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 program gathers together 14 basic research units – working on topics ranging from tumor immunology to gene therapy, from genomics to advanced imaging – and 5 clinical units of IRCCS Ospedale San Raffaele.
It exploits shared state-of-the-art omics, including at single-cell level, advanced imaging, flow cytometry, and histological platforms, and takes advantage of the roadmaps previously established at San Raffaele for the development of gene and cell therapies in other indications.
The ultimate mission of this AIRC translational program 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.
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.
By matched and multi-level analyses on patients’ biological samples, Program 1 has:
- identified different immunoregulatory receptors and molecules involved in the immune suppression and exhaustion distinctive of hepatic metastases (first milestone achieved);
- selected several tumor antigens eligible for CAR development and/or TCR redirection (second milestone achieved).
By an optimized pipeline for T cell gene editing (patent application submitted), Program 2 has established the genetic deletion of those immunoregulatory receptors identified by Program 1. Moreover, new CAR- and TCR-T cell products have been generated and are now under functional and safety validation, either administered alone or in combination with novel agents able to enhance adoptive T cell therapy.
Program 3 has designed and produced different peptide-based formulations for tumor/stroma targeting and a tunable lentivirus-based platform for liver-targeted cytokine delivery (patent application submitted), by which a candidate antitumoral cytokine has been selectively expressed in liver metastases of tumor-bearing mice, exerting promising therapeutic effects in the absence of systemic toxicity.
The institutional biobank (Center of Biological Resources, CRB) assures the availability of several biological specimens from patients enrolled in LiMeT clinical study (over 400 patients since its authorization in November 2019), including follow-up samples, that allow cross-sectional and longitudinal analyses planned by Program 1.
Patients’ clinical data are collected at enrollment and during follow-up visits and archived in a GDPR-compliant intramural database (Cohort Genomics Platform, CGP), providing clinical correlates of experimental results from Program 1.
Different ex-vivo and in vivo models have been developed and shared by the AIRC5x1000 consortium, to recapitulate and intervene on hepatic metastases of colorectal and pancreatic ductal adenocarcinomas. They will be instrumental for efficacy and toxicity studies planned by Program 2 and 3.
In March 2022 the Program has passed the 3rd-year midterm review by a panel of 9 international experts in translational oncology, clinical immunology and genetics, who confirmed the viability of the projects and endorsed the merit of clinical and research teams. The next midterm review will be in the 5th year.
Last updated: 27.05.2022
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
The program gather together 5 clinical units of IRCCS Ospedale San Raffaele:
Ruggiero E, Carnevale E, Prodeus A, Magnani ZI, Camisa B, Merelli I, Politano C, Stasi L, Potenza A, Cianciotti BC, Manfredi F, Di Bono M, Vago L, Tassara M, Mastaglio S, Ponzoni M, Francesca Sanvito, Liu D, Balwani I, Galli R, Genua M, Ostuni R, Doglio M, O'Connell D, Dutta I, Yazinski SA, McKee M, Arredouani MS, Schultes B, Ciceri F, Bonini C. CRISPR-based gene disruption and integration of high-avidity, WT1-specific T cell receptors improve anti-tumor T cell function. Sci Transl Med. 2022 Feb 9;14(631):eabg8027. doi: 10.1126/scitranslmed.abg8027
Pocaterra A, Catucci M, and Mondino A. Adoptive T cell therapy of solid tumors: time to team up with immunogenic chemo/radiotherapy. Curr Opin Immunol. 2022 Feb;74:53-59. doi: 10.1016/j.coi.2021.10.004.
De Sanctis F, Lamolinara A, Boschi F, Musiu C, Caligola S, Trovato R, Fiore A, Frusteri C, Anselmi C, Poffe O, Cestari T, Canè S, Sartoris S, Giugno R, Del Rosario G, Zappacosta B, Del Pizzo F, Fassan M, Dugnani E, Piemonti L, Bottani E, Decimo I, Paiella S, Salvia R, Lawlor RT, Corbo V, Park Y, Tuveson DA, Bassi C, Scarpa A, Iezzi M, Ugel S, Bronte V. Interrupting the nitrosative stress fuels tumor-specific cytotoxic T lymphocytes in pancreatic cancer. J Immunother Cancer. 2022 Jan;10(1):e003549. doi: 10.1136/jitc-2021-003549.
Greco B, Malacarne V, De Girardi F, Scotti GM, Manfredi F, Angelino E, Sirini C, Camisa B, Falcone L, Moresco MA, Paolella K, Di Bono M, Norata R, Sanvito F, Arcangeli S, Doglioni C, Ciceri F, Bonini C, Graziani A, Bondanza A, Casucci M. Disrupting N-glycan expression on tumor cells boosts chimeric antigen receptor T cell efficacy 1 against solid malignancies. In Press, Science Translational Medicine
Fumagalli V, Ravà M, Marotta D, Di Lucia P, Laura C, Sala E, Grillo M, Bono E, Giustini L, Perucchini C, Mainetti M, Sessa A, Garcia-Manteiga JM, Donnici L, Manganaro L, Delbue S, Broccoli V, De Francesco R, D'Adamo P, Kuka M, Guidotti LG, Iannacone M. Administration of aerosolized SARS-CoV-2 to K18-hACE2 mice uncouples respiratory infection from fatal neuroinvasion. Sci Immunol. 2021 Nov 23:eabl9929. Online ahead of print.
