A Phase I/II, Prospective Multi-Center Study of the Safety and Preliminary Efficacy of Intravenous Allogeneic Mesenchymal Bone Marrow Cells in Chronic Ischemic Stroke

Abstract INTRODUCTION Stroke is a leading cause of disability, affecting patients for years. We examined safety and preliminary efficacy for a cellular therapy targeting patients with chronic disabling stroke, a population for whom limited treatment options currently exist. METHODS Entry criteria included ischemic stroke > 6 mo prior, substantial disability (subject confined to wheelchair, had home-nursing care, or needed assistance with activities of daily living), and NIH Stroke Scale (NIHSS) score = 6 to 20. Enrollees received a single intravenous dose of allogeneic mesenchymal bone marrow cells. Phase 1 used a dose escalation design (3 tiers, n = 5 each). Phase 2 (n = 21) was an expanded safety cohort. The primary endpoint was safety over 1-yr. Secondary endpoints examined behavior, with a pre-specified focus at 6-mo. RESULTS In phase 1, each dose (0.5, 1.0, and 1.5 million cells/kg body weight) was found safe, so phase 2 subjects received 1.5 million cells/kg. At baseline, subjects (n = 36) averaged 4.2 ± 4.6 yr poststroke, age 61.1 ± 10.8 yr, NIHSS score 8.7 ± 3.0, and Barthel Index 65 ± 29. Two were lost to follow-up, one was withdrawn, and two died (unrelated to study treatment). There were 15 serious adverse events, none possibly or probably related to study treatment. Two adverse events were possibly related to study treatment, a UTI and IV site irritation. Treatment was safe based on serial exams, EKGs, laboratory tests, and pan-computed tomography scans. Change from baseline to 6-mo post-transfusion was significant for all 4 secondary endpoints: Barthel Index (6.8 ± 11.4 points, P = .002), NIHSS (−1.25 ± 1.7 points, P < .001), MiniMental Status Exam (1.8 ± 2.8 points, P < .001), and Geriatric Depression Scale (−1.6 ± 3.8 points, P = .015). At baseline 11.4% (4/35 subjects) had Barthel Index = 95 to 100 (favorable outcome); at 6-mo, 27.3% (9/33); by 12-mo, 35.5% (11/31). CONCLUSION Transfusion of mesenchymal bone marrow cells in patients with disabling chronic stroke was safe and significantly improved several behavioral measures. The initial results were potentially equivalent to or exceeded those of prior studies utilizing stereotactic implantation. These data support proceeding to a randomized, placebo-controlled study.

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Transfer and expression of the human multiple drug resistance gene in human CD34+ cells

Blood ◽

10.1182/blood.v84.5.1408.bloodjournal8451408 ◽

1994 ◽

Vol 84 (5) ◽

pp. 1408-1414 ◽

Cited By ~ 5

Author(s):

M Ward ◽

C Richardson ◽

P Pioli ◽

L Smith ◽

S Podda ◽

...

Keyword(s):

Bone Marrow ◽

Drug Resistance ◽

Gene Transfer ◽

Bone Marrow Cells ◽

Multiple Drug Resistance ◽

Phase 1 ◽

Multiple Drug ◽

Facs Analysis ◽

Cd34 Cells ◽

Marrow Cells

The human multiple-drug resistance (MDR1) gene has been transferred into human hematopoietic progenitors using retroviral gene transfer. Human bone marrow cells and isolated CD34+ cells isolated from marrow were exposed to growth factors interleukin-3 (IL-3), IL-6, and stem cell factor for 48 hours and then to two changes of MDR retroviral supernatants over the next 24 hours. Progenitor assays in methylcellulose at this time showed that 18% to 70% of BFU-E and 30% to 60% of CFU-GM contain the transferred MDR gene by polymerase chain reaction analysis. Up to 11.2% of the progeny of these cells express increased amounts of MDR glycoprotein on their surface by fluorescence- activated cell sorter (FACS) analysis. In addition, transduced cells are enriched in high MDR-expressing cells after exposure to taxol as assessed by FACS analysis, and by resistance of BFU-E to taxol (Bristol- Myers Squibb, Princeton, NJ). These studies indicate the feasibility of using MDR gene transfer as a means of enriching marrow for MDR- transduced cells. They also provide the basis of a phase 1 clinical protocol in patients with advanced cancers not involving the bone marrow for the use of MDR gene transfer as a means of protecting marrow cells, which normally express low levels of MDR, from the myelosuppressive effects of drugs like taxol.

