Targeted Cancer Gene Therapy
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.
Nucera S§, Giustacchini A§, Boccalatte F§, Calabria A, Fanciullo C, Plati T, Ranghetti A, Garcia-Manteiga J, Cittaro D, Benedicenti F, Lechman ER, Dick JE, Ponzoni M, Ciceri F, Montini E, Gentner B*, Naldini L*. miR-126 Orchestrates an Oncogenic Program in B-Cell Precursor Acute Lymphoblastic Leukemia. Cancer Cell 2016 Jun 13;29(6):905-21. § equal contribution * senior authorship.
Lechman ER*, Gentner B*, Ng SW, Schoof EM, van Galen P, Kennedy JA, Nucera S, Ciceri F, Kaufmann KB, Takayama N, Dobson SM, Trotman-Grant A, Krivdova G, Elzinga J, Mitchell A, Nilsson B, Hermans KG, Eppert K, Marke R, Isserlin R, Voisin V, Bader GD, Zandstra PW, Golub TR, Ebert BL, Lu J, Minden M, Wang JC, Naldini L, Dick JE. miR-126 Regulates Distinct Self-Renewal Outcomes in Normal and Malignant Hematopoietic Stem Cells. Cancer Cell. 2016 Feb 8;29(2):214-28. * Equal contribution
Escobar G.,Moi D., Ranghetti A., Ozkal-Baydin P., Squadrito M.L., Kajaste- Rudnitski A., Bondanza A., Gentner B., De Palma M., Mazzieri R. and Naldini L. Genetic Engineering of Hematopoiesis for Targeted IFN-α Delivery Inhibits Breast Cancer Progression. Science Transl Med. 2014 Jan 1;6(217):217ra3.
Zonari E., Pucci F., Saini M., Mazzieri R., Politi LS., Gentner B., Naldini L. A role for miR-155 in enabling tumor-infiltrating innate immune cells to mount effective anti-tumor responses. Blood. 2013 Jul 11;122(2):243-52.
Amendola M, Giustacchini A, Gentner B, Naldini L. A double-switch vector system positively regulates transgene expression by endogenous microRNA expression (miR-ON vector). Mol Ther. 2013 May; 21(5):934-46.
Lechman ER.*, Gentner B.*, van Galen P.*, Giustacchini A.*, Saini M., Boccalatte FE., Hiramatsu H., Restuccia U., Bachi A., Voisin V., Bader GD., Dick JE. and Naldini L. Attenuation of miR-126 Activity Expands HSC In Vivo without Exhaustion. Cell Stem Cell. 2012 Dec 7;11(6):799-811. *Co-first authors: ERL, BG, PvG and AG. Co-senior corresponding authors: LN and JED.
Mazzieri R.*, Pucci F.*, Moi D., Zonari E., Ranghetti A., Berti A., Politi L.S., Gentner B., Brown J.L., Naldini L., and De Palma M. Targeting the Angiopoietin-2/TIE2 axis Inhibits Tumor Progression and Metastasis by Impairing Angiogenesis and Disabling Rebounds of Proangiogenic Myeloid Cells. Cancer Cell. 2011, Apr 12;19(4):512-26. Co-first authors: RM and FP. Co-senior corresponding authors: LN and MDP.
Pucci F.*, Venneri M.A*., Biziato D., Nonis A., Moi D., Sica A., Di Serio C., Naldini L. and De Palma M. A distinguishing gene signature shared by tumor-infiltrating Tie2-expressing monocytes (TEMs), blood “resident” monocytes and embryonic macrophages suggests common functions and developmental relationships. Blood. 2009 Apr 21. Jul 23; 114(4):901-14.
De Palma M.*, Mazzieri R.*, Politi L.S., Pucci F., Zonari E., Mazzoleni S., Sitia G., Moi D., Venneri M.A., Indraccolo S., Falini A., Guidotti L.G., Galli R. and Naldini L. Tumor-targeted interferon-α delivery by Tie2-expressing monocytes inhibits tumor growth and metastasis. Cancer Cell. 2008 Oct 7;14(4):299-311. *Co-first authors: MDP and RM. Corresponding authors: LN and MDP.
Venneri MA, De Palma M, Ponzoni M, Pucci F, Scielzo C, Zonari E, Mazzieri R, Doglioni C, Naldini L. Identification of Proangiogenic TIE2-Expressing Monocytes (TEMs) in Human Peripheral Blood and Cancer. Blood. 2007. 109(12):5276-85.
De Palma M*, Venneri MA*, Galli R, Sergi Sergi L, Politi LS, Sampaolesi M, Naldini L. Tie2 Identifies a Hematopoietic Lineage of Pro-Angogenic Monocytes Required for Tumor Vessel Formation and a Mesenchymal Population of Pericyte Progenitors. Cancer Cell. 2005. 8(3):211-26. *Co-first authors: MDP and MAV.