Nadia Coltella RicercatoreMedicina
Immunotherapy has gained renewed interest for cancer treatment thanks to the efficacy of immune checkpoint blockers and adoptive therapy with genetically engineered T cells. However, many patients fail to respond or develop resistance mainly because of an immunosuppressive tumor microenvironment. We have developed a strategy for targeted gene-based delivery of type I Interferon (IFN) to tumors by tumor-infiltrating monocytes/macrophages, expressing the angiopoietin receptor Tie2 (TEMs), which induces robust tumor responses in several experimental tumor models. Hematopoietic Stem/Progenitor Cells are genetically engineered ex vivo with lentiviral vectors (LV) that target expression to their TEM progeny by a combination of transcriptional and micro-RNA mediated control.
Recently, we showed that targeted delivery of immune stimulatory cytokines by TEMs can effectively reprogram the immune suppressive tumor microenvironment, leading to enhanced recruitment, activation and effector function of immune cells, which in turn induce protective immunity against multiple tumor associated antigens.
Our current research aims to:
- Develop new conditional lentiviral vectors (LV) and transgenes for endogenously and/or exogenously regulated targeted delivery of immune stimulatory cytokines in the tumor microenvironment;
- Characterize the immune cell infiltrate of experimental tumors treated by our gene therapy strategy and identify cellular phenotypes and gene expression signatures providing readouts of the response to our treatment;
- Explore new cytokine payloads to be used alternatively or in combination with IFNα, and dissect their role in mediating antitumor responses alone or in combination with immune checkpoint blockers;
- Score a panel of human cancers using the above identified signatures to identify cancer types more likely to respond to our strategies.
Regulated expression by newly designed vectors and transgenes, and adoption of emerging strategies for engrafting the engineered progenitors will increase the safety and applicability of this platform to several types of tumors. Therapeutic efficacy of our strategy can be enhanced by synergy with immune checkpoint blockers and selecting candidate target cancers types according to specific features of the immune infiltrate.
2008: PhD degree, in Cellular Sciences and Technologies, University of Torino, Torino, Italy
2000: M.Sc. in Biological Sciences (single-cycle degree, 5 years) (110/110 summa cum laude)
September 2016 – present: Project leader, Targeted Cancer Gene Therapy Unit, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Milano, Italy. Prof. Luigi Naldini
June 2008 – August 2016: Postdoctoral fellow, Pre-clinical Models of Cancer, San Raffaele Scientific Institute, Milano, Italy. Dr. Rosa Bernardi
2009: Postdoctoral fellow, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Prof. Pier Paolo Pandolfi
January 2008 – May 2008: Postdoctoral fellow, Institute for Cancer Research and Treatment (IRCC), University of Torino School of Medicine, Candiolo (TO), Italy. Prof. Maria Flavia Di Renzo
2004 – 2007: PhD student, IRCC, University of Torino School of Medicine, Candiolo (TO), Italy. Prof. Maria Flavia Di Renzo
2002-2003: Italian Association for Cancer Research (AIRC/FIRC) Research fellow, IRCC, University of Torino School of Medicine, Candiolo (TO), Italy. Prof. Maria Flavia Di Renzo
2001-2002: Research Fellow, IRCC, University of Torino School of Medicine, Candiolo (TO), Italy. Prof. Riccardo Ferracini
Grants, Professional Memberships and Honors
2018 – ongoing: Co-PI of an AIRC (Italian Association for Cancer Research) Investigator Grant to Prof. Luigi Naldini
2015: Lady Tata Memorial Trust International Award
2011 – 2016: Member of the European Hematology Association (EHA)
2009: Winner of a fellowship from the Human Frontiers Science Project (HFSP)
2008: Winner of 2-year ‘Assegno di Ricerca’ as part of ‘Reduction of Brain Drain’ from the convention between University of Torino and Regione Piemonte
2006 – 2007: Winner of a 18 months ‘Assegno di Ricerca’ from the University of Torino
2004 – 2006: Winner of a 3-year University fellowship from ISASUT months ‘Assegno di Ricerca’ from the University of Torino
2002 – 2003: Recipient of 2-year fellowship of the Italian Association for Cancer Research (AIRC/FIRC)
- Ponente M., Campanini L., Cuttano R., Piunti A., Delledonne G.A., Coltella N., Valsecchi R., Villa A., Cavallaro U., Pattini L., Doglioni C., Bernardi R. ‘PML promotes metastasis of triple-negative breast cancer through transcriptional regulation of HIF1A target genes’ JCI Insight. 2017 Feb 23;2(4):e87380
- Soncini M., Corna G., Moresco M., Coltella N., Restuccia U., Maggioni D., Raccosta L., Lin C.Y., Invernizzi F., Crocchiolo R., Doglioni C., Traversari C., Bachi A., Bernardi R., Bordignon C., Gustafsson J.A., Russo V. ‘24-Hydroxycholesterol participates in pancreatic neuroendocrine tumor development’ Proc Natl Acad Sci U S A. 2016 Oct 11;113(41):E6219-E6227.
