Anti-GD2 CAR MSCs against metastatic Ewing's sarcoma

Golinelli, Giulia; Grisendi, Giulia; Dall’Ora, Massimiliano; Casari, Giulia; Spano, Carlotta; Talami, R.; Banchelli, Federico; Prapa, Malvina; Chiavelli, Chiara; Rossignoli, Filippo; Candini, Olivia; D’Amico, Roberto; Nasi, Milena; Cossarizza, Andrea; Casarini, Livio; Dominici, Massimo

doi:10.1016/j.tranon.2021.101240

Cited by 12 publications

(10 citation statements)

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“…Additionally, only a portion of MSCs had been trapped into the matrix of VITVO50. As it does not lead to total MSCs retention, the proposed fluidic setting could be applied to study interactions between tumor cells and MSCs, where tumor affinity of MSCs has been increased by novel targeting strategies ( Golinelli et al, 2020 ; Golinelli et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

“…In future application, the VITVO50-based fluidic circuit could be employed to study tumor-MSC interaction where the MSC affinity for the tumor has been increased by novel targeting strategies ( Golinelli et al, 2020 ). Our group recently optimized tumor-localizing potential of TRAIL MSCs by the expression of an anti-GD2 chimeric antigen receptor (GD2 tCAR) ( Golinelli et al, 2020 ; Golinelli et al, 2021 ). The disialoganglioside GD2 is a surface molecule expressed at high levels by a wide range of tumors such as osteosarcoma, ES ( Heiner et al, 1987 ; Chang et al, 1992 ; Kailayangiri et al, 2012 ; Dobrenkov et al, 2016 ), neuroblastoma ( Prapa et al, 2015 ) and glioblastoma ( Golinelli et al, 2020 ) and with restricted and low expression in normal tissues ( Nazha et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…Despite MSCs tropism for tumors, the therapeutic targeting of metastases remains challenging and the interaction occurring between tumor cells and MSCs has not yet been deeply investigated ( Kean et al, 2013 ). Setting up in vitro and in vivo models to study this interaction is a prerequisite for novel approaches where the MSCs affinity for the tumor and the retention inside the tumor microenvironment are ameliorated to ultimately increase the therapeutic efficacy ( Golinelli et al, 2020 ; Golinelli et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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A 3D Platform to Investigate Dynamic Cell-to-Cell Interactions Between Tumor Cells and Mesenchymal Progenitors

Golinelli

Talami

Frabetti³

et al. 2022

Front. Cell Dev. Biol.

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We here investigated the dynamic cell-to-cell interactions between tumor and mesenchymal stromal/stem cells (MSCs) by the novel VITVOⓇ 3D bioreactor that was customized to develop in vivo-like metastatic nodules of Ewing’s sarcoma (ES). MSCs are known to contribute to tumor microenvironment as cancer associated fibroblast (CAF) precursors and, for this reason, they have also been used as anti-cancer tools. Using dynamic conditions, the process of tissue colonization and formation of metastatic niches was recreated through tumor cell migration aiming to mimic ES development in patients. ES is an aggressive tumor representing the second most common malignant bone cancer in children and young adults. An urgent and unmet need exists for the development of novel treatment strategies to improve the outcomes of metastatic ES. The tumor-tropic ability of MSCs offers an alternative approach, in which these cells can be used as vehicles for the delivery of antitumor molecules, such as the proapoptotic TNF-related apoptosis inducing ligand (TRAIL). However, the therapeutic targeting of metastases remains challenging and the interaction occurring between tumor cells and MSCs has not yet been deeply investigated. Setting up in vitro and in vivo models to study this interaction is a prerequisite for novel approaches where MSCs affinity for tumor is optimized to ultimately increase their therapeutic efficacy. Here, VITVOⓇ integrating a customized scaffold with an increased inter-fiber distance (VITVO50) was used to develop a dynamic model where MSCs and tumor nodules were evaluated under flow conditions. Colonization and interaction between cell populations were explored by droplet digital PCR (ddPCR). VITVO50 findings were then applied in vivo. An ES metastatic model was established in NSG mice and biodistribution of TRAIL-expressing MSCs in mice organs affected by metastases was investigated using a 4-plex ddPCR assay. VITVOⓇ proved to be an easy handling and versatile bioreactor to develop in vivo-like tumor nodules and investigate dynamic cell-to-cell interactions with MSCs. The proposed fluidic system promises to facilitate the understanding of tumor-stroma interaction for the development of novel tumor targeting strategies, simplifying the analysis of in vivo data, and ultimately accelerating the progress towards the early clinical phase.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A 3D Platform to Investigate Dynamic Cell-to-Cell Interactions Between Tumor Cells and Mesenchymal Progenitors

Golinelli

Talami

Frabetti³

et al. 2022

Front. Cell Dev. Biol.

