Induced pluripotent stem cell-derived neural stem cells transduced with baculovirus encoding CD40 ligand for immunogene therapy in mouse models of breast cancer.
The interaction between CD40 ligand (CD40L) and CD40 can directly inhibit growth of CD40-positive carcinoma cells and may indirectly inhibit tumor growth through coordination of immune responses. Many efforts in CD40L cancer gene therapy have been focused on direct CD40L gene transfer into malignant target cells. This in vivo gene therapy approach relies on high-efficiency gene transfer and could be technically challenging for the treatment of certain cancers, especially multisite metastases. We report herein an alternative means of using the tumor-homing property of neural stem cells (NSCs) to deliver CD40L molecules into tumor tissues. NSCs were derived from human induced pluripotent stem cells, transduced in vitro with a baculoviral vector encoding CD40L, and intravenously injected into immunocompetent mice with orthotopic and metastatic breast cancers. Through a bystander mechanism of intercellular transfer of CD40L from the donor NSCs to tumor target cells, the treatment impeded tumor growth, leading to prolonged survival of the tumor-bearing mice. We further showed that compared with the stem cell-based gene therapy that employed a suicide gene, the CD40L immunogene therapy did not cause liver and kidney injury in the treated mice. This new approach may be particularly valuable for metastatic cancer treatments after systemic stem cell administration.
1 Department of Biological Sciences, National University of Singapore , Singapore 117543.
Detu
D
Zhu
Can
C
Chen
Yovita Ida
YI
Purwanti
Shouhui
S
Du
Dang Hoang
DH
Lam
Chunxiao
C
Wu
Jieming
J
Zeng
Han Chong
HC
Toh
Shu
S
Wang
D000818:Animals; D017209:Apoptosis; D016367:Baculoviridae / Q000235:genetics*; D001943:Breast Neoplasms / Q000473:pathology / Q000628:therapy*; D023201:CD40 Ligand / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D008175:Lung Neoplasms / Q000556:secondary / Q000628:therapy*; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D058953:Neural Stem Cells / Q000378:metabolism*; D014161:Transduction, Genetic
D016207:Cytokines; D023201:CD40 Ligand