Abstract 765: Costimulatory SA-4-1BBL and monophosphoryl lipid A as novel adjuvant system for the development of cancer vaccines with robust therapeutic efficacy

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Subunit vaccines based on tumor-associated antigens (TAAs) represent an attractive alternative to conventional treatments for cancer due to their safety profile and ability to control recurrences by establishing long-term immunological memory. However, the efficacy of TAA-based therapeutic vaccines is limited by weak immunogenic nature of these antigens and various immune evasion mechanisms employed by the progressing tumor. To overcome these limitations, we herein used SA-4-1BBL costimulatory molecule and toll-like receptor 4 agonist monophosphoryl lipid A (MPL) as two immunomodulators with distinct mechanisms of action as a novel adjuvant system for the development of HPV16 E7 and survivin TAA-based therapeutic vaccines against TC-1 cervical and 3LL pulmonary carcinoma mouse models, respectively. A single immunization with a vaccine formulation containing E7 protein plus SA-4-1BBL and MPL resulted in the eradication of established E7 expressing TC-1 tumors in 100% of mice. Similarly, a single vaccination with survivin, as a bona fide self-TAA, resulted in control and/or eradication of established 3LL pulmonary metastases and the efficacy of the vaccine was further improved by a booster injection. Combined adjuvants had better therapeutic efficacy over the individual agents while SA-4-1BBL significantly performed better than MPL. The therapeutic efficacy achieved with the combinatorial use of both adjuvants and SA-4-1BBL as monotherapy was correlated with elevated levels of IFN-γ+TNF-α+IL-2+ triple positive antigen-specific CD8+ T cells, cytotoxic response, long-term immune memory, and most importantly an increase in the intratumoral number of CD8+ T effector cells with simultaneous decrease in the number of CD4+FoxP3+ T regulatory cells, resulting in a favorable T effector/T regulatory cell ratio. In marked contrast, although MPL as monotherpay improved the effector function of CD8+ T cells, it did not increase the infiltration of these cells into the tumor. Surprisingly, MPL as monotherapy increased the number of CD4+FoxP3+ T regulatory cells infiltrating into the tumor, resulting in an unfavorable T effector/T regulatory cell ratio. Taken together, these data demonstrate the utility of using SA-4-1BBL and MPL as a novel adjuvant system for the development of therapeutic TAA-based subunit cancer vaccines with strong clinical implications. Work is in part funded by NIH 2R44 [AI071618][1]-02, R43 [AI074176][2], R41 [CA121665][3], KLCP, the W.M. Keck Foundation, and the Commonwealth of Kentucky Research Challenge Trust Fund. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 765. doi:10.1158/1538-7445.AM2011-765 [1]: /lookup/external-ref?link_type=GEN&access_num=AI071618&atom=%2Fcanres%2F71%2F8_Supplement%2F765.atom [2]: /lookup/external-ref?link_type=GEN&access_num=AI074176&atom=%2Fcanres%2F71%2F8_Supplement%2F765.atom [3]: /lookup/external-ref?link_type=GEN&access_num=CA121665&atom=%2Fcanres%2F71%2F8_Supplement%2F765.atom