Expedited Cell Therapy After STEMI Shows Promise

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NEW YORK, NY—Data from a pair of small, preliminary studies suggest that stem cell therapy is safe and may improve long-term cardiac function in patients with ST-segment elevation myocardial infarction (STEMI). New cell therapy strategies for early use in the setting of primary percutaneous coronary intervention (PCI) were presented January 26, 2012, at the Seventh International Conference on Cell Therapy for Cardiovascular Disease in New York, NY. 

‘Off-the-Shelf’ Cells Injected into the Infarct-Related Artery

The first study, presented by Marc S. Penn, MD, PhD, of Northeast Ohio Medical University, evaluated the safety and feasibility of a novel ‘off-the-shelf’ preparation of healthy bone marrow-derived cells (Multistem; Athersys, Cleveland, OH). The product was injected directly into arterial adventitial tissue, thereby avoiding compromised stem cell homing after infusion into atherosclerotic vessels.

For the multicenter, phase I trial, researchers enrolled 25 patients with a first STEMI who had undergone PCI resulting in TIMI flow 3 and an ejection fraction of 45% or less. Nineteen patients were treated with 3 escalating doses of the cell preparation 2 to 5 days after primary PCI:

• 20 million cells (n = 6)
• 50 million cells (n = 7)
• 100 million cells (n = 6)

In addition, 6 patients were assigned to a registry and served as controls.

No Safety Issues

Overall, catheter delivery of the preparation was well tolerated, with no changes in vital signs, rise in cardiac enzymes, or increased arrhythmias. Over a 30-day observational period, no clinically significant events related to treatment occurred. One patient suffered a myocardial rupture after cell infusion and died, but the death was deemed to be unrelated to the procedure. Importantly, 89% of patients developed no antibodies to the allogeneic cells, and none mounted a cellular immune response.

In terms of cardiac function, at 4 months echocardiography showed a 4.1% absolute increase in LVEF over baseline in patients who received 20 million cells and a significant 8.7% absolute increase in those who received 50 million cells (P < 0.05). However, there was no improvement in those who received 100 million cells.

Benefit Greater for Patients with Low LVEF

When analysis was confined to patients whose baseline ejection fraction was confirmed by a core lab to be 45% or lower, results even more strongly favored the intermediate dosage. LVEF rose by 13.5% with 50 million cells and by 10.9% with 100 million cells. At 12 months, most patients saw sustained improvements.

Left ventricular stroke volume was similarly increased in the 50 million-cell group (+14.6 mL) and 100 million-cell group (+7.9 mL), while it decreased in both the low-dose and control groups (-3.6 mL and -4.3 mL, respectively). In those with confirmed low LVEF, the best results were seen with the higher doses. Between 4 and 12 months, stroke volume declined in controls, whereas it was maintained in the low- and intermediate-dose groups and increased in the high-dose group.

Though the mechanism behind the therapy is still under investigation, its multipotent adult progenitor cells have been shown to inhibit the inflammatory response and cardiac myocyte death and to induce angiogenesis, Dr. Penn observed. He reported that a larger phase II study is now being planned and will likely test the highest cell dose.

APOLLO: Therapeutic Lift-off for Adipose-Derived Cells

Eric J. Duckers, MD, PhD, of Thoraxcenter Erasmus Medical Center (Rotterdam, The Netherlands), meanwhile, presented a first-in-human study that assessed use of autologous adipose tissue-derived regenerative cells, obtained via patient liposuction.

The prospective APOLLO trial randomized 14 patients with anterior wall STEMI who underwent successful primary PCI, all with residual LVEF between 30% and 50%, in a 3:1 ratio to intracoronary infusion of the culprit artery with 20 million adipose-derived cells (n = 10) or placebo (n = 4). Subjects underwent liposuction of the periumbilical region. The aspirate was processed using the Cytori Celution System (Cytori Therapeutics; San Diego, CA) to obtain the stem cells, which were then infused within 24 hours of PCI.

Liposuction was well tolerated, except for significant bleeding in 2 patients, which led to adjustment in anticoagulation. The cell infusion did not result in coronary flow impediment. One patient in the treatment group underwent TLR. The percentages of severe adverse events in the 2 groups were similar, and importantly no unanticipated adverse effects related to the adipose-derived cell therapy were reported.

Positive Trends in Cardiac Function

At 6- and 18-month follow-up of 9 analyzable patients, trends emerged suggesting a relative benefit from the cell therapy. SPECT assessment showed an improvement in LVEF in treated patients (from 52.1% at baseline to 56.1%) compared with deterioration in controls (from 52.0% at baseline to 50.3%), for an absolute difference of 5.7% at 6 months. Similar patterns were seen at 18 months.

In addition, perfusion defect decreased significantly over 6 months in the treated group (from 16.9 ± 2.1% to 10.9 ± 2.4%; P = 0.004), whereas it worsened slightly in the placebo group; the difference was largely sustained at 18 months. Moreover, infarct size as assessed by MRI was more reduced by adipose-derived cells than placebo at 6 and 18 months. However, none of the differences between treatment and placebo groups achieved statistical significance (table 1).

Table 1. Changes in Cardiac Outcomes from Baseline

 

“The advantage of adipose tissue as a cell source is that it allows physicians to get a meaningful dose of the patient’s own cells at the point of care . . . without cell culture or use of donor cells,” Dr. Duckers said in a prepared statement. “We believe delivering cells within the first 24 to 36 hours takes advantage of the body’s signaling and initiates the repair process before irreparable damage occurs.”

The ongoing randomized, placebo-controlled phase IIb/III ADVANCE trial will assess the safety and feasibility of the adipose-derived cells at doses of 20 and 30 million in up to 375 STEMI patients, Dr. Duckers reported.

 

 

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Sources:1. Penn MS. Periadventitial MAPC administration in STEMI. Presented at: Seventh International Conference on Cell Therapy for Cardiovascular Disease; January 26, 2012; New York, NY.

 

2. Penn MS, Ellis S, Gandhi S, et al. Adventitial delivery of an allogeneic bone marrow-derived adherent stem cell in acute myocardial infarction: Phase I clinical study. Circ Res. 2012;110:304-311.

3. Duckers E. Adipose cells for STEMI: APOLLO and ADVANCE randomized trials. Presented at: Seventh International Conference on Cell Therapy for Cardiovascular Disease; January 26, 2012; New York, NY.

4. Houtgraaf JH, den Dekker WK, Van Dalen BM, et al. First experience in humans using adipose tissue-derived regenerative cells in the treatment of patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2012;59:539-543.

 

 

 

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