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. 2023 Dec;4(4):e00062.
doi: 10.1227/neuprac.0000000000000062. Epub 2023 Oct 13.

Phase 1, Dose Escalation, Nonrandomized, Open-Label, Clinical Trial Evaluating the Safety and Preliminary Efficacy of Allogenic Adipose-Derived Mesenchymal Stem Cells for Recurrent Glioblastoma: A Clinical Trial Protocol

Andres Ramos-Fresnedo  1 , Rawan Al-Kharboosh  2 , Erin L Twohy  3 , Aleeshba N Basil  1 , Ewa C Szymkiewicz  1 , Abba C Zubair  4   5 , Daniel M Trifiletti  6 , Nisha Durand  5 , Dennis W Dickson  4 , Erik H Middlebrooks  7 , David N Abarbanel  8 , Stephany Y Tzeng  9 , Joao Paulo Almeida  1 , Kaisorn L Chaichana  1 , Jordan J Green  9 , Wendy J Sherman  8 , Alfredo Quiñones-Hinojosa  1
Affiliations

Phase 1, Dose Escalation, Nonrandomized, Open-Label, Clinical Trial Evaluating the Safety and Preliminary Efficacy of Allogenic Adipose-Derived Mesenchymal Stem Cells for Recurrent Glioblastoma: A Clinical Trial Protocol

Andres Ramos-Fresnedo et al. Neurosurg Pract. 2023 Dec.

Abstract

Background and objectives: Despite standard of care with maximal safe resection and chemoradiation, glioblastoma is the most common and aggressive type of primary brain cancer. Surgical resection provides a window of opportunity to locally treat gliomas while the patient is recovering, and before initiating concomitant chemoradiation. To assess the safety and establish the maximum tolerated dose of adipose-derived mesenchymal stem cells (AMSCs) for the treatment of recurrent glioblastoma (GBM). Secondary objectives are to assess the toxicity profile and long-term survival outcomes of patients enrolled in the trial. Additionally, biospecimens will be collected to explore the local and systemic responses to this therapy.

Methods: We will conduct a phase 1, dose escalated, non-randomized, open label, clinical trial of GBM patients who are undergoing surgical resection for recurrence. Up to 18 patients will receive intra-cavitary application of AMSCs encapsulated in fibrin glue during surgical resection. All patients will be followed for up to 5 years for safety and survival data. Adverse events will be recorded using the CTCAE V5.0.

Expected outcomes: This study will explore the maximum tolerated dose (MTD) of AMSCs along with the toxicity profile of this therapy in patients with recurrent GBM. Additionally, preliminary long-term survival and progression-free survival outcome analysis will be used to power further randomized studies. Lastly, CSF and blood will be obtained throughout the treatment period to investigate circulating molecular and inflammatory tumoral/stem cell markers and explore the mechanism of action of the therapeutic intervention.

Discussion: This prospective translational study will determine the initial safety and toxicity profile of local delivery of AMSCs for recurrent GBM. It will also provide additional survival metrics for future randomized trials.

Keywords: Human Mesenchymal Stem Cells; Prospective; Stem Cell; Stromal Cell; Window of Opportunity.

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Conflict of interest statement

The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. Alfredo Quiñones-Hinojosa and Jordan J. Green are co-founders with equity and Managers of the startup company Dome Therapeutics.

Figures

FIGURE 1.
FIGURE 1.
Study design flowchart. AMSC, adipose-derived mesenchymal stem cell; GBM, glioblastoma.
FIGURE 2.
FIGURE 2.
Visual schematic of study procedures and correlative research (with time points). Patients will undergo intraoperative delivery of AMSCs encapsulated in fibrin glue to the resection cavity immediately after tumor excision. An ipsilateral CSF reservoir will also be placed at the time of surgery and will be used to collect CSF samples throughout the study. Tissue will undergo immunohistochemistry to evaluate immune infiltration and the long-term presence of AMSCs within the tissue. An inflammatory cytokine profile and next-generation sequencing will be performed in all CSF and blood samples. AMSC, adipose-derived mesenchymal stem cell; CSF, cerebrospinal fluid.
FIGURE 3.
FIGURE 3.
Fibrin glue + AMSC mixture preparation. A, Under sterile conditions, the surgeon will remove 1 mL of thrombin (component 2) from the fibrin glue applicator. B, Then, cell suspension (1 mL) will be injected into the thrombin barrel using an 18-gauge needle. C, The fibrin glue applicator is then built following the manufacturers' instructions. This mixture will yield a final volume of 4 mL consisting of 2 mL fibrinogen + 1 mL thrombin + 1 m cell mixture. AMSC, adipose-derived mesenchymal stem cell.
See this image and copyright information in PMC

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