The Dolcetti Lab performs pre-clinical and clinical research aimed at improving the applicability and efficacy of cancer immunotherapy with particular focus on antigen-specific strategies.

The lab has particular expertise in the identification and functional validation of immunogenic tumour antigens, which are exploited within novel cancer vaccine platforms and in clinically applicable immunoassays to monitor tumour-specific immune responses in cancer patients. Moreover, to overcome immunotherapy resistance and local immunosuppression typically associated with tumour progression, the lab is exploring novel combination therapies, including cell- and gene-based strategies for the tumour-targeted delivery of biomolecules. Proof of feasibility, efficacy, and safety, as well as insights into therapy-induced immune modulation, are provided using both murine and humanised models of primary and metastatic tumours. The lab is located in the VCCC Centre for Cancer Immunotherapy on Level 13 of the VCCC building.

Main research themes in our laboratory include:

  • Pre-clinical exploitation of a novel nanoparticle-based vaccination platform targeting cross-presenting Clec9A+ dendritic cells in vivo, particularly in combination with checkpoint modulators and CAR T-cell therapies.
  • Identification and characterisation of novel classes of tumour neo-antigens to improve immunotherapy of triple negative breast cancer.
  • Identification and pre-clinical exploitation of novel immunotherapeutic targets for the treatment of primary and metastatic brain tumours.
  • Clinical application of advanced assays to monitor anti-tumour immune responses in cancer patients enrolled in immunotherapy trials.
  • Development of an engineered monocyte-based platform for efficient intra-tumour delivery of biomolecules able to revert local immunosuppression.
  • Development of new strategies to overcome immunotherapy resistance.
  • Development and application of humanised mouse models to investigate the in vivo immunogenicity of human tumour antigens and the efficacy of immunotherapeutic strategies.

People

Dr Roberta Mazzieri, Senior Scientist
Dr Bijun Zeng, Senior Postdoctoral Fellow
Davide Moi, Senior Research Assistant

Key publications

(*shared senior authorship).

