Purpose: Despite the great success of HER2 vaccine strategies in animal models, effective clinical results have not yet been obtained. Westudied the feasibility of usingDNAcoding for chimeric rat/human HER2 as a tool to break the unresponsiveness of T cells from patients with HER2-overexpressing tumors (HER2-CP). Experimental Design: Dendritic cells (DCs) generated from patients with HER2-overexpressing breast (n ¼ 28) and pancreatic (n ¼ 16) cancer were transfected with DNA plasmids that express human HER2 or heterologous rat sequences in separate plasmids or as chimeric constructs encoding rat/human HER2 fusion proteins and used to activate autologous T cells. Activation was evaluated by IFN-g ELISPOT assay, perforin expression, and ability to halt HER2þ tumor growth in vivo. Results: Specific sustained proliferation and IFN-g production by CD4 and CD8 T cells from HER2-CP was observed after stimulation with autologous DCs transfected with chimeric rat/human HER2 plasmids. Instead, T cells from healthy donors (n ¼ 22) could be easily stimulated with autologous DCs transfected with any human, rat, or chimeric rat/human HER2 plasmid. Chimeric HER2-transfected DCs from HER2- CP were also able to induce a sustained T-cell response that significantly hindered the in vivo growth of HER2þ tumors. The efficacy of chimeric plasmids in overcoming tumor-induced T-cell dysfunction relies on their ability to circumvent suppressor effects exerted by regulatory T cells (Treg) and/or interleukin (IL)-10 and TGF-b1. Conclusions: These results provide the proof of concept that chimeric rat/human HER2 plasmids can be used as effective vaccines for any HER2-CP with the advantage of being not limited to specific MHC.

Chimeric Rat/Human HER2 Efficiently Circumvents HER2 Tolerance in Cancer Patients.

OCCHIPINTI, SERGIO;SPONTON, LAURA;ROLLA, SIMONA;Satolli MA;CAVALLO, Federica;CAPPELLO, Paola;PIEROBON, DANIELE;NOVELLI, Francesco;GIOVARELLI, Mirella
2014-01-01

Abstract

Purpose: Despite the great success of HER2 vaccine strategies in animal models, effective clinical results have not yet been obtained. Westudied the feasibility of usingDNAcoding for chimeric rat/human HER2 as a tool to break the unresponsiveness of T cells from patients with HER2-overexpressing tumors (HER2-CP). Experimental Design: Dendritic cells (DCs) generated from patients with HER2-overexpressing breast (n ¼ 28) and pancreatic (n ¼ 16) cancer were transfected with DNA plasmids that express human HER2 or heterologous rat sequences in separate plasmids or as chimeric constructs encoding rat/human HER2 fusion proteins and used to activate autologous T cells. Activation was evaluated by IFN-g ELISPOT assay, perforin expression, and ability to halt HER2þ tumor growth in vivo. Results: Specific sustained proliferation and IFN-g production by CD4 and CD8 T cells from HER2-CP was observed after stimulation with autologous DCs transfected with chimeric rat/human HER2 plasmids. Instead, T cells from healthy donors (n ¼ 22) could be easily stimulated with autologous DCs transfected with any human, rat, or chimeric rat/human HER2 plasmid. Chimeric HER2-transfected DCs from HER2- CP were also able to induce a sustained T-cell response that significantly hindered the in vivo growth of HER2þ tumors. The efficacy of chimeric plasmids in overcoming tumor-induced T-cell dysfunction relies on their ability to circumvent suppressor effects exerted by regulatory T cells (Treg) and/or interleukin (IL)-10 and TGF-b1. Conclusions: These results provide the proof of concept that chimeric rat/human HER2 plasmids can be used as effective vaccines for any HER2-CP with the advantage of being not limited to specific MHC.
20
20(11)
2910
2921
http://clincancerres.aacrjournals.org.offcampus.dam.unito.it/content/early/2014/05/06/1078-0432.CCR-13-2663.full.pdf+html
HER2; tolerance; DNA vaccine; Treg cells
Occhipinti S; Sponton L; Rolla S; Caorsi C; Novarino A; Donadio M; Bustreo S; Satolli MA; Pecchioni C; Marchini C; Amici A; Cavallo F; Cappello P; Pierobon D; Novelli F; Giovarelli M.
File in questo prodotto:
File Dimensione Formato  
Occhipinti_Clin Cancer Res_4APERTO.pdf

Accesso aperto

Tipo di file: POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione 817.1 kB
Formato Adobe PDF
817.1 kB Adobe PDF Visualizza/Apri
Occhipinti et al_ClinCancRes_2014.pdf

Accesso riservato

Tipo di file: PDF EDITORIALE
Dimensione 1.5 MB
Formato Adobe PDF
1.5 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/149910
Citazioni
  • ???jsp.display-item.citation.pmc??? 10
  • Scopus 18
  • ???jsp.display-item.citation.isi??? 15
social impact