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1.
ACS Cent Sci ; 7(11): 1838-1846, 2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34841057

RESUMO

Cancer vaccine structure is emerging as an important design factor that offers tunable parameters to enhance the targeted immune response. We report the impact of altering the antigen release rate from spherical nucleic acid (SNA) vaccines-nanoparticles with a liposomal core and surface-anchored adjuvant DNA-on immune stimulation. Peptide antigens were incorporated into SNAs using either a nonreducible linker or one of a series of reduction-triggered traceless linkers that release the native peptide at rates controlled by their substitution pattern. Compared with a nonreducible linkage, the traceless attachment of antigens resulted in lower EC50 of T cell proliferation in vitro and greater dendritic cell (DC) activation and higher T cell killing ability in vivo. Traceless linker fragmentation rates affected the rates of antigen presentation by DCs and were correlated with the in vitro potencies of SNAs. Antigen release was correlated with the ex vivo -log(EC50), and more rapid antigen release resulted in an order of magnitude improvement in the EC50 and earlier and greater antigen presentation over the same time-period. In vivo, increasing the rate of antigen release resulted in higher T cell activation and target killing. These findings provide fundamental insights into and underscore the importance of vaccine structure.

2.
Front Immunol ; 11: 1333, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32733447

RESUMO

Although the strategy of therapeutic vaccination for the treatment of prostate cancer has advanced to and is available in the clinic (Sipuleucel-T), the efficacy of such therapy remains limited. Here, we develop Immunostimulatory Spherical Nucleic Acid (IS-SNA) nanostructures comprised of CpG oligonucleotides as adjuvant and prostate cancer peptide antigens, and evaluate their antitumor efficacy in syngeneic mouse models of prostate cancer. IS-SNAs with the specific structural feature of presenting both antigen and adjuvant CpG on the surface (hybridized model (HM) SNAs) induce stronger cytotoxic T lymphocyte (CTL) mediated antigen-specific killing of target cells than that for IS-SNAs with CpG on the surface and antigen encapsulated within the core (encapsulated model (EM) SNAs). Mechanistically, HM SNAs increase the co-delivery of CpG and antigen to dendritic cells over that for EM SNAs or admixtures of linear CpG and peptide, thereby improving cross-priming of antitumor CD8+ T cells. As a result, vaccination with HM SNAs leads to more effective antitumor immune responses in two prostate cancer models. These data demonstrate the importance of the structural positioning of peptide antigens together with adjuvants within IS-SNAs to the efficacy of IS-SNA-based cancer immunotherapy.


Assuntos
Vacinas Anticâncer/farmacologia , Imunoterapia/métodos , Nanoestruturas , Oligodesoxirribonucleotídeos/farmacologia , Neoplasias da Próstata , Animais , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/farmacologia , Vacinas Anticâncer/imunologia , Apresentação Cruzada/efeitos dos fármacos , Apresentação Cruzada/imunologia , Citotoxicidade Imunológica/efeitos dos fármacos , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oligodesoxirribonucleotídeos/imunologia , Neoplasias da Próstata/imunologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia
3.
Proc Natl Acad Sci U S A ; 116(21): 10473-10481, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31068463

RESUMO

In the case of cancer immunotherapy, nanostructures are attractive because they can carry all of the necessary components of a vaccine, including both antigen and adjuvant. Herein, we explore how spherical nucleic acids (SNAs), an emerging class of nanotherapeutic materials, can be used to deliver peptide antigens and nucleic acid adjuvants to raise immune responses that kill cancer cells, reduce (or eliminate) tumor growth, and extend life in three established mouse tumor models. Three SNA structures that are compositionally nearly identical but structurally different markedly vary in their abilities to cross-prime antigen-specific CD8+ T cells and raise subsequent antitumor immune responses. Importantly, the most effective structure is the one that exhibits synchronization of maximum antigen presentation and costimulatory marker expression. In the human papillomavirus-associated TC-1 model, vaccination with this structure improved overall survival, induced the complete elimination of tumors from 30% of the mice, and conferred curative protection from tumor rechallenges, consistent with immunological memory not otherwise achievable. The antitumor effect of SNA vaccination is dependent on the method of antigen incorporation within the SNA structure, underscoring the modularity of this class of nanostructures and the potential for the deliberate design of new vaccines, thereby defining a type of rational cancer vaccinology.


Assuntos
Vacinas Anticâncer , Neoplasias Experimentais/prevenção & controle , Ácidos Nucleicos/química , Animais , Camundongos
4.
J Am Chem Soc ; 140(4): 1227-1230, 2018 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-29356509

RESUMO

Spherical nucleic acids (SNAs) can be potent sequence-specific stimulators of antigen presenting cells (APCs). When loaded with peptide antigens, they can be used to activate the immune system to train T-cells to specifically kill cancer cells. Herein, the role of peptide chemical conjugation to the DNA, which is used to load SNAs with antigens via hybridization, is explored in the context of APC activation. Importantly, though the antigen chemistry does not impede TLR-9 regulated APC activation, it significantly augments the downstream T-cell response in terms of both activation and proliferation. A comparison of three linker types, (1) noncleavable, (2) cleavable but nontraceless, and (3) traceless, reveals up to an 8-fold improvement in T-cell proliferation when the traceless linker is used. This work underscores the critical importance of the choice of conjugation chemistry in vaccine development.


Assuntos
DNA/química , Peptídeos/química , Linfócitos T/imunologia , Antígenos/imunologia , Proliferação de Células , Humanos , Linfócitos T/citologia
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