Microenvironment and Immunology SA-4-1BBL and Monophosphoryl Lipid A Constitute an Efficacious Combination Adjuvant for Cancer Vaccines

Vaccines based on tumor-associated antigens (TAA) have limited therapeutic efficacy due to their weak immunogenic nature and the various immune evasion mechanisms active in advanced tumors. In an effort to overcome these limitations, we evaluated a combination of the T-cell costimulatorymolecule SA-4-1BBLwith the TLR4 agonist monophosphoryl lipid A (MPL) as a novel vaccine adjuvant system. In the TC-1 mouse allograft model of human papilloma virus (HPV)-induced cancer, a single administration of this combination adjuvant withHPVE7 protein caused tumor rejection in all tumor-bearingmice. On its own, SA-4-1BBL outperformedMPL in this setting. Against established tumors, two vaccinations were sufficient to elicit rejection in the majority of mice. In the metastatic model of Lewis lung carcinoma, vaccination of the TAA survivin with SA-4-1BBL/MPL yielded superior efficacy against pulmonary metastases. Therapeutic efficacy of SA-4-1BBL/MPL was achieved in the absence of detectable toxicity, correlating with enhanced dendritic cell activation, CD8þ T-cell function, and an increased intratumoral ratio of CD8þ T effector cells to CD4þFoxP3þ T regulatory cells. Unexpectedly, use of MPL on its own was associated with unfavorable intratumoral ratios of these T-cell populations, resulting in suboptimal efficacy. The efficacy of MPL monotherapy was restored by depletion of T regulatory cells, whereas eliminating CD8þ T cells abolished the efficacy of its combination with SA-4-1BBL. Mechanistic investigations showed that IFNg played a critical role in supporting the therapeutic effect of SA-4-1BBL/MPL. Taken together, our results offer a preclinical proof of concept for the use of a powerful new adjuvant system for TAA-based cancer vaccines. Cancer Res; 74(22); 1–11. 2014 AACR.