Regression of mouse tumours and inhibition of metastases following administration of a Semliki Forest virus vector with enhanced expression of IL-12.
The Semliki Forest virus (SFV) vector is an RNA-based suicide expression vector that has been used experimentally for tumour therapy. Recently, a new enhanced vector pSFV10-E has been developed that expresses foreign genes at levels up to 10 times higher than the original vector. Interleukin-12 (IL-12), an immunomodulatory cytokine, plays a key role in the induction of T-helper1 responses. The two IL-12 gene subunits were cloned from mouse splenocytes and inserted into the pSFV10-E and pSFV10 (non-enhanced) vectors. Both constructs expressed and secreted biologically active murine IL-12. Administration of high titre rSFV10-E-IL12 particles intratumourally to treat implanted K-BALB tumours in BALB/c mice demonstrated complete tumour regression in comparison to control or rSFV10-IL12 treated groups. High titre rSFV10-E-IL12 particles were also effective in the CT26 tumour model. Histological and immunohistochemical studies revealed tumour necrosis in addition to aggressive influx of CD4+ and CD8+ T cells and other immune cells. Furthermore, inhibition of primary tumour growth and lung metastases of a metastatic (4T1) tumour model indicated the potential of high titres of rSFV10-E-IL12 particles as an efficient antitumour therapeutic agent.
Chikkanna-Gowda
C P
CP
Department of Microbiology, Moyne Institute, Trinity College, Dublin, Ireland.
Sheahan
B J
BJ
Fleeton
M N
MN
Atkins
G J
GJ
D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D007150:Immunohistochemistry / Q000379:methods; D007167:Immunotherapy / Q000379:methods*; D018664:Interleukin-12 / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic; D012672:Semliki forest virus / Q000235:genetics; D014161:Transduction, Genetic / Q000379:methods
D014408:Biomarkers, Tumor; D018664:Interleukin-12