title: SA-4-1BBL and monophosphoryl lipid A constitute an efficacious combination adjuvant for cancer vaccines.
abstract: 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 costimulatory molecule SA-4-1BBL with 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 with HPV E7 protein caused tumor rejection in all tumor-bearing mice. On its own, SA-4-1BBL outperformed MPL 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, CD8(+) T-cell function, and an increased intratumoral ratio of CD8(+) T effector cells to CD4(+)FoxP3(+) 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 CD8(+) T cells abolished the efficacy of its combination with SA-4-1BBL. Mechanistic investigations showed that IFNγ 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.
authors.affiliation: Institute for Cellular Therapeutics and Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky.
authors.forename: Abhishek K
authors.initials: AK
authors.lastname: Srivastava
authors.affiliation: Institute for Cellular Therapeutics and Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky.
authors.forename: Gunes
authors.initials: G
authors.lastname: Dinc
authors.affiliation: Institute for Cellular Therapeutics and Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky.
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Sharma
authors.affiliation: Institute for Cellular Therapeutics and Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky.
authors.forename: Esma S
authors.initials: ES
authors.lastname: Yolcu
authors.affiliation: Institute for Cellular Therapeutics and Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Institute for Cellular Therapeutics and Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky. haval.shirwan@louisville.edu.
authors.forename: Haval
authors.initials: H
authors.lastname: Shirwan
mesh_terms: D053330:4-1BB Ligand / Q000494:pharmacology*; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D015551:Autoimmunity; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D007371:Interferon-gamma / Q000502:physiology; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D019809:Streptavidin / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D053330:4-1BB Ligand; D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D008050:Lipid A; D007371:Interferon-gamma; D019809:Streptavidin; C048436:monophosphoryl lipid A