Tedesco M, Giannese F, Lazarević D, Giansanti V, Rosano D, Monzani S, Catalano I, Grassi E, Zanella ER, Botrugno OA, Morelli L, Panina Bordignon P, Caravagna G, Bertotti A, Martino G, Aldrighetti L, Pasqualato S, Trusolino L, Cittaro D, Tonon G. Chromatin Velocity reveals epigenetic dynamics by single-cell profiling of heterochromatin and euchromatin. Nat Biotechnol. 2021 Oct 11.doi: 10.1038/s41587-021-01031-1. Online ahead of print.
Greco R, Lorentino F, Albanese S, Stanghellini MTL, Giglio F, Piemontese S, Clerici D, Lazzari L, Marcatti M, Mastaglio S, Xue E, Farina F, Pavesi F, Assanelli A, Carrabba MG, Marktel S, Vago L, Bonini C, Corti C, Bernardi M, Ciceri F, Peccatori J. Posttransplantation Cyclophosphamide- and Sirolimus-Based Graft-Versus-Host-Disease Prophylaxis in Allogeneic Stem Cell Transplant. Transplant Cell Ther 2021 09; 27: 776.e1-776.e13
Fedeli M, Kuka M, Finardi A, Albano F, Viganò V, Iannacone M, Furlan R, Dellabona P, Casorati G. miR-21 sustains CD28 signalling and low-affinity T-cell responses at the expense of self-tolerance. Clin Transl Immunology. 2021 Sep 21;10(9):e1321. doi: 10.1002/cti2.1321.
Conforti A, Marra E, Palombo F, Roscilli G, Ravà M, Fumagalli V, Muzi A, Maffei M, Luberto L, Lione L, Salvatori E, Compagnone M, Pinto E, Pavoni E, Bucci F, Vitagliano G, Stoppoloni D, Pacello ML, Cappelletti M, Ferrara FF, D'Acunto E, Chiarini V, Arriga R, Nyska A, Di Lucia P, Marotta D, Bono E, Giustini L, Sala E, Perucchini C, Paterson J, Ryan KA, Challis AR, Matusali G, Colavita F, Caselli G, Criscuolo E, Clementi N, Mancini N, Groß R, Seidel A, Wettstein L, Münch J, Donnici L, Conti M, De Francesco R, Kuka M, Ciliberto G, Castilletti C, Capobianchi MR, Ippolito G, Guidotti LG, Rovati L, Iannacone M, Aurisicchio L. COVID-eVax, an electroporated DNA vaccine candidate encoding the SARS-CoV-2 RBD, elicits protective responses in animal models. Mol Ther. 2021 Sep 20:S1525-0016(21)00466-4. doi: 10.1016/j.ymthe.2021.09.011. Online ahead of print.
De Simone G, Andreata F, Bleriot C, Fumagalli V, Laura C, Garcia-Manteiga JM, Di Lucia P, Gilotto S, Ficht X, De Ponti FF, Bono EB, Giustini L, Ambrosi G, Mainetti M, Zordan P, Bénéchet AP, Ravà M, Chakarov S, Moalli F, Bajenoff M, Guidotti LG, Ginhoux F, Iannacone M. Identification of a Kupffer cell subset capable of reverting the T cell dysfunction induced by hepatocellular priming. Immunity. 2021 Sep 14;54(9):2089-2100.e8. doi: 10.1016/j.immuni.2021.05.005.
Ferrara B, Pignatelli C, Cossutta M, Citro A, Courtyì J, Piemonti L. The Extracellular Matrix in Pancreatic Cancer: Description of a Complex Network and Promising Therapeutic Options. Cancers 2021, 13, 4442
Grioni M, Brevi A, Cattaneo E, Rovida A, Bordini J, Bertilaccio MTS, Ponzoni M, Casorati G, Dellabona P, Ghia P, Bellone M,Calcinotto A. CD4+ T cells sustain aggressive chronic lymphocytic leukemia in Eμ-TCL1 mice through a CD40L-independent mechanism. Blood Adv 2021 07; 5: 2817-2828
Ratti F, Casadei-Gardini A, Cipriani F, Fiorentini G, Pedica F, Burgio V, Cascinu S, Aldrighetti L. Laparoscopic Surgery for Intrahepatic Cholangiocarcinoma: A Focus on Oncological Outcomes. J CLIN MED 2021 Jun; 10:
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)
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.
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 Front Chem. 2021 May 28;9:690357. doi: 10.3389/fchem.2021.690357. eCollection 2021. (* Co-Corresponding Author)
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.
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.
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)
Exley MA, Dellabona P, Casorati G. Exploiting CD1-restricted T cells for clinical benefit. MOL IMMUNOL 2021 Feb; 132: 126-131
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
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.
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
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.
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.
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)
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
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).
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
Protti, MP and De Monte L. Dual Role of Inflammasome Adaptor ASC in Cancer.Front Cell Dev Bio 2020 Feb; 8: Article 40
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
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
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 Nov 1;30(11):1740-1750. doi: 10.1093/annonc/mdz285.
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 Oct;574(7777):200-205. doi: 10.1038/s41586-019-1620-6.
Total Publications: 38
Total IF: 423.490
Mean IF: 12.100
Last update: 27/05/2022