  1. Chan JD, von Scheidt B, Zeng B, Oliver AJ, Davey AS, Ali AI, Thomas R, Trapani JA, Darcy PK, Kershaw MH*, Dolcetti R*, Slaney CY*. Enhancing chimeric antigen receptor T-cell immunotherapy against cancer using a nanoemulsion-based vaccine targeting cross-presenting dendritic cells. Clin Transl Immunology. 2020 Jul 22;9(7):e1157.
  2. Chew HY, De Lima PO, Gonzalez Cruz JL, Banushi B, Echejoh G, Hu L, Joseph SR, Lum B, Rae J, O'Donnell JS, Merida de Long L, Okano S, King B, Barry R, Moi D, Mazzieri R, Thomas R, Souza-Fonseca-Guimaraes F, Foote M, McCluskey A, Robinson PJ, Frazer IH, Saunders NA, Parton RG, Dolcetti R, Cuff K, Martin JH, Panizza B, Walpole E, Wells JW, Simpson F. Endocytosis Inhibition in Humans to Improve Responses to ADCC-Mediating Antibodies. Cell. 2020;180(5):895‐914.e27.
  3. Cox M, Castiello L, Mattei M, Santodonato L, D'Agostino G, Muraro E, Martorelli D, Lapenta C, Di Napoli A, Di Landro F, Cangemi M, Pavan A, Castaldo P, Hohaus S, Donati S, Montefiore E, Berdini C, Carlei D, Monque DM, Ruco L, Prosperi D, Tafuri A , Spadaro F, Sestili P, Spada M, Dolcetti R, Santini SM, Rozera C, Capone I, Belardelli F. Clinical and antitumor immune responses In Relapsed/Refractory Follicular Lymphoma patients after intranodal injections of IFNα-Dendritic Cells and Rituximab. Clin Cancer Res, 2019, 25(17):5231-5241.
  4. Lam PY, Kobayashi T, Soon M, Zeng B, Dolcetti R, Leggatt G, Thomas R, Mattarollo S. NKT cell-driven enhancement of anti-tumor immunity induced by Clec9a-targeted Tailorable Nanoemulsion. Cancer Immunol Res. 2019, Jun;7(6):952-962.
  5. Cangemi M, Montico B, Faè DA, Steffan A, Dolcetti R. Dissecting the multiplicity of immune effects of immunosuppressive drugs to better predict the risk of de novo malignancies in solid organ transplant patients. Front Oncol 2019, Mar 27;9:160.
  6. Budhwani M, Mazzieri R, Dolcetti R. Plasticity of Type I Interferon-Mediated Responses in Cancer Therapy: From Anti-tumor Immunity to Resistance. Front Oncol. 2018 Aug 21;8:322.
  7. Zeng B, Middelberg A, Gemiarto A, MacDonald K, Baxter AG, Talekar M, Moi D, Tullett K, Caminschi I, Lahoud M, Mazzieri R, Dolcetti R*, Thomas R*. Self-adjuvanting nanoemulsion targeting dendritic cell receptor Clec9A enables antigen-specific immunotherapy. J Clin Invest, 2018 May 1;128(5):1971-1984.
  8. Montico B, Lapenta C, Ravo M, Martorelli D, Muraro E, Zeng B, Comaro E, Spada M, Donati S, Santini SM, Tarallo R, Giurato G, Rizzo F, Weisz A, Belardelli F, Dolcetti R*, Dal Col J*. Exploiting a new strategy to induce immunogenic cell death to improve dendritic cell-based vaccines for lymphoma immunotherapy OncoImmunology 2017 Jul 31;6(11):e1356964
  9. McKee SJ, Tuong ZK, Kobayashi T, Doff BL, Soon MS, Nissen M, Lam PY, Keane C, Vari F, Moi D, Mazzieri R, Leggatt G, Gandhi MK, Mattarollo SR. B cell lymphoma progression promotes the accumulation of circulating Ly6Clo monocytes with immunosuppressive activity. Oncoimmunology 2017 Dec 18;7(2):e139359
  10. Muraro E, Furlan C, Avanzo M, Martorelli D, Comaro E, Rizzo A, Fae’ DA, Berretta M, Militello L, Del Conte A, Spazzapan S, Dolcetti R*, Trovo’ M*. Local High-Dose Radiotherapy Induces Systemic Immunomodulating Effects of Potential Therapeutic Relevance in Oligometastatic Breast Cancer. Front Immunol 2017 Nov 6;8:1476
  11. Martine LC, Holzapfel BM, McGovern JA, Wagner F, Quent VM, Hesami P, Wunner FM, Vaquette C, De-Juan-Pardo EM, Brown TD, Nowlan B, Wu DJ, Hutmacher CO, Moi D, Oussenko T, Piccinini E, Zandstra PW, Mazzieri R, Lévesque JP, Dalton PD, Taubenberger AV, Hutmacher DW. Engineering a humanized bone organ model in mice to study bone metastases. Nature Protocols 2017 12(4):639-663.
  12. Turrini R, Merlo A, Martorelli D, Faè DA, Sommaggio R, Montagner IM, Barbieri V, Marin O, Zanovello P, Dolcetti R*, Rosato A*. A BARF1-specific mAb as a new immunotherapeutic tool for the management of EBV-related tumors. Oncoimmunology 2017, Mar 16;6(4):e1304338.
