AIRC 5x1000 | Advanced Therapies for Liver Metastases
Colorectal and pancreatic ductal adenocarcinomas are the second and fourth most common cause of cancer death, respectively.Patients affected by these cancers often die of liver metastases, which represent the major unmet clinical need for these malignancies.
Based on preliminary data and published observations, we believe that innovative cancer immune gene and cell therapy approaches might overcome the tolerogenic liver microenvironment and represent powerful therapeutic tools for colorectal and pancreatic ductal adenocarcinomas derived liver metastases.
The ultimate mission of this AIRC translational project is to develop, validate and implement clinical testing of new advanced therapy medicinal products (ATMP), based on immune gene and cell therapies, for liver metastases that arise from colorectal and pancreatic ductal adenocarcinomas.
Resources & expertise
The project will gather together 14 basic research units (see below) – working on topics ranging from tumor immunology to gene therapy, from genomics to advanced imaging – and 5 clinical units of IRCCS Ospedale San Raffaele:
- Hepatobiliary surgery - Head: Luca Aldrighetti
- Anatomic pathology and histopathology - Head: Claudio Doglioni
- Pancreatic surgery - Head: Massimo Falconi
- Pancreatic oncology - Head: Michele Reni
- Clinical and experimental radiology Unit – Head: Francesco De Cobelli
It will exploit shared state-of-the-art omics, including at single-cell level, advanced imaging, flow cytometry, and histological platforms, and will take advantage of the roadmaps previously established at San Raffaele for the development of gene and cell therapies in other indications.
The proposal spans 7 years and is built on 4 highly integrated programs:
- Program 1 (coordinators: Paolo Dellabona; Luca Aldrighetti) aims at unraveling - using biological samples collected through an observational clinical study (LiMeT) - the immune infiltrate and cancer cell profiles in liver metastasis from colorectal and pancreatic ductal adenocarcinomas, to identify tumor associated antigens and immune suppressive and regulatory pathways to be targeted in these two diseases.
Results of this discovery program will progressively shape two independents but potentially combinatorial translational Programs, tackling hepatic metastasis by rational and targeted modification of the immune effectors within the tumor microenvironment, through state-of-the-art cell therapies and gene transfer/editing tools.
- Program 2 (coordinators: Chiara Bonini; Massimo Falconi) aims at harnessing T cells with genetic tools that allow their retargeting against cancer cells, while ensuring resistance to the immunosuppressive tumor microenvironment.
- Program 3 (coordinators: Luigi Naldini; Michele Reni) will modify the immunosuppressive microenvironment through novel targeted in vivo gene therapies, aimed at enhancing spontaneous innate and adaptive immunity against the tumor, as well as the efficacy of exogenous T cell responses.
The most promising ATMPs generated by the 3 Programs will be selected for further development in a successive phase (Program 4): they will be stringently assessed for efficacy and toxicity in preclinical models and the best performing products will be prioritized for early phase clinical trials launched towards the end of the funding period.
Beta cell biology
Lorenzo Piemonti, Group leader
Dynamics of immune responses
Matteo Iannacone, Group leader
Chiara Bonini, Group leader
Giovanni Sitia, Group leader
Giulia Casorati, Group leader
Functional genomics of cancer
Giovanni Tonon, Group leader
Gene transfer technologies and new gene therapy strategies
Luigi Naldini, Group leader
Genomics of the innate immune system
Renato Ostuni, Group leader
Immuno-biotherapy of melanoma and solid tumors
Vincenzo Russo, Group leader
Luca Guidotti, Group leader
Monica Casucci, Group leader
Anna Mondino, Group leader
Tumor biology and vascular targeting
Angelo Corti, Group leader
Maria Pia Protti, Group leader
Corti A*, Sacchi A, Gasparri AM, Monieri M , Anderluzzi G, Colombo B, Gori A, Mondino A and Curnis F*. Enhancement of doxorubicin anti-cancer activity by vascular targeting using IsoDGR/cytokine-coated nanogold. J Nanobiotechnology. 2021 May 5;19(1):128. doi:10.1186/s12951-021-00871-y. (* Co-Corresponding Author)
Iannacone M, Guidotti LG. Immunobiology and pathogenesis of hepatitis B virus infection. Nat Rev Immunol. 2021 May 17. doi: 10.1038/s41577-021-00549-4.
