Michele Pezzella

Istituti di Ricovero e Cura a Carattere Scientifico

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Franco Locatelli

Università Cattolica del Sacro Cuore

Concetta Quintarelli

Bambino Gesù Children's Hospital

Biagio De Angelis

Bambino Gesù Children's Hospital

Roselia Ciccone

Bambino Gesù Children's Hospital

Laura Iaffaldano

Istituti di Ricovero e Cura a Carattere Scientifico

Simona Manni

Bambino Gesù Children's Hospital

Stefano Di Cecca

Bambino Gesù Children's Hospital

Matilde Sinibaldi

Bambino Gesù Children's Hospital

Francesca Del Bufalo

Bambino Gesù Children's Hospital

Marika Guercio

Bambino Gesù Children's Hospital

Cooperative Institutions

Istituti di Ricovero e Cura a Carattere Scientifico

Bambino Gesù Children's Hospital

Sapienza University of Rome

University of Rome Tor Vergata

Boston Children's Hospital

Università Cattolica del Sacro Cuore

University of Naples Federico II

National Research Council

University of Florence

National Institutes of Health

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Supplemental Figure 16 from GD2-Targeting CAR T-cell Therapy for Patients with GD2+ Medulloblastoma

Roselia Ciccone Concetta Quintarelli Antonio Camera Michele Pezzella Simona Caruso

Supplemental Figure 16. Evaluation of the efficacy of AP1903 CAR.GD2 T-cells infiltrating tumor in in vivo MB xenograft mouse model.

10.1158/1078-0432.25956298

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Supplemental Figure 14 from GD2-Targeting CAR T-cell Therapy for Patients with GD2+ Medulloblastoma

Roselia Ciccone Concetta Quintarelli Antonio Camera Michele Pezzella Simona Caruso

Supplemental Figure 14. Orthotopic PDX mouse model of human MED-411 FH mCherry/Luc cell line to evaluate anti-tumor activity of CAR.GD2 T-cells.

10.1158/1078-0432.25956307

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MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting

Nature Communications (2023)

Silvia Pomella Matteo Cassandri Lucrezia D’Archivio Antonella Porrazzo Cristina Cossetti

Abstract Rhabdomyosarcomas (RMS) are pediatric mesenchymal-derived malignancies encompassing PAX3/7-FOXO1 Fusion Positive (FP)-RMS, and Fusion Negative (FN)-RMS with frequent RAS pathway mutations. RMS express the master myogenic transcription factor MYOD that, whilst essential for survival, cannot support differentiation. Here we discover SKP2, an oncogenic E3-ubiquitin ligase, as a critical pro-tumorigenic driver in FN-RMS. We show that SKP2 is overexpressed in RMS through the binding of MYOD to an intronic enhancer. SKP2 in FN-RMS promotes cell cycle progression and prevents differentiation by directly targeting p27 Kip1 and p57 Kip2 , respectively. SKP2 depletion unlocks a partly MYOD-dependent myogenic transcriptional program and strongly affects stemness and tumorigenic features and prevents in vivo tumor growth. These effects are mirrored by the investigational NEDDylation inhibitor MLN4924. Results demonstrate a crucial crosstalk between transcriptional and post-translational mechanisms through the MYOD-SKP2 axis that contributes to tumorigenesis in FN-RMS. Finally, NEDDylation inhibition is identified as a potential therapeutic vulnerability in FN-RMS.

Neddylation

SKP2

MyoD Protein

PITX2

10.1038/s41467-023-44130-0

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Neutralization of IFNγ improves the safety profile of CAR T-cells while maintaining unaffected efficacy against B-cell malignancies

Research Square (Research Square) (2023)

Simona Manni Francesca Del Bufalo Pietro Merli Domenico Alessandro Silvestris Marika Guercio

Abstract Chimeric antigen receptor (CAR) T-cell therapy represents a revolutionary approach to induce long-lasting remission in patients with B-cell malignancies not responding to conventional therapies. Nevertheless, possible severe side effects, including cytokine release syndrome (CRS), neurotoxicity and macrophage activation syndrome, whose management is still challenging, as well as lack of pathophysiological experimental models to investigate novel interventions, limit the widespread use of this therapy. In light of these considerations, we developed a comprehensive humanized mouse model to investigate the role of IFNγ neutralization, provided by the clinically approved monoclonal antibody, emapalumab, in controlling severe toxicity related to CAR T cells. We demonstrated that emapalumab reduces the pro-inflammatory environment in the animal model, allowing severe CRS control and preventing brain damage, characterized by multifocal hemorrhages. Furthermore, we proved that IFNγ inhibition does not affect the ability of CAR.CD19 T cells to eradicate CD19+ lymphoma cells, both in vitro and in vivo .