  13. Muraro E, Merlo A, Martorelli D, Cangemi M, Dalla Santa S, Dolcetti R*, Rosato A*. Fighting Viral Infections and Virus-Driven Tumors with Cytotoxic CD4+ T Cells. Front Immunol. 2017 Feb 27; 8:197
  14. Dolcetti R. Predictive Value of FcR Polymorphisms: A Further Step on the Long and Winding Road to Application. JAMA Oncol. 2017 Mar 1;3(3):342-343.
  15. Carbone A, Gloghini A, Caruso A, De Paoli P, Dolcetti R. The impact of EBV and HIV infection on the microenvironmental niche underlying Hodgkin lymphoma pathogenesis. Int J Cancer. 2017 Mar 15;140(6):1233-1245.
  16. Faè DA, Martorelli D, Mastorci K, Muraro E, Dal Col J, Franchin G, Barzan L, Comaro E, Vaccher E, Rosato A, Dolcetti R. Broadening specificity and enhancing cytotoxicity of adoptive T cells for nasopharyngeal carcinoma immunotherapy. Cancer Immunol Res. 2016 May;4(5):431-40.
  17. Dolcetti R, Giagulli C, He W, Selleri M, Caccuri F, Eyzaguirre LM, Mazzuca P, Corbellini S, Campilongo F, Marsico S, Giombini E, Muraro E, Rozera G, De Paoli P, Carbone A, Capobianchi MR, Ippolito G, Fiorentini S, Blattner WA, Lu W, Gallo RC, Caruso A. Role of HIV-1 matrix protein p17 variants in lymphoma pathogenesis. Proc Natl Acad Sci U S A. 2015 Nov 17; 112(46):14331-6.
  18. Dolcetti R, Gloghini A, Caruso A, Carbone A. A lymphomagenic role for HIV beyond immune suppression? Blood. 2016 Mar 17;127(11):1403-9.
  19.  Muraro E, Comaro E, Talamini R, Turchet E, Miolo G, Scalone S, Militello L, Lombardi D, Spazzapan S, Perin T, Massarut S, Crivellari D, Dolcetti R*, Martorelli D*. Improved Natural Killer cell activity and retained anti-tumor CD8(+) T cell responses contribute to the induction of a pathological complete response in HER2-positive breast cancer patients undergoing neoadjuvant chemotherapy. J Transl Med. 2015 Jun 27;13:204
  20. Ronca R, Giacomini A, Di Salle E, Coltrini D, Pagano K, Ragona L, Matarazzo S, Rezzola S, Maiolo D, Torrella R, Moroni E, Mazzieri R, Escobar G, Colombo G, Presta M. A long-pentraxin 3 derivative as the first small molecule FGF-trap for cancer therapy. Cancer Cell 2015 28(2):225-39.
  21. Martorelli D, Muraro E, Mastorci K, Dal Col J, Faè DA, Furlan C, Giagulli C, Caccuri F, Rusnati M, Fiorentini S, Carbone A, Caruso A, Dolcetti R. A natural HIV p17 protein variant up-regulates the LMP-1 EBV oncoprotein and promotes the growth of EBV-infected B-lymphocytes: Implications for EBV-driven lymphomagenesis in the HIV setting. Int J Cancer. 2015 137(6):1374-85.
  22. Miolo G, Muraro E, Martorelli D, Lombardi D, Scalone S, Spazzapan S, Massarut S, Perin T, Viel E, Comaro E, Talamini R, Bidoli E, Turchet E, Crivellari D, Dolcetti R. Anthracycline-free neoadjuvant therapy induces pathological complete responses by exploiting immune proficiency in HER2+ breast cancer patients. BMC Cancer. 2014 Dec 15;14(1):954.
  23. Genovese P, Schiroli S, Escobar G, Di Tomaso T, Firrito C, Calabria A, Moi D, Mazzieri R, Bonini C, Holmes MC, Gregory PD, van der Burg M, Gentner B, Montini E, Lombardo L, Naldini L. Targeted Genome Editing in Human Repopulating Hematopoietic Stem Cells.  Nature 2014 510(7504):235-40
  24. G. Escobar, D. Moi, A. Ranghetti, P. Ozkal-Baydin, M. L. Squadrito, M. De Palma, R. Mazzieri* and L. Naldini*. Genetic Engineering of Hematopoiesis for Tumor-Targeted Delivery of Interferon-α Inhibits Breast Cancer Progression in Mouse and Human Hematochimeric Models. Science Translational Medicine 2014 4:217ra3 
  25. Ferreri AJ, Govi S, Pasini E, Mappa S, Bertoni F, Zaja F, Montalbàn C, Stelitano C, Cabrera ME, Resti AG, Politi LS, Doglioni C, Cavalli F, Zucca E, Ponzoni M, Dolcetti R. Chlamydophila Psittaci eradication with doxycycline as lymphoma: final results of an International phase II trial. J Clin Oncol. 2012 Aug; 30(24):299-94.
  26. Martorelli D, Guidoboni M, De Re V, Muraro E, Turrini R, Merlo A, Pasini E, Caggiari L, Romagnoli L, Spina M, Mortarini M, Gasparotto D, Mazzucato M, Carbone, Rosato A, Anichini, Dolcetti R. IGKV3 proteins as candidate “off-the-shelf” vaccines for kappa-light chain-restricted B cell non-Hodgkin’s lymphomas. Clin Cancer Res. 2012 Aug; 18(15):4080-91

Research programs