Long-term CTL induction and therapeutic tumor suppression by antigen- and adjuvant-carrying polymer nanoparticles
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1
Selecta Biosciences, United States
Encapsulation of a model antigen and a TLR agonist (adjuvant) within a polymer-based nanoparticle (NP) leads to strong and rapid induction of adaptive immune responses upon subcutaneous NP injection. An efficient cytotoxic T lymphocyte (CTL) response is induced after a single inoculation with NP-encapsulated peptide, multiple peptides or protein antigens. Prime immunization followed by a tumor injection and repeated therapeutic immunizations at a tumor-distant site resulted in 100% survival in a mouse model. Concurrent evaluation of such NP formulations in a more stringent, strictly therapeutic regimen initially demonstrated less protection when NPs were administered at a tumor-distant site as compared to peritumoral delivery. However, an improved NP formulation of the protein antigen, ovalbumin (OVA), led to augmented survival upon tumor-distant subcutaneous therapeutic immunization with 25-70% animals staying tumor-free for >6 weeks after inoculation with 0.25x106 EG.7-OVA cells. This enhanced survival corresponded to a preferred NP uptake by several classes of antigen-presenting cells and to prolonged kinetics of CTL induction with strong systemic in vivo CTL activity (75-90% specific cytotoxicity) seen up to 21 days after a single NP administration and still detectable at 31 days. This superior long-term CTL induction was demonstrated by several approaches to persist both locally (draining lymph nodes) and centrally (spleen) occurring in parallel with the induction of CD8+ cells with T cell effector memory phenotype at the same locations. Re-challenge of surviving mice with EG.7-OVA tumor cells (without any further NP treatment) has shown that those immunized with initial NP-OVA formulation had a moderate resistance to tumor reintroduction. At the same time, those mice previously immunized with improved NP-OVA formulations were mostly refractory to tumor reintroduction with a few mice developing tumors followed by their complete regression resulting in 80-100% survival upon re-challenge. Even a single NP injection administered to tumor-bearing mice at a later point of tumor development induced high levels (≥90%) of specific CTL activity and led to reduction in tumor burden. A similar approach using NPs carrying dominant immunogenic peptides and TLR agonist has shown a protective potential against intravenously or subcutaneously delivered B16-F10 melanoma cells.
Keywords:
Nanoparticles,
Antigens,
formulation,
CTL response,
Immunotherapy, Active,
tumor suppression,
immune memory
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Citation:
Ilyinskii
PO,
Roy
C,
O'Neil
C,
Altreuter
D and
Kishimoto
K
(2013). Long-term CTL induction and therapeutic tumor suppression by antigen- and adjuvant-carrying polymer nanoparticles.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00942
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Received:
27 Jun 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Dr. Petr O Ilyinskii, Selecta Biosciences, Watertown, Massachusetts, 02472, United States, p.ilyinskii@verizon.net