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Mirella Prof. Giovarelli

HER2 tyrosine kinase receptor is an oncoantigen particularly appealing for a broad spectrum immunotherapy. It is overexpressed by several carcinomas, whereas low or absent in normal tissues. Effective inhibition of the HER2 receptor arrests the whole process and renders the selection of HER2-receptor-loss variants unlikely. Targeting oncoantigens rather than other tumor antigens with vaccines will have a strong clinical impact. In human effective clinical results have not been yet obtained, probably due to tumor-induced immunosuppressive mechanisms, such as the expansion of  CD4+CD25+FoxP3+ T regulatory cells. IL-10 and TGF-β1 cytokines as well as interactions between membrane programmed death receptor (PD)-1 [on T cells] and its ligand (PDL1) [on DCs] during tumor antigen presentation, have been implicated in these regulatory mechanisms and may determine the balance toward antigen–specific T-cell inhibition instead of activation.

We propose a new combinatorial strategy to enhance HER2 therapeutical efficacy in humans: bimodular DNA plasmids coding for chimeric rat/human HER2 sequences associated with small interference RNA (siRNA) to knock-down the expression of IL-10, TGF-β1 and/or PD-L1. By inhibiting the negative regulatory mechanisms that interfere with the antigen presentation, these

siRNA convert immunosuppressive in immunostimulatory environment leading to an effective presentation of the antigen coded by the plasmid.

The project is aimed to validation of DNA plasmids coding for chimeric rat/human HER2 combined with silencing of IL-10, TGF-β1 and/or PD-L1 inhibitory molecules as immunotherapeutic tools for the treatment of patients with HER2-overexpressing cancer, with the objective to break the unresponsiveness against human HER2.

The experimental plan foresees the evaluation of:

  1.  the potency of dendritic cells (DCs) transfected with DNA plasmids coding for chimeric HER2 protein to activate in vitro T cells from patients with HER2-overexpressing cancer, against human HER2;
  2.  the efficacy of strategies contrasting immunosuppressed status of cancer patients, using siRNA, to knock-down IL-10, TGF-β1 and/or PD-L1,inserted in bimodular plasmids coding for HER2;
  3.  the antitumor efficacy of patients' T cells activated by co-culture with transfected DCs in a xenograft mouse model, by using NOD/SCID/IL-2Rgamma null mice.


Negli ultimi anni Mirella Giovarelli ha acquisito una significativa esperienza nella biologia delle cellule dendritiche (DC). Ha studiato come alcune molecole naturali (la chemochina CCL16 e la  lattoferrina) e il microambiente ipossico modulano  il profilo di espressione chemochine / recettore delle DC e influenzano la loro capacità di presentare l'antigene per attivare i linfociti T. Attualmente le principali attività di ricerca riguardano: a) lo sviluppo di nuove strategie di immunoterapia basate su vaccini a DNA codificanti l’HER2 associati a short hairpin RNA per bloccare gli “immune check points” per i pazienti con tumore iperesprimente HER ; b) l’individuazione di nuovi bersagli molecolari coinvolti nella progressione di tumori della regione testa-collo, correlati o meno all’HPV;  c) lo studio del ruolo delle cellule di Langherans  in patologie cutanee associate con ipossia

 

  • Daniele Pierobon,   post-doctoral fellow
  • Sergio Occhipinti,   post-doctoral fellow
  • Laura Sponton, Ph.D. student
  • Costanza Angelini, Ph.D. student
  • Sara Bulfamante, graduate student
  • Giovenale Moirano, undergraduated student

 

 

Last update: 17/05/2019 10:33
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