RENEW Trial Shows Stem Cell Mobilization Has Some Potential for Refractory Angina


The RENEW clinical trial has examined the ability of “CD34+” stem cells from bone marrow to alleviate the symptoms of refractory angina.

Angina pectoris is a crushing chest pain that afflicts people when the heart receives too little oxygen to support it for the workload placed upon it. Angina pectoris typically results from the blockage of coronary arteries as a result of atherosclerosis. Treatment of angina pectoris usually includes PCI or percutaneous coronary intervention, which involves the placement of a stent in the narrowed coronary artery, in combination with drug treatments like beta blockers, and/or cardiac nitrate (e.g., nitroglycerine).

Angina pectoris is also classified according to the severity of the disease. The Canadian Cardiovascular Society grading of angina pectoris (which is very similar to the New York Heart Association classification) uses four classes (I-IV) to classify the disease. Patients with Class I angina only experience pain during strenuous or prolonged physical activity. Those with Class II angina have a slight limitation in physical activity and experience pain during vigorous physical activity (climbing several flights of stairs). Class III angina manifests as pain during everyday living activities, such as climbing one flight of stairs. These patients experience moderate limitation of their physical activity. Those with Class IV angina experience pain at rest and are unable to perform any activity without angina, and therefore, suffer from severe limitations on their activity.

Refractory angina pectoris (also known as chronic symptomatic coronary artery disease) stubbornly resists medical therapy and is unamenable to conventional revascularization procedures. Patients with refractory angina pectoris have reproducible lifestyle-limiting symptoms of chest pain, shortness of breath, and easy fatigability.

The results of the RENEW clinical trial were presented at the Society for Cardiovascular Angiography and Interventions 2016 sessions. Even though the trial was prematurely ended for financial reasons, the results that were collected suggest that cell-based therapies might provide relief for suffers of refractory angina pectoris.

RENEW tested the effectiveness of the intravenous infusion of the protein called granulocyte-colony simulating factor (G-CSF), which mobilizes CD34+ stem cells from the bone marrow. Once summoned from the bone marrow, CD34+ stem cells can help establish new blood vessels and increase blood flow throughout the heart. CD34+ stem cells also seem to have some ability to home to sites of damage. Therefore, G-CSF infusions might provide some relief to patients with refractory angina pectoris.

Dr. Timothy D. Henry of the Cedars-Sinai Heart Institute in Los Angles, CA, said: “Clinicians are seeing more RA (refractory angina) patients because people are living longer. Unfortunately, despite better medical care, these people are still confronting ongoing symptoms that affect their daily lives.”

Patients enrolled in the RENEW trial had either class III or IV angina and experiences ~7 chest pain episodes each week. These patients were also not candidates for revascularization (PCI) and their treadmill exercise times were between 3-10 minutes.

112 RA patients were randomly broken into three groups. Group 1 received standard care (28), group 2 received placebo injections (27), and group 3 received treatment with CD34+ cells. The trial was double-blinded and placebo controlled. The original aim was to test 444 RA patients, but financial concerns truncated the study at 112 patients.

All patients were assessed at three, six, 12, and 24 months after treatment by means of exercise tolerance, anginal attacks, and major adverse cardiovascular events (MACEs).

The cell-treated patients increased their exercise times by more than two minutes at three (average 122-second increase), six (average 142-second increase), and twelve (average 124-second increase) months. This is significant, since the other two groups showed no significant increase in their exercise times.

Patients in the cell-treated group also experienced 40 percent fewer anginal attacks at six months relative to the placebo-treated group.

At two years after the treatment, the CD34+-treated group have lower mortality rates (3.7 percent) compared to those who received standard care (7.1 percent) and those who received the placebo (10 percent).

Finally, after two years, the cell-treated group had lower MACE rates (46 percent) than the standard care group (68 percent). The MACE rate for the placebo-treated group was 43 percent.

On the strength of these results, Dr. Henry said, “Cell therapy appears to be a promising approach for these patients who have few options. Our results were consistent with phase 2 results from the ACT34 trial (author’s note: which gave patients infusions of cells and not G-CSF).”

Tom Povsic of the Duke Clinical Research Institute said of the RENEW trial, “It is unfortunate the early termination of this study precludes a full evaluation of the efficacy of this therapy for these patients with very few options.  Studies like RENEW are critical to developing reliable and effective therapies for heart patients, and continued cellular therapies for heart patients, and continued funding is essential to advancing the work that this study began.  We need to find a way to bring these therapies as quickly as safely as possible.”

