Gentner lab

Our research program leverages on genetic engineering of hematopoietic stem cells (HSC) in order to develop disruptive new cell therapies against tumors. Bone marrow transplantation (BMT) is a clinically-established treatment, which allows body-wide substitution of a hypofunctional hematopoietic & immune cell compartment with donor-derived cells. Progress in genetic engineering has made HSC gene therapy a reality. Clinical studies now show sustained gene addition and gene knockout in almost 100% of the blood cells, which has led to market-approval of HSC gene therapies for several genetic diseases. Capitalizing on 16 years of experience at the San Raffaele Telethon Institute for Gene Therapy, the lab strives to program HSC with anti-tumor genes that are selectively activated in the progeny once recruited into the tumor microenvironment, as a “next generation” BMT to obtain blood cells with synthetic functions. Parallel evolution of the HSC transplantation platform will make this treatment accessible to cancer patients. *The lab is currently recruiting Post-Docs, PhD candidates and Research Assistants. ...

Research projects

Engineering Hematopoietic Stem Cells to Reprogram the Tumor Microenvironment

Getting into the tumor microenvironment with the help of tumor-infiltrating myeloid cells (TIMs) is a novel strategy with tremendous potential, naturally complementing the numerous T cell-based approaches, which have so far shown unsatisfactory results in most solid tumors. An ongoing clinical study (NCT03866109) has shown the feasibility to replace a fraction of the TIMs with genetically-engineered cells after BMT. In this project, we will evaluate novel strategies to target transgene expression to TIMs, leveraging on increasing knowledge on how these cells are transcriptionally wired. HSC will be engineered with lentiviral vectors carrying TIM-specific promoters, or by gene editing for direct payload knock-in into genomic loci activated in TIMs. Taking advantage of the unique expertise of Hi-TiDe, we will equip TIMs with therapeutic payloads to generate synthetic cell networks that synergize with adoptive T-cell therapies (T-cell ACT) to ultimately reprogram the tumor microenvironment to support anti-cancer immune responses.  

Team

Bernhard Gentner

Associate Professor of Immuno-Oncology, Department of Oncology UNIL&CHUV, Attending Physician, Immuno-Oncology Service, Hematologist, Specialist in Hematologic Stem Cell Transplantation and Cellular Therapy, Hematopoietic Stem Cell Engineering Lab, Hi-TiDe.

bernhard.gentner@chuv.ch

Selected Publications

Myeloid cell-based delivery of IFN-γ reprograms the leukemia microenvironment and induces anti-tumoral immune responses.

Mucci A, Antonarelli G, Caserta C, (...), Merelli I, Naldini L, Gentner B

EMBO molecular medicine – 2021 Aug 30

Expanded circulating hematopoietic stem/progenitor cells as novel cell source for the treatment of TCIRG1 osteopetrosis.

Capo V, Penna S, Merelli I, (...), Sobacchi C, Gentner B, Villa A

Haematologica – 2021 Jan 1

Interferon gene therapy reprograms the leukemia microenvironment inducing protective immunity to multiple tumor antigens.

Escobar G, Barbarossa L, Barbiera G, (...), Ostuni R, Gentner B, Naldini L

Nature communications – 2018 Jul 24

Efficient Ex Vivo Engineering and Expansion of Highly Purified Human Hematopoietic Stem and Progenitor Cell Populations for Gene Therapy.

Zonari E, Desantis G, Petrillo C, (...), Ferrari G, Naldini L, Gentner B

Stem cell reports – 2017 Mar 16

miRNA-126 Orchestrates an Oncogenic Program in B Cell Precursor Acute Lymphoblastic Leukemia.

Nucera S, Giustacchini A, Boccalatte F, (...), Montini E, Gentner B, Naldini L

Cancer cell – 2016 Jun 13

miR-126 Regulates Distinct Self-Renewal Outcomes in Normal and Malignant Hematopoietic Stem Cells.

Lechman ER, Gentner B, Ng SWK, (...), Wang JCY, Naldini L, Dick JE

Cancer cell – 2016 Apr 11

Dual-regulated lentiviral vector for gene therapy of X-linked chronic granulomatosis.

Chiriaco M, Farinelli G, Capo V, (...), Naldini L, Gentner B, Aiuti A

Molecular therapy : the journal of the American Society of Gene Therapy – 2014 May 29

Targeted genome editing in human repopulating haematopoietic stem cells.

Genovese P, Schiroli G, Escobar G, (...), Montini E, Lombardo A, Naldini L

Nature – 2014 May 28

Genetic engineering of hematopoiesis for targeted IFN-α delivery inhibits breast cancer progression.

Escobar G, Moi D, Ranghetti A, (...), De Palma M, Mazzieri R, Naldini L

Science translational medicine – 2014 Jan 1

A role for miR-155 in enabling tumor-infiltrating innate immune cells to mount effective antitumor responses in mice.

Zonari E, Pucci F, Saini M, (...), Politi LS, Gentner B, Naldini L

Blood – 2013 Mar 13

Identification of hematopoietic stem cell-specific miRNAs enables gene therapy of globoid cell leukodystrophy.

Gentner B, Visigalli I, Hiramatsu H, (...), Dick JE, Biffi A, Naldini L

Science translational medicine – 2010 Nov 17

Stable knockdown of microRNA in vivo by lentiviral vectors.

Gentner B, Schira G, Giustacchini A, (...), Brown BD, Ponzoni M, Naldini L

Nature methods – 2008 Nov 30

Endogenous microRNA can be broadly exploited to regulate transgene expression according to tissue, lineage and differentiation state.

Brown BD, Gentner B, Cantore A, (...), Lazzari G, Galli C, Naldini L

Nature biotechnology – 2007 Nov 16

Retroviral vector integration occurs in preferred genomic targets of human bone marrow-repopulating cells.

Laufs S, Gentner B, Nagy KZ, (...), Ho AD, Zeller WJ, Fruehauf S

Blood – 2002 Nov 7