Rapid adenoviral transduction of freshly resected tumour explants with therapeutically useful genes provides a rationale for genetic immunotherapy for colorectal cancer.
To develop protocols for the molecular immunotherapy of colorectal cancer, we compared the efficacy of three separate classes of therapeutic genes to induce antitumour responses in a murine colorectal cell model. Thus, the effects of two cytokines (IL-2 and GM-CSF) were compared with those of a costimulatory gene (B7.1) and a suicide gene (HSVtk). The rank order of efficacy against primary tumour growth was HSVtk[GCV], B7.1 > puro, IL-2 > GM-CSF, neo whereas the order of efficacy in inducing antitumour immunity was GM-CSF, IL-2, > B7.1, HSVtk[GCV] > puro, neo in a prophylactic vaccination model. To exploit these data in a clinically relevant and realistic way, we also demonstrated that colorectal tumours can reproducibly be explanted and established in short-term culture. Finally, a rapid transduction protocol has been developed by which, using adenoviral vectors, as many as 90% of the cells in these fresh tumour explants can be engineered to express high levels of the clinically relevant genes (GM-CSF or IL-2) within 1-2 weeks of surgery. Adenovirus-mediated gene delivery was reproducibly and significantly more efficient than retroviral transduction using the MFG-beta-Gal retroviral vector over the time-frame of importance for vaccination. Hence, combination of the animal model data with the ex vivo modification protocol suggests that vaccination of colorectal patients of the appropriate stage will be possible and effective.
Diaz
R M
RM
Richard Dimbleby Department of Cancer Research/ICRF Laboratory, Rayne Institute, St Thomas' Hospital, London, UK.
Todryk
S
S
Chong
H
H
Hart
I R
IR
Sikora
K
K
Dorudi
S
S
Vile
R G
RG
D000256:Adenoviridae; D000818:Animals; D000963:Antimetabolites / Q000627:therapeutic use; D018122:B7-1 Antigen / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D016207:Cytokines / Q000235:genetics*; D015774:Ganciclovir / Q000627:therapeutic use; D015870:Gene Expression; D005822:Genetic Vectors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D013937:Thymidine Kinase / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured
D000963:Antimetabolites; D018122:B7-1 Antigen; D016207:Cytokines; D007376:Interleukin-2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013937:Thymidine Kinase; D015774:Ganciclovir