Researchers are currently exploring the use of stem cell therapies in a range of conditions including cardiovascular disease, neurodegenerative disorders, and chronic obstructive pulmonary disease (COPD), among others.1,2 To date, however, these products have been approved by the U.S. Food and Drug Administration (FDA) only for use in certain cancers, hematological diseases, and immune system disorders.3

Given the chronic and incurable nature of COPD and the limited impact of available therapies, it is understandable why the lure of a promising new treatment approach would be appealing to individuals living with COPD. Unfortunately, these factors also render patients with COPD vulnerable to exploitation by companies offering false hope for novel remedies, explained Marilyn K. Glassberg, MD, of the Division of Pulmonology, Critical Care, and Sleep at the University of Arizona College of Medicine, and colleagues, in a recent review published in Chest.4

Commercial stem cell clinics may attract patients using unsubstantiated claims regarding the efficacy of unapproved stem cell therapies, and boast affiliations with academic medical centers. These centers may also promote studies that have not undergone peer review but may appear legitimate to patients.3


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Based on the small number of legitimate studies in this area thus far, preliminary evidence suggests that stem cell therapies could ultimately prove useful in the treatment of COPD.

“Theoretically, stem cell therapy could benefit COPD patients by decreasing airway inflammation and promoting structural repair,” although extensive work is needed to further this nascent area of investigation, according to David G. Hill, MD, national board member of the American Lung Association, assistant clinical professor of medicine at both Yale University School of Medicine and the Frank H. Netter MD School of Medicine at Quinnipiac University in Connecticut, and director of clinical research at Waterbury Pulmonary Associates.

In a randomized, placebo-controlled trial published in 2013, researchers explored the safety and potential efficacy of systemically administered mesenchymal stem cells (MSCs) derived from bone marrow in 62 patients with moderate to severe COPD.5 Among the 74% of patients who completed the full 2 years of follow-up after the first infusion, there were no infusional toxicities, deaths, or serious adverse events linked to MSC administration.

While a significant reduction in circulating C-reactive protein (CRP) levels was found in patients receiving MSCs who had elevated CRP at baseline, there were no significant differences in disease worsening, exacerbation frequency, pulmonary function testing, or quality of life measures in the MSC group compared to controls. “Systemic MSC administration appears to be safe in patients with moderate to severe COPD and provides a basis for subsequent cell therapy investigations,” the study authors concluded.5

A pilot study published in February 2020 in Stem Cell Research and Therapy examined the effects of treatment with MSCs derived from umbilical cord tissue in 20 patients with moderate to severe COPD. The researchers found similar results supporting safety, without notable changes in clinical outcomes — although some improvement in quality of life measures was observed.6

In 2021, Daniel J Weiss, MD, PhD, of the University of Vermont College of Medicine, and colleagues published a post-hoc analysis7 of their earlier data5 in which patients were stratified by baseline CRP levels. The results showed significant improvements in forced expiratory volume in 1 second (FEV1), forced vital capacity, and 6-minute walk distance in patients with baseline CRP4 mg/L or higher who were treated with MSC vs placebo.7

These findings indicate that it may be fruitful to “reassess potential efficacies of MSC-based cell therapies in carefully stratified patient groups,” wrote Dr Weiss and colleagues. “Accordingly, future studies may focus on patients with high levels of circulating inflammatory cytokines including [interleukin] IL-6, IL-1 and [tumor necrosis factor-alpha] TNF-α as well as CRP to investigate further the clinical efficacy and impact of inflammatory cytokines on cell-based therapies.”7

Currently, Jorge M. Mallea, MD, pulmonologist and critical care specialist at the Mayo Clinic in Jacksonville, Florida, is conducting a pilot study investigating the safety and feasibility of MSC treatment in patients with advanced COPD (Mesenchymal Stem Cells in the Treatment of Subjects with Advance Chronic Obstructive Pulmonary Disease [COPD]; ClinicalTrials.gov identifier NCT04047810).

Pulmonology Advisor interviewed Dr Mallea and Dr Hill for additional insights regarding progress and the need for patient caution in this emerging field.

Pulmonology Advisor: Overall, what does the evidence suggest thus far about the potential effects and possible role of stem cell therapy in COPD?

Dr Mallea: Both animal and human studies suggest that there are potential benefits of stem cell therapy in COPD. Stem cells home preferentially in the lungs after intravenous administration and are known to have immunomodulatory effects and antimicrobial properties and to promote tissue repair. COPD is a heterogeneous lung disease with multiple systemic manifestations. The subgroup of COPD patients that will benefit from cell therapy has yet to be identified, and the optimal dose and frequency of cell therapies has not been established.

Dr Hill: Currently, there is limited evidence regarding the effects and role of stem cell therapies for the treatment of COPD. Most of the available peer-reviewed data is from preclinical, nonhuman trials. Published data show some evidence that stem cells may have an anti-inflammatory effect, which could be beneficial in COPD. These findings are not consistent across all published trials. 

There are also some clinical trials that suggest stem cells may foster structural repair of an injured lung. The preclinical trials are limited, using different animal models, different doses and administration methodology for the stem cells, and different parameters measured to define efficacy. The largest published clinical trial to date involves 62 patients. This trial revealed no safety concerns, but no benefit of stem cell treatment in terms of lung function or quality of life in participants. Given the small size of the trial it was underpowered to determine beneficial response.5

Can you tell us a bit about your pilot study on stem cell therapy for COPD, including the current status, anticipated completion date, and plans for next steps?

Dr Mallea: The Mayo Clinic Center for Regenerative Medicine is sponsoring a phase 1 trial of stem cells in patients with COPD. The goal of the trial is to assess the feasibility and safety of administering allogeneic bone marrow-derived MSCs to patients with advanced COPD and at least one acute exacerbation in the previous year. The cells are cultured and expanded at our own good manufacturing practice (GMP) facility.

