SA-4-1BBL and monophosphoryl lipid A as an adjuvant system for the development of effective therapeutic cancer vaccines (156.10)

Abstract

Abstract TAAs based subunit vaccines have compromised efficacy due to their weak immunogenic nature and various immune evasion mechanisms employed by the progressing tumors. To overcome these limitations, we herein used costimulatory molecule SA-4-1BBL and toll-like receptor 4 agonist MPL with distinct modes of action as a novel adjuvant system. A single immunization with both adjuvants and E7 TAA resulted in eradication of established E7 expressing TC-1 tumors in 100% of mice. Similarly, a single vaccination with survivin, a bona fide self-TAA, resulted in control/eradication of established 3LL pulmonary metastases. Combined adjuvants had better therapeutic efficacy over the individual adjuvants, while SA-4-1BBL as monotherapy significantly outperformed MPL. The therapeutic efficacy of combined adjuvants and SA-4-1BBL as monotherapy was correlated with potent Th1 responses and increased intratumoral CD8+ Teff/CD4+FoxP3+ Treg cell ratio. Surprisingly, MPL as monotherapy did not improve the intratumoral CD8+ Teff/Treg cell ratio as compared to controls, and depletion of Treg cells improved the efficacy of MPL from 50 to 100%. Taken together, these data demonstrate the utility of SA-4-1BBL/MPL as a promising adjuvant system for the development of therapeutic cancer vaccines with significant clinical potential.