The Potential of Mesenchymal Stromal Cells in Neuroblastoma Therapy for Delivery of Anti-Cancer Agents and Hematopoietic Recovery
Abstract
:1. Introduction
2. MSCs as Delivery Vehicles
2.1. MSCs Delivering Anti-Cancer Agents
2.2. MSCs Delivering Oncolytic Viruses
3. MSCs in Hematopoietic Stem Cell Transplantation
3.1. Allogeneic MSCs
3.2. Autologous MSCs
4. Safety and Feasibility of MSC Therapy in NB
4.1. Safety of MSC (Co-) Infusion
4.2. Influence of MSCs on Tumor Progression
4.3. Cell-Free Approach Using Extracellular Vesicles
4.4. Influence of Administration Route on MSC Migration
4.5. MSC Engraftment in the BM after HSCT
4.6. Tumor-Tropism of MSCs upon Use as Delivery Vehicles
4.7. Influence of Ex Vivo Expansion of MSCs
5. Future Directions and Concluding Remarks
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Phase | Anti-Cancer Agent | Properties and Dose of MSCs | Administration Route | Nr. of Patients | Disease Context | Key Findings | Publication/Status | ClinicalTrials.gov Identifier | Year | |
---|---|---|---|---|---|---|---|---|---|---|
Delivery of Oncolytic Viruses in MSCs | ||||||||||
A | n/a | ICOVIR-5, an oncolytic adenovirus | autologous irradiated BM-MSCs (“CELYVIR”), 2–4 doses of each 0.1–0.9 × 106 cells/kg | “infused through a central line” | n = 4, single-arm study | Therapy-resistant NB patients | CR (>3 years) in 1 out of 4 patients, virus detected in BM biopsy | García-Castro et al. [71] | n/a (exploratory study) | 2010 |
Very low systemic toxicity | ||||||||||
B | n/a | ICOVIR-5, an oncolytic adenovirus | autologous irradiated BM-MSCs (“CELYVIR”), 4–70 doses of each 150–2640 × 106 cells | “systemic infusion” | n = 12, single-arm study | NB | In vitro assays: adhesion molecules like CXCR1 and CCR1 significantly higher in MSCs of responders | Melen et al. [74] | n/a (compassionate use program) | 2016 |
Mild and auto-limited virus-related toxicities; none had grade 3+ toxicities | ||||||||||
Clinical response (SD, PR, CR) in 5 out of 12 patients | ||||||||||
C | I/II | ICOVIR-5, an oncolytic adenovirus | autologous irradiated BM-MSCs (“CELYVIR”), 2 × 106 cells/kg (children) or 0.5–1 × 106 cells/kg (adults) | intra-venous | n = 9 (pediatric), n = 7 (adult); single-arm study | Metastatic and refractory tumors, including NB | Adenoviral replication detected by PCR in 7 out of 9 pediatric patients but in none of the adults | Ruano et al. [70] | NCT01844661 | 2013 |
SD in 2 out of 4 patients | ||||||||||
Increasingly higher numbers of circulating lymphocytes (B and T) in responders compared to non-responders | ||||||||||
No grade 2–5 toxicities were reported. |
Phase | Details | Properties and Median Dose of MSCs | Nr. of Patients | Disease Context | Key Findings | Publication/Status | ClinicalTrials.gov Identifier | Year | |
---|---|---|---|---|---|---|---|---|---|
allo-MSCs | |||||||||
A | I | Allogeneic MSCs co-transplanted with haplo-HSCT and subsequent DLI | Allogeneic BM-MSCs, 0.75 × 106 MSC/kg | n = 5 (all received MSCs, no control) | NB (relapsed/refractory) | 2 of 5 patients achieved long-lasting remission (40 and 42 months) | Toporski et al. [82] | NCT00790413 | 2008 |
Neutrophil recovery in all children (median 13 days), platelet recovery in 4/5 children (12 days) | |||||||||
Rapid immune reconstitution of NK- and T cells | |||||||||
No primary aGVHD, but 4/4 patients had secondary GvHD after DLI | |||||||||
B | I | Allogeneic MSCs co-transplanted with haplo-HSCT and DLI | Allogeneic MSCs, no details or dose mentioned | MSC(+): n = 9, MSC(-): n = 17 | NB (relapsed/refractory) | Primary engraftment in 96% (25/26) of the patients | Illhardt et al. [83] | NCT00790413 | 2018 |
GvHD: no significant differences between MSC and non-MSC group |
Model | MSC Origin | Labeling Method | Administration Route | Maximum Follow up | Detection in Tumor | Publication |
---|---|---|---|---|---|---|
NB xenograft model in NOD/SCID mice | human, BM | Radiolabeling | IP | 48 h | Yes | Cussó et al. [126] |
TH-MYCN transgenic mouse | human, AT | Near-IR | IP, IV | 24 h | Only i.p. | Kimura et al. [127] |
TH-MYCN transgenic mouse | mouse, BM | GFP | IP | 2 weeks | Yes | Maniwa et al. [57] |
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Hochheuser, C.; Kunze, N.Y.; Tytgat, G.A.M.; Voermans, C.; Timmerman, I. The Potential of Mesenchymal Stromal Cells in Neuroblastoma Therapy for Delivery of Anti-Cancer Agents and Hematopoietic Recovery. J. Pers. Med. 2021, 11, 161. https://doi.org/10.3390/jpm11030161
Hochheuser C, Kunze NY, Tytgat GAM, Voermans C, Timmerman I. The Potential of Mesenchymal Stromal Cells in Neuroblastoma Therapy for Delivery of Anti-Cancer Agents and Hematopoietic Recovery. Journal of Personalized Medicine. 2021; 11(3):161. https://doi.org/10.3390/jpm11030161
Chicago/Turabian StyleHochheuser, Caroline, Nina Y. Kunze, Godelieve A. M. Tytgat, Carlijn Voermans, and Ilse Timmerman. 2021. "The Potential of Mesenchymal Stromal Cells in Neuroblastoma Therapy for Delivery of Anti-Cancer Agents and Hematopoietic Recovery" Journal of Personalized Medicine 11, no. 3: 161. https://doi.org/10.3390/jpm11030161