Migliorini lab

Our laboratory aims to find new therapeutic approaches to brain cancer, and in particular to glioblastoma, which is a very aggressive form of the disease. Importantly, research over the past decades indicates that immune cells can influence the development of the disease. In this sense, our research focuses on immune therapies for brain tumors. For example, we aim to modify T cells with chimeric antigen receptors (CARs) that allow them to recognize tumor cells. These CAR-T cells can then be infused into patients to specifically eliminate tumor cells. To this end, we are seeking to discover markers that are overexpressed in glioblastoma and then engineer CAR-T cells that specifically recognize these markers. We are also investigating several approaches that may improve the accumulation, survival and antitumor functions of CAR-T cells in tumors, with the ultimate goal of establishing long-term antitumor immunity in patients ...

Research projects

Our efforts are directed towards the following points, which we believe will be critical for the development of successful translational programs:

  1. Identifying scFv specific for multiple glioblastoma (GBM) antigens, providing the starting point for the development of CAR T cell therapy.
  2. Developing robust models of multi-antigen targeting using RNA-electroporated CAR T cells, as targeting GBM tumour heterogeneity is crucial.
  3. Using single-cell genomics and synthetic biology-based therapeutics to repurpose tumour-associated macrophages (TAMs) in GBM.
  4. Reducing CD19-targeting CAR T cell-induced neurotoxicity.

CAR T cell therapy

Our work on glioma antigen identification offers the opportunity to develop cell therapy for glioma. The CAR approach involves expressing an antitumor antibody at the T cell surface, allowing redirection of the T cell to the tumor. The identified glioma antigens are ideal targets for this approach, allowing the design of multiple anti-glioma CARs. In collaboration with the group of Profs. Carl June and Avery D. Posey at the University of Pennsylvania, we are developing this approach for the treatment of patients diagnosed with glioma.

Glioma tumor microenvironment

Optimization of glioma immunotherapies must take into consideration the very special features of the brain. Indeed, glioma occurs in an organ surrounded by the blood-brain barrier and bathed into multiple immunosuppressive factors. This implies that the initiation and regulation of antitumor immune responses follow particular rules. We are therefore investigating the glioma tumor microenvironment, using various approaches and notably oncolytic viruses able to selectively infect and replicate in tumor cells, to then use their machinery to produce fusion proteins able to target bystanding glioma associated macrophages

Avoiding neurotoxicity of CD19 targeting CAR-T cells

We recently reported evidence suggesting that one mechanism of neurotoxicity of CD19 CAR T cells  is “on-target off-tumour” effect on CD19-expressing brain pericytes. In order to address this issue, we are designing CAR T cells that are inhibited upon contact with brain pericytes (inhibitory, iCAR T cells). These iCAR T cells bear a CD19-activating construct and a pericyte marker-inhibitory construct. We designed multiple versions of inhibitory CAR constructs targeting canonical markers expressed in brain pericytes and generated bispecific anti-CD19 activatory/anti-brain pericyte inhibitory CAR T cells. In parallel, we are engineering human B cell acute lymphoblastic leukaemia cell lines to express these canonical markers in addition to their constitutive expression of CD19 in order to test the cytotoxicity inhibition of our iCAR T cells. We are generating scRNA seq data focused on human brain pericytes obtained from patients operated in Geneva in order to identify reliable brain pericytes cell surface markers to design novel inhibitory CAR T cells.

Team

Denis Migliorini

MD Assistant Professor, Faculty of Medicine, University of Geneva, ISREC Foundation chair in brain tumor immunology, Head of the Neuro oncology Unit, Dpt. of Oncology, Geneva University Hospitals (HUG), Member of the Swiss Cancer Center Leman (SCCL)

denis.migliorini@unige.ch MiglioriniLab

Other members

Selected Publications

Allogeneic CAR T Cells: An Alternative to Overcome Challenges of CAR T Cell Therapy in Glioblastoma.

Martínez Bedoya D, Dutoit V, Migliorini D

Frontiers in immunology – 2021 Mar 3

Clonal Evolution of a High-Grade Pediatric Glioma With Distant Metastatic Spread.

Marinari E, Dutoit V, Nikolaev S, (...), Dietrich PY, Tsantoulis P, Migliorini D

Neurology. Genetics – 2021 Feb 15

Oncolytic Viruses as a Platform for the Treatment of Malignant Brain Tumors.

Sostoa J, Dutoit V, Migliorini D

International journal of molecular sciences – 2020 Oct 9

Single-Cell Analyses Identify Brain Mural Cells Expressing CD19 as Potential Off-Tumor Targets for CAR-T Immunotherapies.

Parker KR, Migliorini D, Perkey E, (...), Chang HY, Posey AD Jr, Satpathy AT

Cell – 2020 Sep 21

Phase I/II trial testing safety and immunogenicity of the multipeptide IMA950/poly-ICLC vaccine in newly diagnosed adult malignant astrocytoma patients.

Migliorini D, Dutoit V, Allard M, (...), Walker PR, Patrikidou A, Dietrich PY

Neuro-oncology – 2019 Jul 11

Actively personalized vaccination trial for newly diagnosed glioblastoma.

Hilf N, Kuttruff-Coqui S, Frenzel K, (...), Sahin U, Dietrich PY, Wick W

Nature – 2018 Dec 19

Glycan-directed CAR-T cells.

Steentoft C, Migliorini D, King TR, (...), Mandel U, June CH, Posey AD Jr

Glycobiology – 2018 Sep 1

Checkpoint Blockade Reverses Anergy in IL-13Rα2 Humanized scFv-Based CAR T Cells to Treat Murine and Canine Gliomas.

Yin Y, Boesteanu AC, Binder ZA, (...), Lin Z, O'Rourke DM, Johnson LA

Molecular therapy oncolytics – 2018 Aug 28

CAR T-Cell Therapies in Glioblastoma: A First Look.

Migliorini D, Dietrich PY, Stupp R, (...), Linette GP, Posey AD Jr, June CH

Clinical cancer research : an official journal of the American Association for Cancer Research – 2017 Nov 20

Antigenic expression and spontaneous immune responses support the use of a selected peptide set from the IMA950 glioblastoma vaccine for immunotherapy of grade II and III glioma.

Dutoit V, Migliorini D, Ranzanici G, (...), Weinschenk T, Herold-Mende C, Dietrich PY

Oncoimmunology – 2017 Nov 7

First report of clinical responses to immunotherapy in 3 relapsing cases of chordoma after failure of standard therapies.

Migliorini D, Mach N, Aguiar D, (...), McKee T, Dutoit V, Dietrich PY

Oncoimmunology – 2017 Jun 21

BRAF/MEK double blockade in refractory anaplastic pleomorphic xanthoastrocytoma.

Migliorini D, Aguiar D, Vargas MI, Lobrinus A, Dietrich PY

Neurology – 2017 Feb 24

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