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The Potential of Mesenchymal Stromal Cells in Neuroblastoma Therapy for Delivery of Anti-Cancer Agents and Hematopoietic Recovery.

ABSTRACT: Neuroblastoma is one of the most common pediatric cancers and a major cause of cancer-related death in infancy. Conventional therapies including high-dose chemotherapy, stem cell transplantation, and immunotherapy approach a limit in the treatment of high-risk neuroblastoma and prevention of relapse. In the last two decades, research unraveled a potential use of mesenchymal stromal cells in tumor therapy, as tumor-selective delivery vehicles for therapeutic compounds and oncolytic viruses and by means of supporting hematopoietic stem cell transplantation. Based on pre-clinical and clinical advances in neuroblastoma and other malignancies, we assess both the strong potential and the associated risks of using mesenchymal stromal cells in the therapy for neuroblastoma. Furthermore, we examine feasibility and safety aspects and discuss future directions for harnessing the advantageous properties of mesenchymal stromal cells for the advancement of therapy success.

SUBMITTER: Hochheuser C

PROVIDER: S-EPMC7996318 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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The Potential of Mesenchymal Stromal Cells in Neuroblastoma Therapy for Delivery of Anti-Cancer Agents and Hematopoietic Recovery.

Hochheuser Caroline C Kunze Nina Y NY Tytgat Godelieve A M GAM Voermans Carlijn C Timmerman Ilse I

Journal of personalized medicine 20210225 3

Neuroblastoma is one of the most common pediatric cancers and a major cause of cancer-related death in infancy. Conventional therapies including high-dose chemotherapy, stem cell transplantation, and immunotherapy approach a limit in the treatment of high-risk neuroblastoma and prevention of relapse. In the last two decades, research unraveled a potential use of mesenchymal stromal cells in tumor therapy, as tumor-selective delivery vehicles for therapeutic compounds and oncolytic viruses and by ...[more]

PMID: 33668854

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Project description:BackgroundEfficient and sustained hematopoietic recovery after hematopoietic stem cell or bone marrow transplantation is supported by paracrine signaling from specific subpopulations of mesenchymal stromal cells (MSCs). Here, we considered whether in vitro mechanopriming of human MSCs could be administered to predictively and significantly improve in vivo hematopoietic recovery after irradiation injury.MethodsFirst, we implemented regression modeling to identify eight MSC-secreted proteins that correlated strongly with improved rescue from radiation damage, including hematopoietic recovery, in a murine model of hematopoietic failure. Using these partial least squares regression (PLSR) model parameters, we then predicted recovery potential of MSC populations that were culture expanded on substrata of varying mechanical stiffness. Lastly, we experimentally validated these predictions using an in vitro co-culture model of hematopoiesis and using new in vivo experiments for the same irradiation injury model used to generate survival predictions.ResultsMSCs grown on the least stiff (elastic moduli ~ 1 kPa) of these polydimethylsiloxane (PDMS) substrata secreted high concentrations of key proteins identified in regression modeling, at concentrations comparable to those secreted by minor subpopulations of MSCs shown previously to be effective in supporting such radiation rescue. We confirmed that these MSCs expanded on PDMS could promote hematopoiesis in an in vitro co-culture model with hematopoietic stem and progenitor cells (HSPCs). Further, MSCs cultured on PDMS of highest stiffness (elastic moduli ~ 100 kPa) promoted expression of CD123+ HSPCs, indicative of myeloid differentiation. Systemic administration of mechanoprimed MSCs resulted in improved mouse survival and weight recovery after bone marrow ablation, as compared with both standard MSC expansion on stiffer materials and with biophysically sorted MSC subpopulations. Additionally, we observed recovery of white blood cells, platelets, and red blood cells, indicative of complete recovery of all hematopoietic lineages.ConclusionsThese results demonstrate that computational techniques to identify MSC biomarkers can be leveraged to predict and engineer therapeutically effective MSC phenotypes defined by mechanoprimed secreted factors, for translational applications including hematopoietic recovery.

Project description:BackgroundChimeric antigen receptor (CAR)-T therapy has emerged as a promising treatment for hematologic malignancies. However, cytopenia remains one of the most frequent and challenging adverse effects of this therapy.MethodsWe conducted a retrospective analysis of 26 patients with relapsed/refractory aggressive B-cell lymphoma who received CAR-T therapy at our center. Subsequently, to investigate measures to address cytopenias following CAR-T therapy, we isolated and generated murine CAR-T cells and bone marrow-derived mesenchymal stem cells (MSCs), establishing a murine syngeneic CAR-T therapy model. We assessed the impact of MSC infusion on hematopoietic recovery post-CAR-T therapy by evaluating complete blood count, bone marrow hematopoietic stem cells and their subpopulations, bone marrow histomorphology, and hematopoiesis-related genes.ResultsAll patients experienced cytopenias to varying degrees, with complete lineage involvement in half of the patients. Grade ≥ 3 cytopenias were observed in 88.46% of the patients. CAR-T therapy was associated with a higher incidence of biphasic, late-onset, or prolonged cytopenias. Survival analysis indicated that neutropenia and lymphopenia tended to be associated with better prognosis, whereas thrombocytopenia tended to be related to poorer outcomes. Through animal experiments, we discovered that MSCs infusion boosted HSCs and their long-term subpopulations, enhancing hematopoietic recovery, particularly in the megakaryocyte lineage, and mitigating bone marrow damage. Importantly, both in vitro and in vivo experiments demonstrated that MSCs did not compromise the activity or antitumor efficacy of CAR-T cells.ConclusionsOur findings propose MSCs infusion as a promising strategy to address cytopenias, particularly thrombocytopenia, after CAR-T therapy. This approach could help overcome certain limitations of cellular immunotherapy by enhancing hematopoietic recovery without compromising the efficacy of CAR-T cells.Highlights1 Cytopenia is a frequently observed adverse effect following CAR-T therapy, and it is often characterized by biphasic and prolonged patterns. 2 MSCs play a critical role in promoting hematopoietic recovery and mitigating bone marrow damage in a murine model of CAR-T therapy 3 The activity and antitumor efficacy of CAR-T cells were not impaired by MSCs.

Dataset Information

The Potential of Mesenchymal Stromal Cells in Neuroblastoma Therapy for Delivery of Anti-Cancer Agents and Hematopoietic Recovery.

Publications

The Potential of Mesenchymal Stromal Cells in Neuroblastoma Therapy for Delivery of Anti-Cancer Agents and Hematopoietic Recovery.

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