Dr. Povsic’s words certainly ring true.  Even though the results of the RENEW study are essentially positive, RENEW was planed to be almost three times the size of Douglas Losordo’s earlier, successful ACT34 study.  The results of both the ACT34 and RENEW studies are largely positive.  Perhaps more importantly, both studies have also established that cell-based treatments for RA patients are safe.  However, given the voracity of the FDA for clinical data before it will approve a treatment, even for patients with few current options, it is unlikely that these studies will prove large enough to satisfy the agency.  Until a very large study shows cell-based treatments to be not only safe but efficacious, only then will the mighty turtle known as the FDA approve such treatments for RA patients.

High-Dose Stem Cell Treatments in Chronic Heart Patients Increases Survival Rates


The DanCell clinical trial was conducted about seven years ago at the Odense University Hospital, Odense, Denmark by a clinical research team led by Axel Diederichsen. The DanCell study examined 32 patients with severe ischemic heart failure who had received two rounds of bone marrow stem cell treatments.

The DanCell study was small and uncontrolled. However, because the vast majority of stem cell-based clinical trials have examined the efficacy of stem cell treatments in patients who have recently experienced a heart attack, this study was one of the few that examined patients with chronic heart failure.

In this study, patients had an average ejection fraction of 33 ± 9%, which is in the cellar – normal ejection fractions in healthy patients are in the 50s-60s. Therefore, these are patients with distinctly “bad tickers.” All 32 patients received two repeated infusions (4 months apart) of their own bone marrow stem cells, but these stem cell infusions were quantitated to determine the number of “CD34+” cells and the number of “CD133+” cells. CD34 is a cell surface protein found on bone marrow hematopoietic stem cells, but it by no means exclusive to HSCs. CD133 is also a cell surface protein found, although not exclusively, on the surfaces of cells that form blood vessels and blood vessels cells as well.

Initially, patients showed no improvements in heart function after 12 months. However, when patients were classified according to those who received the most or the least number of CD34+ cells, a curious thing emerged: those who received more CD34+ cells had a better chance of surviving than those who received fewer CD34+ cells.

Is this a fluke? To determine if it was, Diederichsen and his colleagues followed these patients for 7 years after the bone marrow infusion. When Diederichsen and his colleague recorded the number of deaths and compared them with the number of CD34+ cells infused, the pattern once again held true. The CD34+ cell count and CD133+ cell count did not significantly correlate with survival, but the CD34+ cell count alone was significantly associated with survival. In the authors own words: “decreasing the injected CD34 cell count by 10[6] increases the mortality risk by 10%.”

The conclusions of this small and admittedly uncontrolled study: “patients might benefit from intracoronary stem cell injections in terms of long-term clinical outcome.”

Three things to consider: Patients with heart conditions have poorer quality bone marrow stem cell numbers. Therefore, allogeneic stem cells might be a better way to go with this patient group. Secondly, the Danish group used Lymphoprep to prepare their bone marrow stem cells, which has been used in other failed studies, and the stem cell quality was almost certainly an issue in these cases (see the heart chapter in my book The Stem Cell Epistles for more information). Therefore, independent tests of the bone marrow quality are probably necessary as well or a different isolation technique in general. Also, a controlled trial must be run in order to confirm the efficacy of bone marrow stem cell infusions for patients with chronic ischemic heart disease. Until them, all we can conclude is that intracoronary injections of a high number of CD34+ cells may have a beneficial effect on chronic ischemic heart failure in terms of long-term survival.

Stroke Patients Improve After Stem Cell Treatments


Neurologists at Imperial College, London have conducted a small pilot study in stroke patients who received stem cell treatments after their strokes. To date, their patients have shown tentative signs of neurological recovery six months after receiving the stem cell treatment.

According to the physicians attending these patients, all five patients who participated in the study have improved after the therapy. Even though these results are hopeful, larger and better controlled trials are required to confirm if the implanted stem cells are responsible for the improvements in these patients. Brain scans of the patients showed that damage caused by the stroke had reduced over time. However, similar improvements are seen in stroke patients as part of the normal recovery process.

When assessed after their six-month check ups, all of the participating patients fared better on standard measures of disability and impairment that are normally caused by stroke. Once again, it is difficult to determine if these improvements result from the stem cell treatments or from standard hospital care.

This pilot study was designed to assess only the safety of the experimental therapy (phase I clinical trial) and with so few patients and no control group to compare them with, it is impossible to draw conclusions about the effectiveness of the treatment at this time.

Paul Bentley is a consultant neurologist at Imperial College London, and his group is presently applying for funding to run a more powerful randomized, controlled trial on this stem cell therapy, which, Bentley hopes, could include at least 50 patients by next year.

