Logo do repositório
 
Publicação

Multicomponente particulates for immune modulation

2018Tese de doutoramento Acesso aberto
Ver registo simples
datacite.subject.fosCiências Médicas::Medicina Básicapt_PT
dc.contributor.advisorFlorindo, Helena Isabel Fialho, 1979-
dc.contributor.advisorBrocchini, Steve
dc.contributor.advisorSilva, Liana Casquinha da
dc.contributor.authorConniot, João Miguel de Oliveira, 1989-
dc.date.accessioned2018-05-04T16:29:58Z
dc.date.available2021-02-01T01:30:13Z
dc.date.issued2018
dc.date.submitted2018
dc.descriptionTese de doutoramento, Farmácia (Tecnologia Farmacêutica), Universidade de Lisboa, Faculdade de Farmácia, 2018pt_PT
dc.description.abstractAlthough immune checkpoint therapy improved the clinical outcomes of melanoma treatment, low response rate, severe side effects, and acquired resistance have been observed in patients. To overcome these limitations, complementary strategies that inhibit tumor immunosuppressive pathways and enhance immunity are urgently needed. We hypothesized that the anticancer activity of the combination of anti-PD-1, for immunosuppression blockade, with the monoclonal anti-OX40 agonist, for T-cell stimulation and expansion, could be improved by cancer vaccination. For this purpose, we designed, synthesized and characterized mannose-grafted poly(lactic coglycolic acid) and poly(lactic acid) (PLGA/PLA) nano-vaccines, containing both melan- A/MART-1 peptides and immune potentiators. These nanoparticle-based vaccines can amplify antitumor immune response by increasing tumor-associated antigen recognition, processing, and presentation to effector T cells. The nanoparticles were shown to have a spherical shape with an average diameter of 170 nm, displaying narrow polydispersity index and near-neutral surface charge. Immunization with these nano-vaccines induced splenocyte activation and antigen specific cytotoxic T-cell activity against melanoma cells ex vivo. Treatment with the combination of the prophylactic nano-vaccines and PD-1/OX40 antibodies in vivo led to maximal tumor growth inhibition, with minimal systemic toxicity. Whereas treatment with anti-PD-1/anti-OX40 alone led to 20% survival 42 days following tumor inoculation, the combination approach with the mannose-PLGA/PLA prophylactic nano-vaccine resulted in 100% survival for the same period. Moreover, the latter presented a survival rate of 50% two months following tumor inoculation and recapitulated a T-cell inflamed tumor microenvironment. On the other hand, the combination of therapeutic mannose-PLGA/PLA nanovaccines with PD-1/OX40 immune checkpoint therapy failed to show benefit in comparison with PD-1/OX40 immune checkpoint in monotherapy. This result seems to be related to infiltration of MDSC into the tumor microenvironment, over time, which may have overcome the effect of CD8+ T cell stimulation, inhibiting T cell infiltration and cytotoxic activity. Altogether, these findings reveal important aspects on the synergism of immune checkpoint targeting with polymeric cancer nano-vaccines, as well as the effect on the modulation of tumor-infiltrating immune cells in melanoma. Therefore, polymeric nanovaccines emerge as a potential strategy to improve clinical outcomes of melanoma treatment.pt_PT
dc.description.provenanceSubmitted by Amelia Janeiro (ajaneiro@reitoria.ul.pt) on 2018-04-16T11:08:54Z No. of bitstreams: 1 ulsd731571_td_Joao_Conniot.pdf: 8413622 bytes, checksum: 4e97e81640ccd228d69a969ba7579055 (MD5)en
dc.description.provenanceMade available in DSpace on 2018-05-04T16:29:58Z (GMT). No. of bitstreams: 1 ulsd731571_td_Joao_Conniot.pdf: 8413622 bytes, checksum: 4e97e81640ccd228d69a969ba7579055 (MD5) Previous issue date: 2018en
dc.description.sponsorshipFundação para a Ciência e a Tecnologia (FCT), projetos SAICTPAC/0019/2015, Pest-OE/SAU/UI4013/2011; EuroNanoMed-II, projeto ENMed/0051/2016; European Structural & Investment Funds (ESIF); Programa Operacional Factores de Competitividade (COMPETE)pt_PT
dc.identifier.tid101488408pt_PT
dc.identifier.urihttp://hdl.handle.net/10451/33135
dc.language.isoengpt_PT
dc.relationMULTICOMPONENT PARTICULATES FOR IMMUNE MODULATION
dc.relationTherMelVac- dendritic cell-targeted peptide vaccine against melanoma by ligand-modified nanoparticles
dc.subjectTeses de doutoramento - 2018pt_PT
dc.titleMulticomponente particulates for immune modulationpt_PT
dc.typedoctoral thesis
dspace.entity.typePublication
oaire.awardNumberSFRH/BD/87150/2012
oaire.awardNumberPTDC/SAU-FAR/119389/2010
oaire.awardNumberUTAP-ICDT/DTP-FTO/0016/2014
oaire.awardNumberUID/DTP/04138/2013
oaire.awardTitleMULTICOMPONENT PARTICULATES FOR IMMUNE MODULATION
oaire.awardTitleTherMelVac- dendritic cell-targeted peptide vaccine against melanoma by ligand-modified nanoparticles
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F87150%2F2012/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FSAU-FAR%2F119389%2F2010/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/UTAP-ICDT%2FDTP-FTO%2F0016%2F2014/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FDTP%2F04138%2F2013/PT
oaire.fundingStream3599-PPCDT
oaire.fundingStream3599-PPCDT
oaire.fundingStream5876
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typedoctoralThesispt_PT
relation.isProjectOfPublication4227d5d1-0f33-4b4a-84e3-4e1a7d1cc239
relation.isProjectOfPublication31cdfbc1-952c-45c2-a626-93d1a7fecf93
relation.isProjectOfPublication99c84e8c-54c7-4a87-b2e4-f6a0da220b9e
relation.isProjectOfPublication3ea9d46e-a653-42ed-aa04-6630ede070cc
relation.isProjectOfPublication.latestForDiscovery4227d5d1-0f33-4b4a-84e3-4e1a7d1cc239
thesis.degree.nameDoutoramento em Farmáciapt_PT

Ficheiros

Principais
A mostrar 1 - 1 de 1
Miniatura
Nome:
ulsd731571_td_Joao_Conniot.pdf
Tamanho:
8.02 MB
Formato:
Adobe Portable Document Format
Ver/Abrir
Licença
A mostrar 1 - 1 de 1
Miniatura indisponível
Nome:
license.txt
Tamanho:
1.2 KB
Formato:
Item-specific license agreed upon to submission
Descrição:
Ver/Abrir

Coleções