Abstract
Subunit vaccines containing universal tumor associated antigens (TAAs) present an attractive treatment modality for cancer primarily due to their safety and potential to generate long-term immunological responses that can safeguard against recurrences. However, TAA-based subunit vaccines require potent adjuvants for therapeutic efficacy. Using a novel form of the 4-1BBL costimulatory molecule, SA-4-1BBL, as the adjuvant of choice, we previously demonstrated that a single vaccination with survivin (SVN) as a bona fide self TAA was effective in eradicating weakly immunogenic 3LL tumors in >70% of C57BL/6 mice. The present study was designed to i) assess the therapeutic efficacy of a prime-boost vaccination and ii) investigate the mechanistic basis of vaccine efficacy. Our data shows that a prime-boost vaccination strategy was effective in eradicating 3LL lung carcinoma in 100% of mice. The vaccine efficacy was correlated with increased percentages of CD8+ T cells expressing IFN-γ as well as potent killing responses of both CD8+ T and NK cells in the absence of detectable antibodies to ssDNA as a sign of autoimmunity. Antibody depletion of CD8+ T cells one day before vaccination completely abrogated therapeutic efficacy, whereas depletion of CD4+ T cells had no effect. Importantly, NK cell depletion had a moderate (∼50% reduction), but significant (p<0.05) effect on vaccine efficacy. Taken together, these results shed light on the mechanistic basis of the SA-4-1BBL/SVN subunit vaccine formulation in a lung carcinoma model and demonstrate the robust therapeutic efficacy of the prime-boost immunization strategy with important clinical implications.
Highlights
A large body of research over several decades has provided unequivocal evidence for the role of immunosurveillance in the control of cancer [1]
We have previously demonstrated that a single vaccination with SA-4-1BBL/SVN was effective in eliminating 3LL tumors in
This efficacy was improved to 100% when a booster injection of SA-4-1BBL/ SVN was given 5 days following primary immunization. This potent therapeutic efficacy was due to SA-4-1BBL as prime-boostimmunization with SVN alone was effective in eradicating tumors in only 25% of the mice (Fig. 2). These data confirm our previous findings with a single vaccination [7] and demonstrate the robust therapeutic efficacy of prime-boost immunization with SA-4-1BBL/SVN vaccine formulation
Summary
A large body of research over several decades has provided unequivocal evidence for the role of immunosurveillance in the control of cancer [1]. A series of clinical studies have recently demonstrated that immune system can effectively be exploited for the control and/or eradication of cancer [2], providing proof-of-feasibility and great opportunity for the development of innovative immune therapies. The therapeutic efficacy of subunit vaccines based on self TAAs is limited by low immunogenicity due to self-tolerance to such antigens and various immune evasion mechanisms employed by the progressing tumors [3,4]. Vaccine efficacy can further be improved by the choice of TAAs; antigens that are expressed/upregulated in the tumor as well as involved in tumor progression and/or immune evasion mechanisms represent ideal choices
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