Talamini L, Picchetti P, Ferreira LM, Sitia G, Russo L, Violatto MB, Travaglini L, Fernandez Alarcon J, Righelli L, Bigini P and De Cola L. Organosilica Cages Target Hepatic Sinusoidal Endothelial Cells Avoiding Macrophage Filtering. ACS Nano. 2021 May 19. doi:10.1021/acsnano.1c00316.
Manfredi F, Abbati D, Cianciotti BC, Stasi L, Potenza A, Ruggiero E, Magnani Z, Carnevale E, Doglio M, Noviello M, Tassi E, Balestrieri C, Buonanno S, Clemente F, De Lalla C, Protti MP, Mondino A, Casorati G, Dellabona P, Bonini C. Flow cytometry data mining by cytoChain identifies determinants of exhaustion and stemness in TCR-engineered T cells. Eur J Immunol. 2021 Jun 3. doi: 10.1002/eji.202049103. Online ahead of print.
Cilenti F*, Barbiera G*, Caronni N, Iodice D, Montaldo E, Barresi E, Lusito E, Cuzzola V, Vittoria FM, Mezzanzanica L, Miotto P, Di Lucia P, Lazarevic D, Cirillo DM, Iannacone M, Genua M^, Ostuni R^. A PGE2-MEF2A axis enables context-dependent control of inflammatory gene expression. IMMUNITY. 2021 June 14. doi:10.1016/j.immuni.2021.05.01. (*= equal contribution ^=equal contribution)
Sacchi A, Gasparri AM, Monieri M, Anderluzzi G , Colombo B , Gori A, Corti A* and Curnis F*. Nanogold functionalized with lipoamide-isoDGR: a simple, robust and versatile nanosystem for avb3-integrin targeting Frontiers in Chemistry. 2021 (in press). (* Co-Corresponding Author)
Tedesco M§, Giannese F§, Lazarević D, Giansanti V, Rosano D, Monzani S, Catalano I, Grassi E, Zanella ER, Botrugno OA, Morelli M, Panina Bordignon P, Caravagna G, Bertotti A, Martino GV, Aldrighetti L, Pasqualato S, Trusolino L, Cittaro D*, Tonon G*. scGET-seq: Epigenetic Profiling, Genomic Anatomy And Chromatin Velocity Of Single Cells. Nature Biotechnology. 2021 (in press). (§ Equal contribution; * Co-Corresponding Author)
Ratti F, Cipriani F, Fiorentini G, Burgio V, Ronzoni M, Della Corte A, Cascinu S, De Cobelli F, and Aldrighetti L. Evolution of surgical treatment of Colorectal Liver Metastases 2in the real world: single center experience in 1212 cases. CANCERS 2021 Mar 9;13(5):1178. doi: 10.3390/cancers13051178
Exley MA, Dellabona P, Casorati G. Exploiting CD1-restricted T cells for clinical benefit. MOL IMMUNOL 2021 Feb; 132: 126-131
Caronni N, Montaldo E, Mezzanzanica L, Cilenti F, Genua M, Ostuni R. Determinants, mechanisms, and outcomes of myeloid cell diversity in cancer. IMMUNOL REV 2021 Feb 9. doi: 10.1111/imr.12944.
Maspes A, Pizzetti F, Rossetti A, Makvandi P, Sitia G, Rossi F. Advances in Bio-Based Polymers for Colorectal CancerTreatment: Hydrogels and Nanoplatforms. Gels. 2021 Jan 11;7(1):6. doi: 10.3390/gels7010006.
Manfredi F, Cianciotti BC, Potenza A, Tassi E, Noviello E, Biondi A, Ciceri F, Bonini C*, Ruggiero E.* TCR redirected T cells for cancer treatment: Acheivements, hurdles and goals. Front Immunol. 2020 Sep 3;11:1689. doi: 10.3389/fimmu.2020.01689 (*= equal contribution)
Protti MP, De Monte L. Thymic stromal lymphopoietin and Cancer: Th2-dependent and -independent mechanisms. Front Immunol. 2020 Sep 16;11:2088. doi: 10.3389/fimmu.2020.02088. eCollection 2020.
Ficht X, Iannacone M. Immune surveillance of the liver by T cells. Sci Immunol. 2020 Sep 4;5(51):eaba2351. doi: 10.1126/sciimmunol.aba2351.