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Transfer and expression of the human multiple drug resistance gene in human CD34+ cells

Blood ◽

10.1182/blood.v84.5.1408.1408 ◽

1994 ◽

Vol 84 (5) ◽

pp. 1408-1414 ◽

Cited By ~ 95

Author(s):

M Ward ◽

C Richardson ◽

P Pioli ◽

L Smith ◽

S Podda ◽

...

Keyword(s):

Bone Marrow ◽

Drug Resistance ◽

Gene Transfer ◽

Bone Marrow Cells ◽

Multiple Drug Resistance ◽

Phase 1 ◽

Multiple Drug ◽

Facs Analysis ◽

Cd34 Cells ◽

Marrow Cells

Abstract The human multiple-drug resistance (MDR1) gene has been transferred into human hematopoietic progenitors using retroviral gene transfer. Human bone marrow cells and isolated CD34+ cells isolated from marrow were exposed to growth factors interleukin-3 (IL-3), IL-6, and stem cell factor for 48 hours and then to two changes of MDR retroviral supernatants over the next 24 hours. Progenitor assays in methylcellulose at this time showed that 18% to 70% of BFU-E and 30% to 60% of CFU-GM contain the transferred MDR gene by polymerase chain reaction analysis. Up to 11.2% of the progeny of these cells express increased amounts of MDR glycoprotein on their surface by fluorescence- activated cell sorter (FACS) analysis. In addition, transduced cells are enriched in high MDR-expressing cells after exposure to taxol as assessed by FACS analysis, and by resistance of BFU-E to taxol (Bristol- Myers Squibb, Princeton, NJ). These studies indicate the feasibility of using MDR gene transfer as a means of enriching marrow for MDR- transduced cells. They also provide the basis of a phase 1 clinical protocol in patients with advanced cancers not involving the bone marrow for the use of MDR gene transfer as a means of protecting marrow cells, which normally express low levels of MDR, from the myelosuppressive effects of drugs like taxol.

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Safety Profile of AMG 531 in Healthy Volunteers and in Thrombocytopenic Patients with Immune Thromobocytopenic Purpura.

Blood ◽

10.1182/blood.v106.11.1240.1240 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1240-1240 ◽

Cited By ~ 3

Author(s):

Daniel E. Stepan ◽

Elaine Sergis-Deavenport ◽

Reggie Kelly ◽

Jenny Christal ◽

Chien-Feng Chen ◽

...

Keyword(s):