“The improvements we saw in these patients are very encouraging, but it’s too early to draw definitive conclusions about the effectiveness of the therapy,” said Soma Banerjee, a lead author and consultant in stroke medicine at Imperial College Healthcare National Health System (NHS) Trust. “We need to do more tests to work out the best dose and timescale for treatment before starting larger trials.”

All five patients who participated in this study were treated within seven days of suffering a severe stroke. Each patient had a bone marrow sample extracted from their hip bones, and these bone marrow cells were processed in the laboratory to isolated the stem cells that give rise to blood cells and blood vessel lining cells (so-called CD34+ cells). These stem cells were infused into one of the main arteries that supplies blood to the brain.

CD34+ cells do not grow into fresh brain tissue, but they might release pro-healing chemicals that suppress inflammation and recruit and stimulate other cells to grow within the damaged brain tissue. Some of the implanted CD34+ cells might also form new blood vessels, said Bentley.

Four out of five of the patients had the most serious type of stroke, and typically, only 4% of these patients survive and are able to live independently after six months. In the pilot study, published in Stem Cells Translational Medicine, all four were alive and three were independent six months later.

“Although they mention some improvement of some of the patients, this could be just chance, or wishful thinking, or due to the special care these patients may have received simply because they were in a trial,” said Robin Lovell-Badge, head of developmental genetics at the MRC’s National Institute for Medical Research in London.

Caution is certainly required in the interpretation of this pilot study, but I think that these results definitely merit a Phase II trial to determine if the improvements are stem cell-independent or stem cell-dependent.

Stem Cells from Bone Marrow Help Heal Hard-to-Heal Bone Fractures


A new study that has appeared in the journal STEM CELLS Translational Medicine demonstrates the potential of a subset of stem cells called CD34+ in treating stubborn bone fractures that prove hard to heal.

The body has mechanisms for the repair of broken bones. Consequently, most patients recover from broken bones with little or no complication. However, up to 10 percent of all fracture patients experience fractures that refuse to heal. Such heard to heal fractures can lead to several debilitating side effects that include infection and bone loss, and the healing of hard to heal fractures often requires extensive treatment that includes multiple operations and prolonged hospitalization as well as long-term disability.

Regenerating broken bones with stem cells could offer an answer to this medical conundrum. Adult human peripheral blood CD34+ cells have been shown to contain a robust population of endothelial progenitor cells (EPCs) and hematopoietic stem cells, which give rise to all types of blood cells. These two types of stem cells might be good candidates for this therapy.

However, while other types of stem cells have been tested for their bone regeneration potential, the ability of CD34+ stem cells to facilitate bone healing has not been examined; that is until now. A phase I/II clinical study that evaluated the capacity of CD34+ to stimulate bone regeneration was published in the current edition of STEM CELLS Translational Medicine. This study was conducted by researchers at Kobe University Graduate School of Medicine, led by Tomoyuki Matsumoto, M.D., and Ryosuke Kuroda, M.D., members of the university’s department of orthopedic surgery and its Institute of Biomedical Research and Innovation (IBRI).

Matsumoto’s and Kuroda’s study was designed to evaluate the safety, feasibility and efficacy of autologous and G-CSF-mobilized CD34+cells in patients with non-healing leg bone breaks that had not healed in nine months. Seven patients were treated with CD34+ stem cells after receiving bone grafts.

In case you were wondering, G-CSF is a drug that releases stem cells from the bone marrow into the blood. It is given by injection or intravenously, and works rather well to mobilize bone marrow stem cells into the peripheral circulation.  It has clinical uses for patients recovering from chemotherapy.  Filgrastim (Neupogen) and PEG-filgrastim (Neulasta) are two commercially-available forms of recombinant G-CSF.

“Bone union was successfully achieved in every case, confirmed as early as 16.4 weeks on average after treatment,” Dr. Kuroda said.

Dr. Matsumoto added, “Neither deaths nor life-threatening adverse events were observed during the one year follow-up after the cell therapy. These results suggest feasibility, safety and potential effectiveness of CD34+ cell therapy in patients with nonunion.”

Atsuhiko Kawamoto, MD, Ph.D., a collaborator in IBRI, said, “Our team has been conducting translational research of CD34+ cell-based vascular regeneration therapy mainly in cardiovascular diseases. This promising outcome in bone fracture opens a new gate of the bone marrow-derived stem cell application to other fields of medicine.”

Although the study documents a relatively small number of patients, the results suggest the feasibility, safety and potential effectiveness of CD34+ cell therapy in patients with non-healing breaks,” said Anthony Atala, M.D., editor of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine.