Natural pattern-recognition-receptor agonists as adjuvants for in situ vaccination lymphoma immunotherapy
| Autor: | Brian D. Brown, Paul Peng, Netonia Marshall, Thomas A. Davis, Linda Hammerich, Tibor Keler, Judith Agudo, Joshua Brody, Michael Yellin, Mark Aleynick, Ranjan Upadhyay |
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| Rok vydání: | 2018 |
| Předmět: |
Cancer Research
medicine.diagnostic_test business.industry medicine.medical_treatment Pattern recognition receptor Context (language use) 02 engineering and technology Immunotherapy 010402 general chemistry 021001 nanoscience & nanotechnology 01 natural sciences 0104 chemical sciences Flow cytometry Vaccination Immune system Oncology Antigen Immunology Medicine Cytotoxic T cell 0210 nano-technology business |
| Zdroj: | Journal of Clinical Oncology. 36:123-123 |
| ISSN: | 1527-7755 0732-183X |
| Popis: | 123 Background: In patients with low-grade lymphoma, in situ vaccination has yielded both partial and complete remissions in clinical trials. Though clinical responses have been observed with multiple pattern recognition receptor agonists (PRRa), the optimal immune stimulant is unknown. We hypothesize that natural PRRa, such as the attenuated pathogens or subunits found in common prophylactic vaccines, could target multiple PRR in a physiologically relevant context and lead to a more robust activation of dendritic cells (DCs) versus synthetic PRRa. Methods: 20 vaccines, including BCG, Typhim Vi, MMR-II, etc. were screened in vitro, where DC phenotype and function were evaluated by flow cytometry. Flt3L-mobilized DC ability to phagocytose, process, present, and cross-present soluble protein or tumor derived antigen, were assessed using CRISPR gene-edited, β2m(-/-) GFP-lymphoma cells and a novel GFP-specific (‘JEDI’) CD8 T cell system. Vaccine mechanism of immune activation was elucidated using a library of PRR-null macrophage cell lines. Potent vaccines were also evaluated in vivo in a Flt3L-primed in situ vaccination using the A20 murine lymphoma model. Results: Several vaccines induced robust DC activation and several showed significant increases in subsequent T cell activation, proliferation, and tumor killing, suggesting increased antigen processing and cross-presentation by DCs. Some vaccines, either as single agents or in combination, were significantly more effective than synthetic PRRa in activating DCs and inducing a T cell response. In vivo, vaccine combination therapies induced tumor regression in a majority of animals, suggesting synergistic immune activation. Conclusions: This data suggests prophylactic vaccines are effective clinical-grade DC activators and can be repurposed for use in the in situ vaccination maneuver, with immediate translation into the clinic. Additionally, by extensive in vitro evaluation in parallel with in vivo studies, this work aims to identify a predictive in vitro molecular immune signature that correlates closely with adjuvant efficacy in vivo. |
| Databáze: | OpenAIRE |
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