Cytokine Release Syndrome

Neurotoxicity

10.21203/rs.3.rs-1482837/v1

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Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies

Nature Communications (2023)

Simona Manni Francesca Del Bufalo Pietro Merli Domenico Alessandro Silvestris Marika Guercio

Abstract Chimeric antigen receptor T (CAR-T) cell therapy may achieve long-lasting remission in patients with B-cell malignancies not responding to conventional therapies. However, potentially severe and hard-to-manage side effects, including cytokine release syndrome (CRS), neurotoxicity and macrophage activation syndrome, and the lack of pathophysiological experimental models limit the applicability and development of this form of therapy. Here we present a comprehensive humanized mouse model, by which we show that IFNγ neutralization by the clinically approved monoclonal antibody, emapalumab, mitigates severe toxicity related to CAR-T cell therapy. We demonstrate that emapalumab reduces the pro-inflammatory environment in the model, thus allowing control of severe CRS and preventing brain damage, characterized by multifocal hemorrhages. Importantly, our in vitro and in vivo experiments show that IFNγ inhibition does not affect the ability of CD19-targeting CAR-T (CAR.CD19-T) cells to eradicate CD19+ lymphoma cells. Thus, our study provides evidence that anti-IFNγ treatment might reduce immune related adverse effect without compromising therapeutic success and provides rationale for an emapalumab-CAR.CD19-T cell combination therapy in humans.

CAR T-cell therapy

10.1038/s41467-023-38723-y

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Citations (23)

Supplemental Figure 4 from GD2-Targeting CAR T-cell Therapy for Patients with GD2+ Medulloblastoma

Roselia Ciccone Concetta Quintarelli Antonio Camera Michele Pezzella Simona Caruso

Supplemental Figure 4. Real-Time killing assay of CAR.GD2 T-cells vs D283 Med-GFP-FF-Luc cell line.

10.1158/1078-0432.25956286.v1

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Supplemental Figure 5 from GD2-Targeting CAR T-cell Therapy for Patients with GD2+ Medulloblastoma

Roselia Ciccone Concetta Quintarelli Antonio Camera Michele Pezzella Simona Caruso

Supplemental Figure 5. Real-Time killing assay of CAR.GD2 T-cells vs DAOY-GFP cell line.

10.1158/1078-0432.25956283.v1

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Novel non-covalent LSD1 inhibitors endowed with anticancer effects in leukemia and solid tumor cellular models

European Journal of Medicinal Chemistry (2022)

Martina Menna Francesco Fiorentino Biagina Marrocco Alessia Lucidi Stefano Tomassi

Demethylase

Quinazoline

10.1016/j.ejmech.2022.114410

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Tumor-derived G-CSF induces an immunosuppressive microenvironment in an osteosarcoma model, reducing response to CAR.GD2 T-cells

Journal of Hematology & Oncology (2024)

Michele Pezzella Concetta Quintarelli Maria Cecilia Quadraccia Andrea Sarcinelli Simona Manni

Sarcomas are rare, mesenchymal tumors, representing about 10–15% of all childhood cancers. GD2 is a suitable target for chimeric antigen receptor (CAR) T-cell therapy due to its overexpression in several solid tumors. In this preclinical study, we investigated the potential use of iCasp9.2A.GD2.CAR-CD28.4–1BBζ (CAR.GD2) T-cells as a treatment option for patients who have GD2-positive sarcomas and we sought to identify factors shaping hostile tumor microenvironment in this setting. GD2 expression was evaluated by flow-cytometry on primary tumor biopsies of pediatric sarcoma patients. GD2 expression in sarcoma cells was also evaluated in response to an enhancer of zeste homolog 2 (EZH2) inhibitor (Tazemetostat). The antitumor activity of CAR.GD2 T-cells was evaluated both in vitro and in vivo preclinical models of orthotopic and/or metastatic soft-tissue and bone sarcomas. GD2 expression was detected in 55% of the primary tumors. Notably, the Osteosarcoma and Alveolar Rhabdomyosarcomas subtypes exhibited the highest GD2 expression levels, while Ewing sarcoma showed the lowest. CAR.GD2 T-cells show a significant tumor control both in vitro and in vivo models of GD2-expressing tumors. Pretreatment with an EZH2 inhibitor (Tazemetostat) upregulating GD2 expression, sensitizes GD2dim sarcoma cells to CAR.GD2 T-cells cytotoxic activity. Moreover, in mouse models of disseminated Rhabdomyosarcomas and orthotopic Osteosarcoma, CAR.GD2 T-cells showed both a vigorous anti-tumor activity and long-term persistence as compared to un-transduced T-cells. The presence of immunosuppressive murine myeloid-derived suppressor (MDSC) cells significantly reduces long-term anti-tumour activity of infused CAR.GD2 T-cells. Tumor-derived G-CSF was found to be one of the key factors driving expansion of immunosuppressive murine and human MDSC, thus indirectly limiting the efficacy of CAR.GD2 T-cells. Our preclinical data strongly suggest that CAR.GD2 T-cells hold promise as a potential therapeutic option for the treatment of patients with GD2-positive sarcomas. Strategies to tackle hostile immunosuppressive MDSC are desirable to optimize CAR.GD2 T-cell activity.

Synovial Sarcoma

10.1186/s13045-024-01641-7

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Supplemental Figure 11 from GD2-Targeting CAR T-cell Therapy for Patients with GD2+ Medulloblastoma

Roselia Ciccone Concetta Quintarelli Antonio Camera Michele Pezzella Simona Caruso

Supplemental Figure 11. Quantification of murine plasma neurofilament (NFL) levels in an orthotopic mouse model of the human DAOY-GFP cell line, treated with NT or CAR.GD2 T-cells.

10.1158/1078-0432.25956316.v1

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