Stem Cell Therapy Will Have an Increasing Role in the Treatment of Critical Limb Ischemia: The RESTORE-CLI Phase IIb Trial
What do we know about stem cell treatment for critical limb ischemia?
In the cath lab, the primary treatment for critical limb ischemia (CLI) patients is endovascular therapy such as atherectomy, angioplasty, and/or stenting, of the lower extremity arteries to improve the blood flow. The other treatment option is to have open bypass surgery on the leg, but there are a fair number of CLI patients who are too sick to have open surgery. Some are not able to have interventional procedures either, because their blockages are too long or the patient is too dehabilitated. Usually CLI patients also have coronary and/or carotid artery disease, so these are very sick patients. People have long been interested in figuring out less invasive ways to treat these patients.
The stem cell therapy we studied in the RESTORE-CLI phase IIb trial is a type of biological therapy, in which we take the patient’s own stem cells (called autologous stem cells). There are varying methods of retrieval and cultivation. In RESTORE-CLI, a 50mL aspirate of bone marrow was taken from the patient’s iliac crest and sent to the sponsoring company. The company put it into a bioreactor and expanded certain cell lines. After two weeks of growing the cells, they were sent back and we injected them into the patient’s leg intramuscularly. Another technique is where you harvest about 250mLs of bone marrow and then the bone marrow aspirate can be prepared right at that time and injected into the leg. That’s a second alternative treatment option.
Once the cells are placed into a leg that has low oxygen because of poor blood flow, the cells change themselves or they behave differently, growing new small blood vessels and releasing various cytokines that can affect healing. We saw about a 50% lower risk of limb loss at one year in patients receiving the cell therapy versus the control group, which was significant. The patients receiving stem cells also had a much-improved clinical outcome. Based on the number of patients whose wounds worsened, who developed gangrene, died, or underwent a major amputation, outcomes were much better in the stem cell-treated patients compared to the placebo patients. At one year, in the patients with tissue loss (patients who had an ulcer when they presented), about 42% of patients who received a placebo either died or had a major amputation compared to about 20% of the patients who were treated with the stem cells. Patients will be followed for five years, but the primary endpoint for efficacy was at one year.
What prompts the stem cells’ success in some patients and not in others?
That is something we do not yet understand. It might have something to do with the composition of the individual bone marrow, because various individuals’ bone marrow may hold different numbers of important stem cells. It may be that one particular patient’s bone marrow is not enriched with particular types of stem cells to start with. The field is early in its development and we do not yet have the data to look for biomarkers determining which patients might respond versus not respond.
What do we know about the blood vessels that developed as a result of the stem cell injection?
They are small. In humans, their existence can’t be proven yet. In animal models, angiogenesis, or the growth of blood vessels in the 300-micron range, can easily be proven. In humans, it is postulated that this happens, but there is as yet no proof. No one has done a study in humans where cells are injected and then tissue retrieved from the area of injection for study and vessel measurement.
So patients weren’t imaged after receiving the injection.
No, there are really no imaging techniques to prove increased blood flow or increased vascularity. Arteriography is not accurate enough and there is too much variability in things like TCP02, or measuring ankle-brachial or toe-brachial index. These techniques, which are the clinical standard, are not sensitive enough. There are other, more experimental techniques, but it is hard to use an experimental technique to validate an experimental treatment.
Is there a general sense of the maximum growth timespan once the cells are injected?
That is a good question, because CLI is an unrelenting disease. The question is whether the patient would need to be redosed at some point down the road. It is unclear. You would reasonably expect that a patient might need to be redosed at some point, but those studies all need to be done.
What do you see happening in the future?
Some phase III trials have started. Ultimately, the major obstacle that the field faces is recruiting enough patients to complete trials, because proving efficacy requires about 500 to 600 patients. It is hard, because patients do not like being enrolled into placebo-controlled trials. Yet in order to get stem cell therapy FDA-approved, such trials have to be completed.
In RESTORE-CLI, we treated “no-option” patients, meaning patients with no option for revascularization either with bypass surgery or an interventional procedure. To some degree, we had to be able to say that no interventional procedure was reasonable, because some physicians feel that they could try to angioplasty the pedal arch. However, these treatments have not yet been well studied in CLI patients.
Dr. Richard Powell can be contacted at richard.powell@hitchcock.org.
Recommended reading
- Powell RJ, Comerota AJ, Berceli SA, Guzman R, Henry TD, Tzeng E, et al. Interim analysis results from the RESTORE-CLI, a randomized, double-blind multicenter phase II trial comparing expanded autologous bone marrow-derived tissue repair cells and placebo in patients with critical limb ischemia. J Vasc Surg. 2011 Oct; 54(4): 1032-1041. doi: 10.1016/j.jvs.2011.04.006.
- Powell RJ. Update on clinical trials evaluating the effect of biologic therapy in patients with critical limb ischemia. J Vasc Surg. 2012 Jul; 56(1): 264-266. doi: 10.1016/j.jvs.2012.03.255.
