Construction and characterization of an attenuated Listeria monocytogenes strain for clinical use in cancer immunotherapy.
Listeria monocytogenes has been exploited previously as a vaccine vector for the delivery of heterologous proteins such as tumor-specific antigens for active cancer immunotherapy. However, for effective use of live vector in clinics, safety is a major concern. In the present study, we describe an irreversibly attenuated and highly immunogenic L. monocytogenes platform, the L. monocytogenes dal-, dat-, and actA-deleted strain that expresses the human prostate-specific antigen (PSA) using an antibiotic resistance marker-free plasmid (the dal dat DeltaactA 142 strain expressing PSA). Despite limited in vivo survival, the dal dat DeltaactA 142 strain was able to elicit efficient immune responses required for tumor clearance. Our results showed that immunization of mice with the dal dat DeltaactA 142 strain caused the regression of the tumors established by the prostate adenocarcinoma cell line expressing PSA. An evaluation of immunologic potency indicated that the dal dat DeltaactA 142 strain elicits a high frequency of PSA-specific immune responses. Interestingly, immunization with the dal dat DeltaactA 142 strain induced significant infiltration of PSA-specific T cells in the intratumoral milieu. Collectively, our data suggest that the dal dat DeltaactA 142 strain is a safe and potent vector for clinical use and that this platform may be further exploited as a potential candidate to express other single or multiple antigens for cancer immunotherapy.
Wallecha
Anu
A
Research and Development, Advaxis Inc., 675 US Highway One, Suite 120, Technology Center of New Jersey, North Brunswick, NJ 08902, USA. wallecha@advaxis.com
Maciag
Paulo Cesar
PC
Rivera
Sandra
S
Paterson
Yvonne
Y
Shahabi
Vafa
V
D000230:Adenocarcinoma / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D017353:Gene Deletion; D005798:Genes, Bacterial; D007167:Immunotherapy / Q000379:methods*; D008089:Listeria monocytogenes / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000628:therapy*; D010957:Plasmids; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000276:immunology; D016019:Survival Analysis; D014613:Vaccines, Attenuated / Q000235:genetics / Q000276:immunology
D019496:Cancer Vaccines; D014613:Vaccines, Attenuated; D017430:Prostate-Specific Antigen