Development of a Listeria monocytogenes based vaccine against prostate cancer.
Prostate specific antigen (PSA) is a likely immunotherapeutic target antigen for prostate cancer, the second leading cause of cancer-related death in American men. Previously, we demonstrated that attenuated strains of Listeria monocytogenes (Lm) can be used as effective vaccine vectors for delivery of tumor antigens causing regression of established tumors accompanied by strong immune responses toward these antigens in murine models of cancer. In the present study, we have developed and characterized a recombinant live attenuated L. monocytogenes/PSA (Lm-LLO-PSA) vaccine with potential use for the treatment of pCa. Human PSA gene was cloned into and expressed by an attenuated Lm strain. This recombinant bacterial vaccine, Lm-LLO-PSA was tested for stability, virulence, immunogenicity and anti-tumor effects in a murine model for pCa. Immunization with Lm-LLO-PSA was shown to lower the number of tumor infiltrating T regulatory cells and cause complete regression of over 80% of tumors formed by an implanted genetically modified mouse prostate adenocarcinoma cell line, which expressed human PSA. Lm-LLO-PSA was immunogenic in C57BL/6 mice and splenocytes from mice immunized with Lm-LLO-PSA showed significantly higher number of IFN-gamma secreting cells over that of the naïve animals in response to a PSA H2Db-specific peptide, as measured by both, ELISpot and intracellular cytokine staining. In addition, using a CTL assay we show that the T cells specific for PSA were able to recognize and lyse PSA-peptide pulsed target cells in vitro. In a comparison study with two other PSA-based vaccines (a pDNA and a vaccinia vaccine), Lm-LLO-PSA was shown to be more efficacious in regressing established tumors when used in a homologues prime/boost regimen. Together, these results indicate that Lm-LLO-PSA is a potential candidate for pCa immunotherapy and should be further developed.
Shahabi
Vafa
V
Research and Development, Advaxis, Inc, North Brunswick, NJ, USA. shahabi@advaxis.com
Reyes-Reyes
Mariela
M
Wallecha
Anu
A
Rivera
Sandra
S
Paterson
Yvonne
Y
Maciag
Paulo
P
D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry; D000970:Antineoplastic Agents / Q000494:pharmacology; D001427:Bacterial Toxins / Q000737:chemistry; D019496:Cancer Vaccines; D006360:Heat-Shock Proteins / Q000737:chemistry; D006460:Hemolysin Proteins / Q000737:chemistry; D006801:Humans; D007107:Immune System; D007167:Immunotherapy / Q000379:methods; D008089:Listeria monocytogenes / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000628:therapy*; D014774:Virulence
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D001427:Bacterial Toxins; D019496:Cancer Vaccines; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; C038705:hlyA protein, Listeria monocytogenes