Programma MD-PhD della Scuola di Medicina

Next Generation Immunotherapy for Pancreatic Cancer: DNA Vaccination is Seeking New Combo Partners. Instructors prof Franco Novelli and Paola Cappello

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Programma

In the last 15 years, we have discovered and characterized the antibody response in pancreatic adenocarcinoma (PDA) patients by a SERological and PROteomic approach, and we have demonstrated the efficacy of the autoantibodies and related antigens as diagnostic markers and therapeutic targets. We focused on alpha-enolase (ENO1), a glycolytic enzyme that catalyzes the conversion of 2-phosphoglycerate to phosphoenolpyruvate, but also acts as a plasminogen receptor. ENO1 is over-expressed in many cancers, including pancreatic cancer. Notably, we found that ENO1 induced a high frequency of antibody responses in PDA patients, and that those patients having anti-ENO1 Ab also displayed T cells secreting IFNγ specifically in response to the recombinant antigen (rENO1). We also developed a DNA vaccine that targets ENO1 to assess its clinical potential in a genetically engineered mouse model of PDA. The ENO1-vaccine efficiently induced many immunological processes: antibody formation and complement-dependent cytotoxicity (CDC)-mediated tumor killing, infiltration of effector T cells, reduction of infiltration of myeloid and Treg suppressor cells, which significantly increase the mouse survival.

Anti-ENO1 antibodies inhibited PDA cell invasion in vitro and in vivo and myeloid-derived suppressor cell (MDSC) infiltration into the tumor.

In order to develop a more efficient vaccine, we are currently characterizing other PDA-associated antigens we identified, and also investigating the possibility to combine the antigen-specific vaccination with the inhibition of immunosuppressive pathways or the activation of the immune system. The idea is to develop a complex vaccine formulation that targets several proteins crucial for PDA progression and simultaneously target the microenvironment.

Attività di supporto

Co-workers: Claudia Curcio

Note

• Progetto del corso: Immuno-terapia dei tumori

• Scientific qualification of the PIs: Entrez-PubMed Link to publications of prof Novelli and prof Cappello

• Laboratory of Tumor Immunology, Dept. Molecular Biotechnology and Healthy Sciences-CeRMS, via Santena 5-10126 Turin, Italy

  The Center for Experimental Research and Medicine Studies (CERMS) is at the Città della Salute e della Scienza di Torino. The institution has fully equipped laboratories for techniques of molecular and cellular biology and for, DNA sequencing and quantitative PCR, mono and two-dimensional electrophoresis, confocal microscopy and analytical flow cytometry and cell-culture.

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