- Migliavacca J., Percio S., Valsecchi R., Ferrero E., Spinelli A., Ponzoni M., Tresoldi C., Pattini L., Bernardi R., *Coltella N. ‘Hypoxia inducible factor-1aregulates a pro-invasive phenotype in acute monocytic leukemia ’ Oncotarget. 2016 Aug 16;7(33):53540-53557
- Valsecchi R., Coltella N., Belloni D., Ponente M., Ten Hacken E., Scielzo C., Scarfò L., Bertilaccio M.T., Brambilla P., Lenti E., Martinelli Boneschi F., Brendolan A., Ferrero E., Ferrarini M., Ghia P., Tonon G., Ponzoni M., Caligaris Cappio F., Bernardi R. ‘HIF-1 a regulates the interaction of chronic lymphocytic leukemia cells with the tumor microenvironment’ Blood. 2016 Apr 21;127(16):1987-97.
- *Coltella N., Valsecchi R., Ponente M., Ponzoni M., Bernardi R. ‘Synergistic leukemia eradication by combined treatment with retinoic acid and HIF inhibition by EZN-2208 (PEG-SN38) in preclinical models of PML-RAR a and PLZF-RAR a driven leukemia’ Clin Cancer Res. 2015 Aug 15;21(16):3685-94
- Percio S., Coltella N., Grisanti S., Bernardi R., Pattini L. ‘A HIF-1 network reveals characteristics of epithelial-mesenchymal transition in acute promyelocytic leukemia’ Genome Med. 2014 Dec 1;6(12):84. Genome Med. 2014 Dec 1;6(12):84.
- Guarnerio J., Coltella N., Ala U., Tonon G., Pandolfi P.P., Bernardi R. ‘Bone marrow endosteal mesenchymal progenitors depend on HIF factors for maintenance and regulation of hematopoiesis’ Stem Cell Reports. 2014 May 15;2(6):794-809
- Coltella N., Percio S., Valsecchi R., Cuttano R., Guarnerio J., Ponzoni M., Pandolfi P.P., Melillo G., Pattini L., Bernardi R. ‘HIF factors cooperate with PML-RAR a to promote acute promyelocytic leukemia progression and relapse’ EMBO Mol Med. 2014 May 1;6(5):640-50
- Bernardi R., Papa A., Egia A., Coltella N., Teruya-Feldstein J., Signoretti S., Pandolfi P.P. ‘PML represses tumour progression through inhibition of mTOR’ EMBO Mol Med. 2011 May; 3(5):249-57
- Costa B., Dettori D., Lorenzato A., Bardella C., Coltella N., Martino C., Cammarata C., Carmeliet P., Olivero M., Di Renzo M.F. ‘Fumarase tumor suppressor gene and MET cooperate in upholding transformation and tumorigenesis.’ FASEB J. 2010 Aug;24(8):2680-8.
- Bardella C., Dettori D., Olivero M., Coltella N., Mazzone M., Di Renzo M.F. ‘The therapeutic potential of HGF to sensitize ovarian cancer cells to cisplatin and paclitaxel in vivo’. Clin Cancer Res. 2007 Apr 1;13(7):2191-8.
- Grethe S., Coltella N., Di Renzo M.F., Porn-Ares M.I. ‘p38 MAPK downregulates phosphorylation of Bad in doxorubicin-induced endothelial apoptosis’. Biochem Biophys Res Commun. 2006 Sep 1;347(3):781-90.
- Coltella N., Rasola A., Nano E., Bardella C., Fassetta M., Filigheddu N., Graziani A., Comoglio P.M., Di Renzo M.F. ‘p38 MAPK turns hepatocyte growth factor to a death signal that commits ovarian cancer cells to chemotherapy-induced apoptosis’. Int J Cancer. 2006 Jun 15;118(12):2981-90.
- Fassetta M., D'Alessandro L., Coltella N., Di Renzo M.F., Rasola A. ‘Hepatocyte growth factor installs a survival platform for colorectal cancer cell invasive growth and overcomes p38 MAPK-mediated apoptosis’. Cell Signal. 2006 Nov 18(11):1967-76.
- Olivero M., Ruggiero T., Saviozzi S., Rasola A., Coltella N., Crispi S., Di Cunto F., Calogero R., Di Renzo M.F. ‘Genes regulated by hepatocyte growth factor as targets to sensitize ovarian cancer cells to cisplatin’. Mol Cancer Ther. 2006 May; 5(5):1126-35.
- Patane’ S., Avnet S., Coltella N., Costa B., Sponza S., Olivero M., Vigna E., Naldini L., Baldini N., Ferracini R., Corso S., Giordano S., Comoglio P.M., Di Renzo M.F. ‘MET overexpression turns human primary osteoblasts into osteosarcomas’. Cancer Res. 2006 May 1;66(9):4750-7.
- *Coltella N., Manara M.C., Cerisano V., Trusolino L., Di Renzo M.F., Scotlandi K., Ferracini R. ‘Role of the MET/HGF receptor in proliferation and invasive behavior of osteosarcoma’. FASEB J. 2003 Jun;17(9):1162-4.
- Olivero M., Ruggiero T., Coltella N., Maffe' A., Calogero R., Medico E., Di Renzo M.F. ‘Amplification of repeat-containing transcribed sequences (ARTS): a transcriptome fingerprinting strategy to detect functionally relevant microsatellite mutations in cancer’. Nucleic Acids Res. 2003 Apr 1;31(7):e33.
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