Costimulation as a platform for the development of vaccines: a peptide-based vaccine containing a novel form of 4-1BB ligand eradicates established tumors.
Vaccines represent an attractive treatment modality for the management of cancer primarily because of their specificity and generation of immunologic memory important for controlling recurrences. However, the efficacy of therapeutic vaccines may require formulations that not only generate effective immune responses but also overcome immune evasion mechanisms employed by progressing tumor. Costimulatory molecules play critical roles in modulating innate, adaptive, and regulatory immunity and have potential to serve as effective immunomodulatory components of therapeutic vaccines. In this study, we tested the function of a novel soluble form of 4-1BB ligand (4-1BBL) costimulatory molecule in modulating innate, adaptive, and regulatory immunity and assessed its therapeutic efficacy in the HPV-16 E7-expressing TC-1 cervical cancer and survivin-expressing 3LL lung carcinoma mouse models. Vaccination with 4-1BBL activated dendritic cells and enhanced antigen uptake, generated CD8(+) T-cell effector/memory responses, and endowed T effector cells refractory to suppression by CD4(+)CD25(+)FoxP3(+) T regulatory cells. Immunization with 4-1BBL in combination with an E7 peptide or survivin protein resulted in eradication of TC-1 and 3LL tumors, respectively. 4-1BBL was more effective than TLR agonists LPS, MPL, and CpG and an agonistic 4-1BB antibody as a component of E7 peptide-based therapeutic vaccine for the generation of immune responses and eradication of TC-1 established tumors in the absence of detectable toxicity. Therapeutic efficacy was associated with reversal of tumor-mediated nonresponsiveness/anergy as well as establishment of long-term CD8(+) T-cell memory. Potent pleiotropic immunomodulatory activities combined with lack of toxicity highlight the potential of 4-1BBL molecule as an effective component of therapeutic cancer vaccines.
Institute for Cellular Therapeutics, Department of Microbiology and Immunology, and James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
Rajesh K
RK
Sharma
Kutlu G
KG
Elpek
Esma S
ES
Yolcu
Rich-Henry
RH
Schabowsky
Hong
H
Zhao
Laura
L
Bandura-Morgan
Haval
H
Shirwan
D053330:4-1BB Ligand / Q000172:deficiency / Q000235:genetics / Q000627:therapeutic use*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D051034:Inhibitor of Apoptosis Proteins; D008175:Lung Neoplasms / Q000276:immunology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000627:therapeutic use; D012097:Repressor Proteins; D000077022:Survivin; D002583:Uterine Cervical Neoplasms / Q000276:immunology
D053330:4-1BB Ligand; C117749:Birc5 protein, mouse; D019496:Cancer Vaccines; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D012097:Repressor Proteins; D000077022:Survivin