by this combination treatment protected these animals against a subcutaneous challenge with parental MCA26 cells, Conclusion: Adenovirus-mediated transfer of IL-12 and 4-1BBL genes directly into liver tumors resulted in tumor regression that required both NK and CD8+ T cells and generated a potent, long-lasting antitumor immunity.
引用
收藏
页码:931 / 936
页数:6
相关论文
共 50 条
  • [21] Liver directed lentiviral gene therapy provides long term phenotypic correction of methylmalonic acidemia in a mouse model
    Barbon, E.
    Negri, C.
    Raimondi, A.
    Fabiano, A.
    Russo, F.
    la Marca, G.
    Cantore, A.
    HUMAN GENE THERAPY, 2022, 33 (23-24) : A171 - A171
  • [22] Gene Therapy for X-Linked Retinitis Pigmentosa: A Long-Term Efficacy Study in a Mouse Model of RPGR Deficiency
    Wu, Zhijian
    Hiriyanna, Suja
    Qian, Haohua
    Mookherjee, Suddhasil
    Kaneshiro, Kayleigh
    Campos, Maria
    Gao, Chun
    Fariss, Robert
    Li, Tiansen
    Colosi, Peter
    Swaroop, Anand
    MOLECULAR THERAPY, 2014, 22 : S209 - S209
  • [23] Neuroprotective Effect of Long-term NDI1 Gene Expression in a Chronic Mouse Model of Parkinson Disorder
    Barber-Singh, Jennifer
    Seo, Byoung Boo
    Nakamaru-Ogiso, Eiko
    Lau, Yuen-Sum
    Matsuno-Yagi, Akemi
    Yagi, Takao
    REJUVENATION RESEARCH, 2009, 12 (04) : 259 - 267
  • [24] Combined 5-fluorouracil/systemic interferon-β gene therapy results in long-term survival in mice with established colorectal liver metastases
    Choi, EA
    Lei, HQ
    Maron, DJ
    Mick, R
    Barsoum, J
    Yu, QC
    Fraker, DL
    Wilson, JM
    Spitz, FR
    CLINICAL CANCER RESEARCH, 2004, 10 (04) : 1535 - 1544
  • [25] 4-1BB promotes long-term survival in skin allografts treated with anti-CD45RB and anti-CD40L monoclonal antibodies
    Lee, J
    Lee, EN
    Kim, EY
    Lee, HJ
    Park, HJ
    Sun, CL
    Lee, SK
    Joh, JW
    Lee, KW
    Kwon, GY
    Kim, SJ
    TRANSPLANTATION PROCEEDINGS, 2005, 37 (01) : 123 - 125
  • [26] Long-Term Improvement of Neurological Signs and Metabolic Dysfunction in a Mouse Model of Krabbe's Disease after Global Gene Therapy
    Marshall, Michael S.
    Issa, Yazan
    Jakubauskas, Benas
    Stoskute, Monika
    Elackattu, Vince
    Marshall, Jeffrey N.
    Bogue, Wil
    Duc Nguyen
    Hauck, Zane
    Rue, Emily
    Karumuthil-Melethil, Subha
    Zaric, Violeta
    Bosland, Maarten
    van Breemen, Richard B.
    Givogri, Maria, I
    Gray, Steven J.
    Crocker, Stephen J.
    Bongarzone, Ernesto R.
    MOLECULAR THERAPY, 2018, 26 (03) : 874 - 889
  • [27] Long term vision restoration by gene therapy in the rd12 mouse model of RPE65 leber congenital amaurosis
    Pang, J
    Chang, B
    Kumar, A
    Nusinowitz, S
    Noorwez, SM
    Rani, A
    McDowell, H
    Foster, TC
    Kaushal, S
    Hauswirth, WW
    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2005, 46
  • [28] Enhanced Insulin Sensitivity Underlies Long-Term Remission in Response to Early Sulfonylurea Therapy in a Mouse Model of KATP-Induced Neonatal Diabetes Mellitus
    Remedi, Maria S.
    Vyas, Arpita K.
    Hruz, Paul W.
    Nichols, Colin G.
    DIABETES, 2011, 60 : A535 - A535
  • [29] LONG-TERM EFFECTS OF AAV9-MICRORNA-MEDIATED GENE SILENCING IN A CMT1A MOUSE MODEL
    Stavrou, Marina
    Richter, Jan
    Tryfonos, Christina
    Heslegrave, Amanda
    Zetterberg, Henrik
    Christodoulou, Christina
    Harper, Scott
    Kleopa, Kleopas
    JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, 2022, 27 : S128 - S129
  • [30] Triple costimulation via CD80, 4-1BB, and CD83 ligand elicits the long-term growth of Vγ9Vδ2 T cells in low levels of IL-2
    Cho, Hyun-Woo
    Kim, Su-Yeon
    Sohn, Dae-Hee
    Lee, Min-Ji
    Park, Mi-Young
    Sohn, Hyun-Jung
    Cho, Hyun-Il
    Kim, Tai-Gyu
    JOURNAL OF LEUKOCYTE BIOLOGY, 2016, 99 (04) : 521 - 529