Bone Marrow ◽

Adverse Events ◽

Healthy Volunteers ◽

Safety Profile ◽

Phase 1 ◽

Phase 2 ◽

Platelet Response ◽

Open Label ◽

Two Phase ◽

Open Label Extension

Abstract AMG 531 is a novel platelet-stimulating peptibody that targets the thrombopoietin (TPO) receptor, resulting in an increased production of platelets. AMG 531 lacks sequence homology to native TPO. To date, AMG 531 has been administered in two phase 1 studies in a total of 56 healthy volunteers and in three phase 2 studies, with the option to continue in an open-label extension study, in a total of 57 patients with immune thrombocytopenic purpura (ITP). In general, no deaths or detectable neutralizing antibodies have occurred across the AMG 531 development program. In the two phase 1 studies, AMG 531 increased platelet counts in a dose-response manner when administered as a single subcutaneous (SC) or intravenous (IV) dose of ≥ 1.0 μg/kg. The dynamics of the platelet response were as expected based on experience with other Mpl ligands. Single doses of AMG 531 ≤ 10.0 μg/kg were well tolerated. No deaths, serious or severe adverse events, or other events of clinical importance were reported at any dose administered (0.1, 0.3, 1.0, and 2.0 μg/kg SC; 0.3, 1.0, and 10.0 μg/kg IV). Commonly reported adverse events in healthy subjects receiving AMG 531 were mild to moderate headache (13% incidence in both studies), malaise/fatigue (4% and 6%), and various flu-like reactions. In the phase 2 studies in patients with ITP, AMG 531 was administered SC using weight-based dosing in all but one study. The maximum dose administered (in the extension study) was 23 μg/kg; most patients received doses of 3 to 9 μg/kg. AMG 531 has been administered as frequently as weekly for > 24 weeks. To date, three studies have been completed: two studies of two administrations on day 1 and 15, administered as unit (μg) doses in one study (N=16 and N=24, respectively), one placebo-controlled study of 6 weeks’ duration with weekly dosing (AMG 531 N=17; placebo N=4). One open-label extension (N=26) is ongoing. AMG 531 has been generally well tolerated in ITP patients. Most of the reported adverse events have been mild to moderate in severity; no dose-related trends have been observed. Across the four studies, the most commonly reported adverse events in patients receiving AMG 531 were headache (29%–54% incidence), contusion (15%–53%), and epistaxis (13%–41%). In the 6-week, weekly-dosing study, contusion and epistaxis were each reported for 50% and 41% of placebo-treated patients, respectively. Across the phase 2 studies, five patients treated with AMG 531 have experienced serious adverse events deemed as serious, unexpected, and reported as related to study drug. These include worsening of thrombocytopenia in three patients after completing treatment, headache and elevated LDH in one patient, and diffuse reticulin formation in the bone marrow reported as myelofibrosis in one patient. The reticulin formation is hypothesized to be due to an excessive accumulation of megakaryocytes in the bone marrow. AMG 531 was discontinued, and a follow-up bone marrow (after 3 months) showed improvement in reticulin. In summary, AMG 531 has been generally well tolerated and able to stimulate platelet production in a dose-response manner in healthy volunteers and ITP patients. Results suggest that both unit dosing and weight-based dosing provide a predictable platelet response. AMG 531 may represent a new treatment option for thrombocytopenic patients with ITP. Safety surveillance is ongoing to further establish the safety profile of AMG 531.

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Two-year safety and clinical outcomes in chronic ischemic stroke patients after implantation of modified bone marrow–derived mesenchymal stem cells (SB623): a phase 1/2a study

Journal of Neurosurgery ◽

10.3171/2018.5.jns173147 ◽

2019 ◽

Vol 131 (5) ◽

pp. 1462-1472 ◽

Cited By ~ 14

Author(s):

Gary K. Steinberg ◽

Douglas Kondziolka ◽

Lawrence R. Wechsler ◽

L. Dade Lunsford ◽

Anthony S. Kim ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Ischemic Stroke ◽

Adverse Events ◽

Clinical Outcomes ◽

Scale Score ◽

Phase 1 ◽

Motor Deficits ◽

Serious Adverse Events

OBJECTIVEThe aim of this study was to evaluate the safety and clinical outcomes associated with stereotactic surgical implantation of modified bone marrow–derived mesenchymal stem cells (SB623) in patients with stable chronic ischemic stroke.METHODSThis was a 2-year, open-label, single-arm, phase 1/2a study; the selected patients had chronic motor deficits between 6 and 60 months after nonhemorrhagic stroke. SB623 cells were administered to the target sites surrounding the subcortical stroke region using MRI stereotactic image guidance.RESULTSA total of 18 patients were treated with SB623 cells. All experienced at least 1 treatment-emergent adverse event (TEAE). No patients withdrew due to adverse events, and there were no dose-limiting toxicities or deaths. The most frequent TEAE was headache related to the surgical procedure (88.9%). Seven patients experienced 9 serious adverse events, which resolved without sequelae. In 16 patients who completed 24 months of treatment, statistically significant improvements from baseline (mean) at 24 months were reported for the European Stroke Scale (ESS) score, 5.7 (95% CI 1.4–10.1, p < 0.05); National Institutes of Health Stroke Scale (NIHSS) score, −2.1 (95% CI −3.3 to −1.0, p < 0.01), Fugl-Meyer (F-M) total score, 19.4 (95% CI 9.9–29.0, p < 0.01); and F-M motor scale score, 10.4 (95% CI 4.0–16.7, p < 0.01). Measures of efficacy reached plateau by 12 months with no decline thereafter. There were no statistically significant changes in the modified Rankin Scale score. The size of transient lesions detected by T2-weighted FLAIR imaging in the ipsilateral cortex at weeks 1–2 postimplantation significantly correlated with improvement in ESS (0.619, p < 0.05) and NIHSS (−0.735, p < 0.01) scores at 24 months.CONCLUSIONSIn this completed 2-year phase 1/2a study, implantation of SB623 cells in patients with stable chronic stroke was safe and was accompanied by improvements in clinical outcomes.Clinical trial registration no.: NCT01287936 (clinicaltrials.gov)

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