Project 1. Development of improved cancer vaccines to enhance the efficacy of immunotherapy combination strategies

Despite the ability of cancer vaccines to generate brand new and strong anti-tumour immune responses, their therapeutic efficacy is still unsatisfactory. This is due to the limited potency and antigen-specificity of available cancer vaccines, which need to be combined with other treatments to overcome the local immune suppression of tumour microenvironment.

This project aims at developing new classes of clinically applicable cancer vaccines targeting tumours with limited inherent immunogenicity by exploiting our recently developed nanoparticle-based vaccination platform targeting cross-presenting dendritic cells in vivo. Novel and more immunogenic antigen formulations will be identified and therapeutically validated in different preclinical cancer models. To overcome immunotherapy resistance and local immunosuppression typically associated with tumour progression, the project will explore mechanism-based combination therapies, also 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 will be provided using both murine and humanised models of primary and metastatic tumours, including melanoma, breast, liver and brain cancers.

Dr. Roberta Mazzieri, Senior Scientist

Dr. Bijun Zeng, Senior Post-Doctoral fellow

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. doi: 10.1002/cti2.1157. PMID: 32704371; PMCID: PMC7374388.

Lam PY, Kobayashi T, Soon M, Zeng B, Dolcetti R, Leggatt G, Thomas R, Mattarollo SR. NKT Cell-Driven Enhancement of Antitumor Immunity Induced by Clec9a-Targeted Tailorable Nanoemulsion. Cancer Immunol Res. 2019 Jun; 7(6):952-962. doi: 10.1158/2326-6066.CIR-18-0650. Epub 2019 May 3. PMID: 31053598.

Zeng B, Middelberg AP, Gemiarto A, MacDonald K, Baxter AG, Talekar M, Moi D, Tullett KM, Caminschi I, Lahoud MH, 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. doi: 10.1172/JCI96791. Epub 2018 Apr 9. PMID: 29485973; PMCID: PMC5919883.

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. doi: 10.1080/2162402X.2017.1356964. PMID: 29147614; PMCID: PMC5674955.

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. doi: 10.1158/2326- 6066.CIR-15-0108. Epub 2016 Mar 23. PMID: 27009165.