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In chronic obstructive pulmonary disease (COPD), current treatments manage symptoms but cannot stimulate repair of the damaged tissue. However, adult lungs retain stem cells that hold promise for regenerative therapies.

A recent study published in Science Translational Medicine by Dr. Yujia Wang and coauthors explored the use of autologous P63+ lung progenitor cells for COPD therapy.¹

Why P63+ progenitor cells? 

P63+ cells are a specific type of progenitor cell found in the airway basal layer that can differentiate into various epithelial cell types that form the lining of the airways, making them attractive candidates for regenerative COPD treatment. In damaged lungs, remaining healthy P63+ cells have been shown to persist and retain their function. Studies in animal models of COPD further demonstrated the ability of P63+ cells to regenerate damaged lung epithelium. 

Trial design 

The study by Wang and colleagues assessed the safety and efficacy of autologous P63+ cell transplantation on lung tissue repair in 28 adult males between the ages of 40 and 75. All were diagnosed with COPD based on GOLD criteria, presented with DLCO <80% predicted value, and received standard of care for COPD for the duration of the study. They were randomly divided into control (n=7) and cell transplant (n=21) groups at baseline. Patients in the cell therapy group underwent autologous transplant of P63+ via bronchoscopy. In the final 24-week follow-up analysis, three control and 17 therapy patients remained.

Safety outcomes

The researchers collected safety data at baseline, 3 days, 4 weeks, 12 weeks, and 24 weeks after transplantation. Grade 1 adverse events were observed in 9 (52.9%) patients receiving cell therapy and one patient in the control group. Grade 2 adverse events occurred in one patient from each group. Overall, cell therapy was well-tolerated by all participants, with no grade 3 to 5 adverse events reported in either group. 

Efficacy outcomes

Diffusion capacity of the lung for carbon monoxide (DLCO), a key indicator of gas exchange efficiency, was measured at weeks 12 and 24 to assess the efficacy of cell transplantation for COPD. The median DLCO in the treatment group increased from 2.73 [interquartile range (IQR), 2.01 to 3.10] at baseline to 3.34 mmol min-1 kPa-1 (IQR, 2.40 to 3.75) at 12 weeks and maintained at 3.20 mmol min-1 kPa-1 (IQR, 2.15 to 3.79) at 24 weeks. Compared to the control group, which experienced a decline in DLCO over time, this difference was statistically significant (P=0.008). The median DLCO% predicted value followed a similar trend, reaching the maximum effect at week 12 and sustained through week 24 and was significantly different from the control group (P=0.007). 

Cell therapy resulted in clinically meaningful improvements in DLCO for most patients in the treatment group. A minimal improvement in DLCO of 1.1 ml/min/mmHg or 11% from baseline is considered clinically significant in COPD patients. In this study, 70.6% of patients receiving cell therapy showed this level of improvement 12 weeks, with 53.3% maintaining it at 24 weeks. In the control group, all patients had worsening minimal clinically important difference at 12 weeks. Notably, existing standard of care treatments rarely lead to substantial DLCO improvement in COPD patients.

Other secondary study outcomes included the St. George's Respiratory Questionnaire (SGRQ) and the 6-minute walking distance (6MWD) test. The average SGRQ score in the cell therapy group decreased from baseline (51.3 [IQR, 37.5 to 66.2]) to 24 weeks (44.2 [IQR, 22.3 to 65.5]), with a Cohen鈥檚 d value of 鈭�0.359 (95% CI, 鈭�1.048 to 0.329). Although lower SGRQ score suggest better quality of life after cell therapy, there were no statistically significant differences in scores between the control and intervention groups within 24 weeks. 

Similarly, the median 6-minute walk distance increased in the cell therapy group but was not statistically different from the control. In patients with COPD, a 30-meter improvement in walking distance is considered a clinically significant benefit. In study patients receiving cell therapy, 66.7% achieved this improvement, compared to none in the control group (P=0.036). Wang and colleagues also report a link between DLCO and exercise capacity, suggesting patients with better gas exchange after cell therapy were more likely to see significant improvement in walking distance. 

P63 Expression linked to better outcomes 

The study also explored potential markers for treatment response. Researchers performed transcriptomic analysis of transplanted progenitor cells collected from seven patients, of which four were responsive to transplantation. Expression of most progenitor genes were similar but cells from therapeutically responsive patients had a higher expression of P63 gene and genes associated with the WNT pathway. Thus, the quality and functionality of the transplanted cells might influence treatment efficacy. 

Refining and validating P63+ cell therapy

Dr. Wang and coauthors provide preliminary evidence for the safety and efficacy of autologous P63+ cell transplantation as a regenerative treatment for COPD. The findings suggest that this therapy may be a safe approach for improving lung function in patients with COPD. This is significant because 鈥淸t]he destruction of bronchiolar and alveolar tissues in the lungs of patients with COPD is currently irreversible. Thus, there is an urgent need for treatment options that support lung regeneration,鈥� the authors noted. 

Interestingly, CT scans revealed reduced emphysematous lesions in two patients with mild emphysema after receiving cell therapy. This suggests the potential for lung tissue regeneration, a significant step forward for COPD treatment.

However, the study has limitations:

• Small sample size, especially in the control group.
• Only male patients included, limiting generalizability.
• No placebo control, making definitive conclusions about efficacy difficult.
• Short follow-up period (24 weeks) limits assessment of long-term effects and mortality.
• No systematic analysis of known serum biomarkers associated with COPD.

The researchers are addressing these limitations in a larger, phase 2 trial with a 48-week follow-up period and additional outcome measures. 

The use of autologous P63+ cells represents a novel and stepping stone for COPD therapy. Clinicians managing COPD patients should stay tuned for further developments in this promising area.

Published: April 15, 2024