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A Chimeric 4‐1BBL as a Potent Adjuvant for Therapeutic Cancer Vaccines
Author(s) -
Sharma Rajesh Kumar,
Elpek Kutlu G,
Yolcu Esma S,
Schabowsky Richard H,
Zhao Hong,
Bandura Laura L,
Shirwan Haval
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1077.3
Subject(s) - adjuvant , immune system , cd8 , cancer immunotherapy , acquired immune system , biology , immunology , immunotherapy , immunity , innate immune system , cancer research , t cell , epitope , antibody
Objective: Inasmuch as adaptive immune responses are critical to immune surveillance and such responses are regulated by CD28 and TNFR family costimulatory molecules, we herein tested whether 4‐1BBL can serve as an effective adjuvant for therapeutic cancer vaccines. The choice of 4‐1BBL is due to its pleiotropic effect on the cells of innate, adaptive, and regulatory immunity. Inasmuch as 4‐1BBL has no function in soluble form, we generated a chimeric molecule consisting extracellular portions of 4‐1BBL fused C‐terminus to core streptavidin. Methods: Mice were injected with 1×10 5 TC‐1 cells expressing HPV E7 oncoprotein in the right flank. Once tumor was established, animals were vaccinated s.c. once with 50 μg of an E7 peptide serving as the dominant epitope for CD8 + T cells and 25 μg of SA‐4‐1BBL. The efficacy of vaccine was assed by monitoring animals for tumor growth, in vivo killing response, and intracellular cytokine staining. Results: Vaccination resulted in the eradication of existing tumors as well as prevention of recurrences after surgical removal of the tumors. The efficacy of immunotherapy was correlated with higher CD8+ T cell infiltration into tumors, the generation of robust T cell killing response, higher frequency of IFN‐γ expressing CD8+ T cells, and long‐term memory. Conclusion: This novel form of 4‐1BBL has the potential to serve as an effective adjuvant for the development of therapeutic cancer vaccines because of its role on adaptive, innate, and regulatory immunity. Funded in parts by 1R41AI071618, R43CA109866, R41 CA121665 , and JBCC Fellowship