Fumagalli V, Di Lucia P, Venzin V, Bono EB, Jordan R, Frey CR, Delaney W, Chisari FV, Guidotti LG#, Iannacone M#. Serum HBsAg clearance has minimal impact on CD8+ T cell responses in mouse models of HBV infection. J Exp Med. 2020 Nov 2;217(11):e20200298. doi: 10.1084/jem.20200298. (#=co-last authors)
Corti A, Gasparri AM, Sacchi A, Colombo B, Monieri M, Rrapaj E, Ferreri AJM, Curnis F. NGR-TNF Engineering with an N-Terminal Serine Reduces Degradation and Post-Translational Modifications and Improves Its Tumor-Targeting Activity. Mol Pharm. 2020 Oct 5;17(10):3813-3824. doi: 10.1021/acs.molpharmaceut.0c00579.
Reni M, Andreasi V , Gasparri AM , Dugnani E , Colombo B, Macchini M, Bianco M, Dallatomasina A, Citro A, Assi E, Protti MP, Esposito A, Falconi M, Curnis F, Piemonti L, and Corti A. Circulating chromogranin A is cleaved into vasoregulatory fragments in patients with pancreatic ductal adenocarcinoma. Front Oncol. 2020 Dec 23;10:613582. doi: 10.3389/fonc.2020.613582. eCollection 2020
Arcangeli S*, Mestermann K*, Weber J*, Bonini C^, Casucci M^, Michael M.^ Overcoming key challenges in engineered T cell cancer immunotherapy. Current Opinion in Oncology. 2020 Sep;32(5):398-407. doi: 10.1097/CCO.0000000000000664. (*= equal contribution ^=equal contribution).
McGrath E, Chabannon C, Terwel S, Bonini C, Kuball J. Opportunities and challenges associated with the evaluation of chimeric antigen receptor T cells in real-life. Current Opinion in Oncology: Sep 2020 - Volume 32 - Issue 5 - p 427-433 doi: 10.1097/CCO.0000000000000665
Protti, MP and De Monte L. Dual Role of Inflammasome Adaptor ASC in Cancer.Front Cell Dev Bio 2020 Feb; 8: Article 40
De Giovanni M, Cutillo V, Giladi A, Sala E, Maganuco CG, Medaglia C, Di Lucia P, Bono E, Cristofani C, Consolo E, Giustini L, Fiore A, Eickhoff S, Kastenmüller W, Amit I, Kuka M, Iannacone M. Spatiotemporal regulation of type I interferon expression determines the antiviral polarization of CD4+ T cells. NAT IMMUNOL 2020 Mar; 21: 321-330
Bénéchet AP, De Simone G, Di Lucia P, Cilenti F, Barbiera G, Le Bert N, Fumagalli V, Lusito E, Moalli F, Bianchessi V, Andreata F, Zordan P, Bono E, Giustini L, Bonilla WV, Bleriot C, Kunasegaran K, Gonzalez-Aseguinolaza G, Pinschewer DD, Kennedy PTF, Naldini L, Kuka M, Ginhoux F, Cantore A, Bertoletti A, Ostuni R, Guidotti LG, Iannacone M. Dynamics and genomic landscape of CD8+ T cells undergoing hepatic priming. NATURE 2019 10; 574: 200-205
Mahata SK, Corti A. Chromogranin A and its fragments in cardiovascular, immunometabolic, and cancer regulation. ANN NY ACAD SCI 2019 Nov; 1455: 34-58
Gasparri AM, Sacchi A, Basso V, Cortesi F, Freschi M, Rrapaj E, Bellone M, Casorati G, Dellabona P, Mondino A, Corti A, Curnis F. Boosting Interleukin-12 Antitumor Activity and Synergism with Immunotherapy by Targeted Delivery with isoDGR-Tagged Nanogold. SMALL 2019 Nov; 15: e1903462
Nardelli F, Ghitti M, Quilici G, Gori A, Luo Q, Berardi A, Sacchi A, Monieri M, Bergamaschi G, Bermel W, Chen F, Corti A, Curnis F, Musco G. A stapled chromogranin A-derived peptide is a potent dual ligand for integrins αvβ6 and αvβ8. CHEM COMMUN 2019 Dec; 55: 14777-14780
Comoli P, Chabannon C, Koehl U, Lanza F, Urbano-Ispizua A, Hudecek M, Ruggeri A, Secondino S, Bonini C, Pedrazzoli P. Development of adaptive immune effector therapies in solid tumors. ANN ONCOL 2019 11; 30: 1740-1750
Total Publications: 26
Total IF: 312.468
Mean IF: 12.018
Last update: 28/06/2021