Priming and activation of human ovarian and breast cancer-specific CD8+ T cells by polyvalent Listeria monocytogenes-based vaccines.
Immunotherapeutic vaccine is potentially an effective strategy to combat cancer. Essential components of an effective vaccine must include antigens that are processed by the major histocompatibility complex class I pathway, presented by the tumor major histocompatibility complex molecules, and an effective antigen delivery platform that is capable of breaking self-tolerance. In this study, we characterized a set of ovarian cancer-specific T-cell epitopes delivered by live-attenuated recombinant Listeria monocytogenes (Lm DeltaactADeltainlB) as a vaccine vector. We present data that peptide-specific T cells recognize the human monocytic cell line THP-1 infected with recombinant Lm DeltaactADeltainlB encoding the epitopes. Furthermore, we demonstrate that recombinant L. monocytogenes (Lm)-infected antigen-presenting cells can prime and expand epitope-specific CD8 T cells in vitro and such CD8 T cells recognize not only peptide-loaded targets but also ovarian and breast tumor cells presenting endogenous epitopes. Finally, peptide-specific T cells generated using peripheral blood mononuclear cell from ovarian cancer patients recognize target cells infected with recombinant Lm DeltaactADeltainlB encoding the epitopes. Our results demonstrate that live-attenuated recombinant Lm can be used effectively as a vehicle to deliver cancer peptide antigens singly or as a multiepitope construct. Thus, the use of recombinant live-attenuated Lm strains encoding endogenously processed and presented tumor epitopes/antigens represents an attractive strategy for active cancer immunotherapy in a clinical setting.
Sinnathamby
Gomathinayagam
G
Immunotope, Inc, The Pennsylvania Biotechnology Center, Doylestown, PA 18902, USA.
Lauer
Peter
P
Zerfass
Jennifer
J
Hanson
Bill
B
Karabudak
Aykan
A
Krakover
Jonathan
J
Secord
Angeles Alvarez
AA
Clay
Timothy M
TM
Morse
Michael A
MA
Dubensky
Thomas W
TW
Brockstedt
Dirk G
DG
Philip
Ramila
R
Giedlin
Martin
M
D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D003001:Cloning, Molecular; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000378:metabolism; D005260:Female; D015789:HLA-A2 Antigen / Q000378:metabolism; D006801:Humans; D008089:Listeria monocytogenes / Q000276:immunology*; D008088:Listeriosis / Q000276:immunology; D008213:Lymphocyte Activation; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D010051:Ovarian Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen