NUOVO-SOLDATI FOUNDATION FOR CANCER RESEARCH
Research grants in cancer research

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Laureates 2019 - 2020

Jebrane BOUAOUD
Marco Mateo BUEHLER
Benoit CAMELLI-ROUSSEAU
Romain COHEN
Déborah MEYRAN
Remco MOLENAAR
Edouard OLLIER
David SCHROEDER

Jebrane BOUAOUD

Title of the project: Evaluation of a DNA-mediated adjuvant immunotherapy for the prevention of oral cancer development

Place of the training course: Service de Chirurgie Maxillo-Faciale et Stomatologie,
Centre Hospitalo-Universitaire Pitié-Salpêtrière,
APHP, Paris 75013

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Summary of the project: Oral squamous cell carcinoma (OSCC), which may develop from oral premalignant lesion (OPL), have high mortality and morbidity. There is currently no therapeutic strategy to prevent this malignant transformation. In this aim, immunoprevention strategies are attractive. We propose to evaluate the efficacy of a non-specific DNA vaccine (pVAX14) associated to the active metabolite of vitamin A (ATRA), to decrease the incidence of OSCC in the 4-NQO murine model of oral tumorigenesis. Mice will be randomized in 4 groups: control, pVAX14 alone, ATRA alone and pVAX14 + ATRA. We will evaluate the vaccine-based strategy effect on OSCC incidence. We will then evaluate i-the in situ immune infiltrate by immunohistochemistry, ii-the peripheral blood immune response (memory T-cell, cytokine and antibodies production) and iii-gene expression profiles of OSCC or dysplasia arising in mice included in all groups. We aim to demonstrate that a non-specific DNA vaccine strategy reduces the incidence of OSCC in a relevant model of oral tumorigenesis, by increasing the pre-existing immune response

Marco Mateo BUEHLER

Title of the project: The genomic landscape and tumoral heterogeneity of mantle cell lymphoma

Place of the training course: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) et Unité de Hematopathologie,
Hospital Clínic de Barcelona,
Barcelona, Espagne

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Summary of the project: Mantle cell lymphoma is a mature B-cell lymphoma with an adverse prognosis. Response to therapy is often short, despite intensive chemotherapy regimens, highlighting the need to investigate therapy targets and therapy resistance mechanisms. In addition, a subset of patients have indolent forms of the disease (e.g. leukemic non nodal mantle cell lymphoma) and need to be confidently diagnosed in order to prevent unnecessary therapy related morbidity and mortality. The first aim of the study is to investigate the genomic landscape of the different forms of mantle cell lymphoma using next generation sequencing techniques to delineate the genome, transcriptome and regulatory mechanisms (WGS, RNA-seq, ChIP-seq, ATAC-seq). The second aim is to determine the intratumoral heterogeneity and its relevance by investigating the clonal architecture of mantle cell lymphoma using ultra-deep targeted sequencing.

Benoit CAMELLI-ROUSSEAU

Title of the project: Hypermutagenesis in low TMB colorectal cancers to induce response to immune checkpoints inhibitors

Place of the training course: Luis Diaz' Lab
Memorial Sloan Kettering Cancer Center,
NCI-designated Comprehensive Cancer Center 300 East 66th Street,
New York, NY 10065, USA

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Summary of the project: Next generation immunotherapy efficacy in colorectal cancer is limited to hypermutated tumors deficient in mismatch repair (d-MMR). Nevertheless, Polymérase E exonucleasic domain mutation in CRC is also responsible of an hypermutated phenotype in proficient Mismatch Repair (p-MMR) tumors and may also benefit from immune checkpoints blockade. Tumor Mutation Burden (TMB) is a complex measure of non synonymous mutation rate in cancer and is correlated with the quantity of neoantigens.
Hypermutability determinants in colorectal cancer remains poorly understood. The identification of genes implicated in the onset of hyper/ultramutated phenotypes could allow to identify new therapeutic targets with the aim to pharmacologically modulate these drivers of hypermutation to induce a rapid genetic drift. Hypermutagenesis in low TMB tumors could be an innovative therapeutic tool favoring the onset of tumoral neoantigens and restoring the activity immune checkpoints colorectal cancers which are currently refractory to these treatments.

Romain COHEN

Title of the project: BRAF mutation in metastatic colorectal cancer and evaluation of the time dependency of its prognostic impact : an exploratory analysis of the ARCAD database

Place of the training course: Unité de biostatistique (team leader: Qian Shi),
Mayo Clinic (Rochester, Minnesota, USA)

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Summary of the project: BRAFV600E mutation is observed in approximately 8% of metastatic colorectal cancer (mCRC) and is associated with poor prognosis. Only one third of BRAF-mutated mCRC patients is treated with a second-line chemotherapy. Therapeutic strategy consists on cytotoxic compounds combined antiangiogenics or anti-EGFR agents. Nevertheless the efficacy of these two targeted therapies has never been properly demonstrated.
Our project will focus on the clinical characterization of BRAF-mutated mCRC patients and on the efficacy of antiangiogenics and anti-EGFR agents. The prognosis of this specific population being heterogeneous, we will also assess the time dependancy of BRAFV600E mutation prognostic value. We will expand this analysis to the other main biomarkers in mCRC (KRAS and NRAS mutation) in mCRC and explore the potential prognostic impact of time from diagnostic of metastatic disease to third-line treatment initiation in the context of clinical trials.
This project will be performed on the ARCAD database, that is managed by the biostatistic unic of Mayo Clinic (Rochester, Minnesota, USA) and that integrates individual patient-level data from a large collection of phase 3 clinical trials in mCRC (> 40,000 mCRC patients).

Déborah MEYRAN

Title of the project: Designing new CARs to enhance cancer immunotherapy in pediatric cancers

Place of the training course: Paul Neeson’s laboratory,
Human Immunology Translational Lab in Cancer immunology Research at the Peter MacCallum Cancer Centre,
Melbourne.

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Summary of the project: Adopting cell transfer is demonstrating exciting potential for cancer treatment. But refractory solid tumors remain an ongoing clinical problem with significant morbidity and mortality. CAR T cell therapy has the potential to address this issue. However, in contrast to their success in B cell malignancies, CAR T cell therapy targeting solid cancer and AML has had limited success so far. We developed two different new CARs recognizing the tumour antigens LeY and GRP78. LeY is highly expressed in various solid tumors but appears to have only limited expression on the surface of normal tissues making this antigen an ideal target for cancer immunotherapy. GRP78 is shuttled to the cell surface on cancer cells under stress/hypoxic conditions and its expression is highly correlated with tumor progression. We generated two novel CARs, comprising the anti-LeY single chain variable fragment (scFv) or the GRP78 scFv and a CD34 detection marker. We then successfully transduced primary human T cells with the anti-LeY CAR or anti-GRP78 CAR and positive cells were sorted using the CD34 marker. After sorting, the majority of the T cells (>90%) were double positive for the anti-LeY/GRP78 CAR and CD34. The CAR-T cells were found to secrete high levels of interferon ? and TNFa following direct stimulation through the CAR or LeY+/GRP78 + tumor targets. The CAR T cells also specifically killed LeY+/GRP78+ tumor cells but not LeY-/GRP78- targets cells indicating a LeY /GRP78 antigen-dependent effect. The preliminary results of the staining of paediatric tumours show an expression of LeY in paediatric AML, and GRP78 in AML, neuroblastoma and brain tumours so we will first test the efficacy of our new CAR-T cells in these tumor models. Furthermore, this innovative tracking system with the CD34 marker will allow better characterisation and monitoring of the infused CAR-T cells in vivo in preclinical mouse models and in patients.

Remco MOLENAAR

Title of the project: Forcing glioblastoma stem cells out of stem cell niches to increase radiotherapy responses: no place to hide

Place of the training course: Institut national de biologie,
Ljubljana, Slovénie

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Summary of the project: Glioblastoma is the most aggressive brain tumour that is notoriously resistant to chemotherapy or radiotherapy. A key determinant of glioblastoma therapy resistance are glioblastoma stem cells, which are protected from therapy by their direct environments, also called glioblastoma stem cell niches. Glioblastoma tumours are highly effective in keeping their glioblastoma stem cells inside these protective niches during therapy by secreting molecules that bind to glioblastoma stem cells. The ultimate goal of my research project is to develop a novel targeted treatment that forces the glioblastoma stem cells out of their protective niches during radiotherapy and chemotherapy to improve the clinical outcomes of glioblastoma patients.

Edouard OLLIER

Title of the project: Extension of network meta-analysis methods to individual survival data : application in head and neck cancer

Place of the training course: Unité de recherche clinique,
CHU de Saint Etienne
équipe Oncostat Inserm U1018

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Summary of the project: Meta-analyzes of randomized trials are recognized as providing the highest level of evidence. The classic meta-analysis approach to summary data has some limitations inherent to the lack of access to individual data making the meta-analysis of individual data the method of reference. The same is true for the network meta-analysis, which aims to compare more than 2 treatments. Although well developed for the analysis of continuous or binary judgments criteria, network meta-analysis of individual survival data has been little studied. This observation is due to algorithmic difficulties that are at the origin of a prohibitive computation time incompatible with the analysis of complex networks as found in current practice. The goal of this project is to develop a fast and easy-to-use individual data meta-analysis algorithm. The proposed method will be applied to the comparison of therapeutic strategies in head and neck cancers.

David SCHROEDER

Title of the project: Studying mechanisms of tumor hyperprogression in patients with metastatic cancer treated with PD-1 blockade.

Place of the training course: Cliniques universitaires Saint Luc,
Bruxelles,
Belgique

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Summary of the project: Cancer immunotherapy, in particular through blockade of the PD-1 inhibitory pathway, is now a treatment option for patients with various types of advanced cancer. Hyperprogressive disease (HPD), an early and fast disease progression, has been observed in patients treated with PD-1 blockade across several cancer types and HPD is associated with reduced survival. Intriguingly, its mechanisms are unknown. My project pursues two objectives. First, I will validate HPD in patients treated with immunotherapy, its association with decreased survival and its increased frequency in patients treated with PD-1 blockade. Second, I will explore potential mechanisms of HPD.