Programmable insect cell carriers for systemic delivery of integrated cancer biotherapy.
Due to cancer's genetic complexity, significant advances in the treatment of metastatic disease will require sophisticated, multi-pronged therapeutic approaches. Here we demonstrate the utility of a Drosophila melanogaster cell platform for the production and in vivo delivery of multi-gene biotherapeutic systems. We show that cultured Drosophila S2 cell carriers can stably propagate oncolytic viral therapeutics that are highly cytotoxic for mammalian cancer cells without adverse effects on insect cell viability or gene expression. Drosophila cell carriers administered systemically to immunocompetent animals trafficked to tumors to deliver multiple biotherapeutics with little apparent off-target tissue homing or toxicity, resulting in a therapeutic effect. Cells of this Dipteran invertebrate provide a genetically tractable platform supporting the integration of complex, multi-gene biotherapies while avoiding many of the barriers to systemic administration of mammalian cell carriers. These transporters have immense therapeutic potential as they can be modified to express large banks of biotherapeutics with complementary activities that enhance anti-tumor activity.
Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada. Electronic address: domroy@ohri.ca.
D G
DG
Roy
Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
A T
AT
Power
Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
M C
MC
Bourgeois-Daigneault
Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
T
T
Falls
Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
L
L
Ferreira
Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
A
A
Stern
Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
C
C
Tanese de Souza
Division of Experimental Therapeutics, Toronto General Research Institute, Toronto, Ontario, Canada.
J A
JA
McCart
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada; Apoptosis Research Center, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
D F
DF
Stojdl
Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics, Michael DeGroote Centre for Learning and Discovery, McMaster University, Hamilton, Ontario, Canada.
B D
BD
Lichty
Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
H
H
Atkins
Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
R C
RC
Auer
Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
J C
JC
Bell
Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
F
F
Le Boeuf
D000818:Animals; D002522:Chlorocebus aethiops; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics* / Q000276:immunology / Q000821:virology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D015316:Genetic Therapy / Q000379:methods*; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D007121:Immunocompetence; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy* / Q000821:virology; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D014709:Vero Cells; D023041:Xenograft Model Antitumor Assays
Cancer biotherapeutics; Cell carriers; Gene delivery; Oncolytic viruses; Systemic delivery