This is a dose escalation trial of 3 different doses;, we have enrolled 11 patients so far. Our goal is to enroll 15 patients by October 2021. We will follow the patients for 1 year after they receive the infusion of stem cells.

We are in the process of applying for funding for a phase 2 trial to be conducted at the 3 Mayo Clinic sites in Arizona, Florida, and Minnesota. Our goal is to start recruiting for this phase 2 trial by the end of 2022.   

What are other notable ongoing lines of research in this area, as well as remaining needs?

Dr Mallea: Identifying biomarkers that will allow us to better characterize the different subpopulations of patients with COPD is an active area of research by many investigator groups in the country. We hope to contribute to this area by measuring the response to stem cells in the group of patients we enroll in our trials. The response can be assessed in many different ways, including changes in pulmonary function tests, quantitative computed tomography of the chest, walk distance, quality of life questionnaires, and cytokine levels, among others. A thorough understanding of the mechanisms by which stem cells can improve the health of patients with COPD will allow us to develop more specific therapies for the future.        

Dr Hill: The safety, efficacy, choice of cell line product, and method of administration needs to be studied in large multicenter trials, with regulatory body oversight and subsequent publication in peer-reviewed journals, before stem cell therapy can be approved by regulatory bodies and utilized outside of the clinical trial arena. The risk to patients, both in terms of safety and economic exploitation, strongly outweighs the potential benefit in the commercial market at this time.

Some experts and the American Lung Association have expressed concerns about potential exploitation of patients seeking stem cell therapies for COPD and other lung diseases.8 How should clinicians advise patients who inquire about these treatments?

Dr Mallea: Patients need to know that so far, cell therapies have not been proven to be effective for the treatment of lung diseases. Cell and cell-derived therapies should only be administered to patients as part of clinical trials. Prior to being enrolled in a clinical trial, the patient should be evaluated by a pulmonologist who ensures that the patient is receiving maximal medical therapy for their condition. In addition, patients should be educated on their disease process and the current status of regenerative therapies.

Finally, other treatment options should be discussed with the patient if indicated. We have several patients who came to ask about cell therapies and ended up receiving and benefiting from lung volume reduction surgery or lung transplantation.

We are looking forward to bringing the different therapies we are investigating at the Center for Regenerative Medicine to the clinic for the benefit of our patients, but until then we should continue to educate our patients and offer them the best current available therapies.

Dr Hill: The American Lung Association and multiple medical societies have expressed concerns regarding the unregulated administration of stem cell therapy to patients. If patients express interest in stem cell therapy, providers should caution their patients regarding the limited data available regarding both safety and efficacy. There are unscrupulous providers who make claims that have not been confirmed by experts or regulatory agencies.

The FDA states that stem cells are drugs that need to undergo a rigorous approval process if not administered in a supervised clinical trial. Patients and providers should be wary of direct-to-consumer advertising of stem cell products. Commercial businesses administering stem cells outside of clinical trials tend to rely extensively on patient testimonials rather than peer-reviewed data to exploit the public.

Providers can visit the International Society for Stem Cell Research to review further information and their excellent guidelines regarding stem cell research.9 Both patients and providers should be wary of “clinical trials” that are not supervised by regulatory bodies or published in peer-reviewed journals. Commercial centers exploit patients by imitating the process of regulated academic scientific trials. Such exploitive trials are often poorly planned, unsupervised at a single center, and include expensive pay-to-participate programs for patients.

References

1. Turner D, Rieger AC, Balkan W, Hare JM. Clinical-based cell therapies for heart disease—Current and future state. Rambam Maimonides Med J. 2020;11(2):e0015. doi:10.5041/RMMJ.10401

2. Aly RM. Current state of stem cell-based therapies: An overview. Stem Cell Investig. 2020;7:8. doi:10.21037/sci-2020-001

3. Stem cell and exosome products. U.S. Centers for Disease Control and Prevention. Updated December 19, 2019. Accessed June 21, 2021. https://www.cdc.gov/hai/outbreaks/stem-cell-products.html

4. Glassberg MK, Csete I, Simonet E, Elliot SJ. Stem cell therapy for COPD: Hope and exploitation. Chest. Published online April 21, 2021. doi:10.1016/j.chest.2021.04.020

5. Weiss DJ, Casaburi R, Flannery R, LeRoux-Williams M, Tashkin DP. A placebo-controlled, randomized trial of mesenchymal stem cells in COPD. Chest. 2013;143(6):1590-1598. doi:10.1378/chest.12-2094

6. Le Thi Bich P, Nguyen Thi H, Dang Ngo Chau H, et al. Allogeneic umbilical cord-derived mesenchymal stem cell transplantation for treating chronic obstructive pulmonary disease: a pilot clinical study. Stem Cell Res Ther. 2020;11(1):60. doi:10.1186/s13287-020-1583-4

7. Weiss DJ, Segal K, Casaburi R, Hayes J, Tashkin D. Effect of mesenchymal stromal cell infusions on lung function in COPD patients with high CRP levels. Respir Res. 2021;22(1):142. doi:10.1186/s12931-021-01734-8

8. NCT04047810Stem cell therapy (advisory). American Lung Association. Updated February 23, 2021. Accessed June 21, 2021. https://www.lung.org/lung-health-diseases/wellness/public-health-issues-lung-health/stem-cell-therapy.

9. ISSCR guidelines for stem cell research and clinical translation. International Society for Stem Cell Research. Accessed June 21, 2021. https://www.isscr.org/policy/guidelines-for-stem-cell-research-and-clinical-translation