Self Cite

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“…The identification of a tumor-antigen with features of high expression on tumor cells and low expression on healthy tissues remains the main challenge for an effective and safe clinical translation of such approaches. Different possible targets for CAR T-cells or mAbs are currently under investigation in sarcomas, including HER2 ( 49 , 50 ), B7-H3 ( 51 ), ErbB2 ( 52 ), GD2 ( 53 , 54 ), or VEGFR2 ( 55 ). The possibility to apply an antibody, CAR-T or CAR-NK approach based on the donor derived immune system in a haploidentical context could represent a fascinating option for the future.…”

Section: Discussionmentioning

confidence: 99%

Haploidentical hematopoietic stem cell transplantation as individual treatment option in pediatric patients with very high-risk sarcomas

Eichholz

Döring²,

Giardino³

et al. 2023

Front. Oncol.

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BackgroundPrognosis of children with primary disseminated or metastatic relapsed sarcomas remains dismal despite intensification of conventional therapies including high-dose chemotherapy. Since haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is effective in the treatment of hematological malignancies by mediating a graft versus leukemia effect, we evaluated this approach in pediatric sarcomas as well.MethodsPatients with bone Ewing sarcoma or soft tissue sarcoma who received haplo-HSCT as part of clinical trials using CD3+ or TCRα/β+ and CD19+ depletion respectively were evaluated regarding feasibility of treatment and survival.ResultsWe identified 15 patients with primary disseminated disease and 14 with metastatic relapse who were transplanted from a haploidentical donor to improve prognosis. Three-year event-free survival (EFS) was 18,1% and predominantly determined by disease relapse. Survival depended on response to pre-transplant therapy (3y-EFS of patients in complete or very good partial response: 36,4%). However, no patient with metastatic relapse could be rescued.ConclusionHaplo-HSCT for consolidation after conventional therapy seems to be of interest for some, but not for the majority of patients with high-risk pediatric sarcomas. Evaluation of its future use as basis for subsequent humoral or cellular immunotherapies is necessary.

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“…The disialoganglioside GD2 is a surface molecule highly expressed in ES tumor cells with restricted and low expression levels in normal tissues [ 92 ]. There are two ongoing clinical trials associated with GD2 CAR T-cell in treatment of Ewing Sarcoma.…”

Section: Pediatric Solid Tumors—preclinical and Clinical Reportsmentioning

confidence: 99%

CAR T-Cell Therapy in Children with Solid Tumors

Kulczycka

Derlatka

Tasior

et al. 2023

JCM

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The limited efficacy of traditional cancer treatments, including chemotherapy, radiotherapy, and surgery, emphasize the significance of employing innovative methods. CAR (Chimeric Antigen Receptor) T-cell therapy remains the most revolutionizing treatment of pediatric hematological malignancies and solid tumors. Patient’s own lymphocytes are modified ex-vivo using gene transfer techniques and programmed to recognize and destroy specific tumor cells regardless of MHC receptor, which probably makes CAR-T the most personalized therapy for the patient. With continued refinement and optimization, CAR-T cell therapy has the potential to significantly improve outcomes and quality of life for children with limited treatment options. It has shown remarkable success in treating hematological malignancies, such as acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). However, its effectiveness in treating solid tumors is still being investigated and remains an area of active research. In this review we focus on solid tumors and explain the concept of CAR modified T cells, and discuss some novel CAR designs that are being considered to enhance the safety of CAR T-cell therapy in under-mentioned cancers. Furthermore, we summarize the most crucial recent reports concerning the solid tumors treatment in children. In the end we provide a short summary of many challenges that limit the therapeutic efficacy of CAR-T in solid tumors, such as antigen escape, immunosuppressive microenvironment, poor trafficking, and tumor infiltration, on-target off-tumor effects and general toxicity.

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Anti-GD2 CAR MSCs against metastatic Ewing's sarcoma

Cited by 12 publications

References 58 publications

A 3D Platform to Investigate Dynamic Cell-to-Cell Interactions Between Tumor Cells and Mesenchymal Progenitors

A 3D Platform to Investigate Dynamic Cell-to-Cell Interactions Between Tumor Cells and Mesenchymal Progenitors

Haploidentical hematopoietic stem cell transplantation as individual treatment option in pediatric patients with very high-risk sarcomas

CAR T-Cell Therapy in Children with Solid Tumors

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