Effect of suicide gene therapy in combination with immunotherapy on antitumour immune response & tumour regression in a xenograft mouse model for head & neck squamous cell carcinoma.
OBJECTIVE
Prodrug activation strategy as well as immunotherapy have been widely used for cancer gene therapy. In the present study, using a head and neck squamous cell carcinoma (HNSCC) xenograft nude mouse model, we have investigated whether the two therapies in combination could improve tumour cell kill. We also investigated induction of immune effector cells viz., NK (DX5+) and DC (CD11c+) in vivo, post-combination gene therapy.


METHODS
A retroviral vector producing cell line (PLTK47.1 VPC) carrying Herpes simplex virus thymidine kinase gene (HSVtk) was used for intratumoural injection into NT8e xenograft tumours followed by the prodrug ganciclovir (GCV). IL-2 plasmid DNA was injected intramuscularly. Immune cells were analyzed by flow-cytometry. Non parametric ANOVA was performed with Kruskal Wallis test.


RESULTS
IL-2 could induce proliferation of both NK cells (DX5+) and dendritic cells (CD11c+) in vivo. Apoptosis was higher in combination therapy group as compared to HSVtk/GCV alone or IL-2 alone and was mediated through caspase-3 dependent pathway. Significant reduction in tumour volume was seen in all 3 treatment arms as compared to controls.


CONCLUSIONS
Combination of suicide gene therapy and immunotherapy leads to successful tumour regression in a HNSCC xenograft mouse model. Immunotherapy could help in a systemic long lived anti-tumour immune response which would prove powerful for the treatment of metastatic cancers, and also for minimal residual disease. The results of this study may form the basis for Phase 1 clinical trials.
Ambade
Aditya V
AV
Advanced Center for Treatment Research & Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India.
Joshi
Ganesh V
GV
Mulherkar
Rita
R
D000704:Analysis of Variance; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects; D005434:Flow Cytometry; D041722:Genes, Transgenic, Suicide / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D020287:In Situ Nick-End Labeling; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects; D051379:Mice; D012190:Retroviridae; D018709:Statistics, Nonparametric; D023041:Xenograft Model Antitumor Assays
D007376:Interleukin-2