Type III secretion system-based vectors and cancer vaccination.
Recent interest in bacterial vectors as potentially useful in cancer therapy has arisen due to efforts to develop cancer vaccines. One type of bacterial vector that has attracted attention are the type III secretion system-based vectors.Studies from the Université Joseph Fourier in Grenoble, France have focussed on a type III Pseudomonas aeruginosa vector with promising results.
A live strain of the bacteria was engineered to allow recombinant antigenic proteins to be delivered to mice using the bacterial secretion system. Using the vector to deliver ovalbuminin to the antigen-presenting dendritic cells of mice resulted in the mice mounting an ovalbumin-specific CD8(+) T lymphocyte immune response and to the mice being resistant to a subsequent challenge with an ovalbumin-expressing melanoma. Also injection of the ovalbumin-delivering vector resulted in cure of five out of six mice that had been implanted with tumour.
Concerns around using these type III vectors in clinical trials for immunotherapy centre around factors such as the intrinsic toxicity of the vectors. The research group have addressed these issues by strategies such as deletion of quorum-sensing genes and the aroA gene. Bacteria use quorum sensing of the local bacterial population density to coordinate behaviours such as biofilm formation. Quorum sensing allows communication within a species and between species.Its mutation was associated with a slight reduction in toxicity while mutation of aroA, which makes the strain auxotrophic for aromatic amino acids, led to strongly reduced toxicity. Combination of both mutations resulted in a highly efficient bacterial strain in terms of T cell activation.
Further work to help improve the performance of the vectors has focussed on injection frequency and interval in mice and on adoption of a dual antigen rather than a single antigen delivery vector. These strategies have led to improvements in therapeutic efficacy, tumour rejection and safety. Safety has been further addressed by using a more attenuated mutant-CHA-OAL strain that is avirulent in mice. The infectivity of this stain is poor, but could be
improved by vaccination at multiple loci.
Altogether, the results of this group suggest potential for live attenuated type III secretion system-base P. aeruginosa vectors in cancer therapy.
Sources
EPAULARD, O. et al., 2008. Optimization of a type III secretion system-based Pseudomonas aeruginosa live vector for antigen delivery. Clinical And Vaccine Immunology: CVI, 15(2), pp. 308-313
EPAULARD, O. et al., 2006. Anti-tumor immunotherapy via antigen delivery from a live attenuated genetically engineered Pseudomonas aeruginosa type III secretion system-based vector. Molecular Therapy: The Journal Of The American Society Of Gene Therapy, 14(5), pp. 656-661
WANG, Y. et al., 2012. Optimization of antitumor immunotherapy mediated by type III secretion system-based live attenuated bacterial vectors. Journal Of Immunotherapy (Hagerstown, Md.: 1997), 35(3), pp. 223-234
Recent interest in bacterial vectors as potentially useful in cancer therapy has arisen due to efforts to develop cancer vaccines. One type of bacterial vector that has attracted attention are the type III secretion system-based vectors.Studies from the Université Joseph Fourier in Grenoble, France have focussed on a type III Pseudomonas aeruginosa vector with promising results.
A live strain of the bacteria was engineered to allow recombinant antigenic proteins to be delivered to mice using the bacterial secretion system. Using the vector to deliver ovalbuminin to the antigen-presenting dendritic cells of mice resulted in the mice mounting an ovalbumin-specific CD8(+) T lymphocyte immune response and to the mice being resistant to a subsequent challenge with an ovalbumin-expressing melanoma. Also injection of the ovalbumin-delivering vector resulted in cure of five out of six mice that had been implanted with tumour.
Concerns around using these type III vectors in clinical trials for immunotherapy centre around factors such as the intrinsic toxicity of the vectors. The research group have addressed these issues by strategies such as deletion of quorum-sensing genes and the aroA gene. Bacteria use quorum sensing of the local bacterial population density to coordinate behaviours such as biofilm formation. Quorum sensing allows communication within a species and between species.Its mutation was associated with a slight reduction in toxicity while mutation of aroA, which makes the strain auxotrophic for aromatic amino acids, led to strongly reduced toxicity. Combination of both mutations resulted in a highly efficient bacterial strain in terms of T cell activation.
Further work to help improve the performance of the vectors has focussed on injection frequency and interval in mice and on adoption of a dual antigen rather than a single antigen delivery vector. These strategies have led to improvements in therapeutic efficacy, tumour rejection and safety. Safety has been further addressed by using a more attenuated mutant-CHA-OAL strain that is avirulent in mice. The infectivity of this stain is poor, but could be
improved by vaccination at multiple loci.
Altogether, the results of this group suggest potential for live attenuated type III secretion system-base P. aeruginosa vectors in cancer therapy.
Sources
EPAULARD, O. et al., 2008. Optimization of a type III secretion system-based Pseudomonas aeruginosa live vector for antigen delivery. Clinical And Vaccine Immunology: CVI, 15(2), pp. 308-313
EPAULARD, O. et al., 2006. Anti-tumor immunotherapy via antigen delivery from a live attenuated genetically engineered Pseudomonas aeruginosa type III secretion system-based vector. Molecular Therapy: The Journal Of The American Society Of Gene Therapy, 14(5), pp. 656-661
WANG, Y. et al., 2012. Optimization of antitumor immunotherapy mediated by type III secretion system-based live attenuated bacterial vectors. Journal Of Immunotherapy (Hagerstown, Md.: 1997), 35(3), pp. 223-234
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