In the Journals

Stem cell therapy safe, feasible in congenital heart defect surgery

Timothy J. Nelson

Intramyocardial injection of autologous umbilical cord blood-derived mononuclear cells into the right ventricular myocardium has shown to be both safe and feasible in pediatric patients undergoing stage II reconstruction for hypoplastic left heart syndrome, according to data from an open-label, prospective, nonrandomized phase 1 clinical trial published in The Journal of Thoracic and Cardiovascular Surgery.

This was a first-in-children study designed to evaluate the safety and feasibility of stem cells delivered directly into the myocardium during the second of three palliative operations to correct the congenital heart defect that causes hypoplastic left heart syndrome.

“Pediatric infant hearts are completely different from adult hearts. Specifically, they can grow and repair at a younger age,” Timothy Nelson, MD, PhD, associate professor of medicine and pharmacology and director of the Todd and Karen Wanek Program for Hypoplastic Left Heart Syndrome at Mayo Clinic, told Cell Therapy Next.

Benefits of cell therapy

Nelson is one of the study’s coauthors, and he explained the anticipated therapeutic benefit of autologous cord blood-derived stem cells in the setting of pediatric congenital heart disease surgery.

“We know that the cells we are injecting from cord blood do not contribute to new heart muscle, so the cells we put in are really a fertilizer. What we have learned is that in a 3-month-old infant’s heart, they are able to have a different effect than in adult hearts,” he said.

Nelson said preclinical studies showed that the 3-month-old human heart maintains its proliferative capacity when these reconstructive surgeries are performed.

“In other words, the cells of the heart muscle are designed to grow and proliferate, and the stem cells we are putting in manufactured from the patient’s own cord blood are causing those heart muscle cells to proliferate, grow and divide to become a stronger heart.”

The narrative is consistent with the cardiac imaging data the researchers have collected in the first 10 patients they treated, Nelson said.

Initial results

The study included 10 patients (aged 4.9 ± 1.4 years, 80% boys, 100% white) who underwent the stage II Fontan procedure for hypoplastic left heart syndrome between October 2013 and January 2018 at one of five participating institutions. Each patient received intramyocardial injections (median 0.6 mL, range 0.5-0.7) of umbilical cord-blood derived mononuclear cells immediately after completion of the surgery before closing the chest.

Nelson said the cells are a minimally processed product with a manufacturing time of about 3 hours to 4 hours from the time they are collected.

“We can usually collect enough cells from a cord blood unit at the time of birth to have sufficient quantity of the product to use for this procedure,” he said.

All patients underwent a successful stage II reconstructive procedure and intramyocardial injection of stem cells, with no operative mortalities. One treatment-related adverse event included injection site bleeding that required a simple oversew.

There was one post-operative mortality that occurred at the 3-month mark but was not considered to be cell therapy-related.

No patient showed evidence of arrythmia, hemodynamic instability or myocardial ischemia after cell therapy injections. None of the trial’s 27 adverse events were considered related to cell therapy or its injection.

The investigators acknowledged the study was limited by its small size and patient population with mostly normal cardiac function. Further, the study was not designed to evaluate the efficacy of intramyocardial umbilical cord-blood derived mononuclear cell treatment.

Continued research

“We are continuing the phase 1 study as an extension study, so to date we have actually treated 23 patients,” Nelson said. His group will continue collecting safety data on these patients and plans to publish these data in a follow-up paper.

Nelson and colleagues have launched a phase 2b study that has so far treated five patients.

“The phase 2 study is designed to look at clinical efficacy end points in a larger cohort that is better controlled, now that the safety and feasilbity have been established,” he told Cell Therapy Next.

Ronald K. Woods
Ronald K. Woods

This study demonstrated both safety and feasibility of stem cell injections during the Fontan procedure, despite the small sample size, according to Ronald K. Woods, MD, PhD, associate professor of surgery in the division of cardiothoracic surgery at Medical College of Wisconsin. He said the data support moving the treatment into a phase 2 study in an accompanying editorial

“If we accept the premise that delivery of the right cell types in the right amount to young infant myocardium will provide durable and clinically meaningful benefit, then this work is important,” Woods wrote.

Yet, how much benefit therapies like this convey to pediatric myocardial growth must be balanced against “what we are willing to pay for these improvements,” Woods observed.

“As this and similar such trials progress, we, as a clinical specialty, and society at large should be prepared for the challenge of defining the success or value of such therapies,” he wrote.

‘The marvel of where we are’

The main takeaway from this phase 1 study may be that intramyocardial stem cell injections during the Fontan procedure are safe and feasible, but the real story for Nelson is the success behind the machinery that made the study possible for a patient population that only amounts to approximately 1,000 infants born annually.

“It took a consortium; it took a philanthropy like the Wanek Family Foundation. It took a unique team that was built from the ground up to be able to execute these types of studies,” he told Cell Therapy Next.

“The marvel of where we are at is really the collaboration, the partnership, and the multi-institutional cooperation focused on a rare disease like congenital heart disease that would otherwise find it difficult to receive corporate investment. This study represents that all of that is feasible, and with that feasibility behind us, we now have a whole series of clinical trials and possibilities that, working together, we can now accelerate behind a rare orphan disease like congenital heart disease.” – by Drew Amorosi

For more information:

Timothy Nelson, MD, PhD, can be reached at Nelson.Timothy@mayo.edu.

Disclosures: Nelson and his institution (Mayo Clinic) report financial interests in ReGen Theranostics. The other authors report no relevant financial disclosures.

Timothy J. Nelson

Intramyocardial injection of autologous umbilical cord blood-derived mononuclear cells into the right ventricular myocardium has shown to be both safe and feasible in pediatric patients undergoing stage II reconstruction for hypoplastic left heart syndrome, according to data from an open-label, prospective, nonrandomized phase 1 clinical trial published in The Journal of Thoracic and Cardiovascular Surgery.

This was a first-in-children study designed to evaluate the safety and feasibility of stem cells delivered directly into the myocardium during the second of three palliative operations to correct the congenital heart defect that causes hypoplastic left heart syndrome.

“Pediatric infant hearts are completely different from adult hearts. Specifically, they can grow and repair at a younger age,” Timothy Nelson, MD, PhD, associate professor of medicine and pharmacology and director of the Todd and Karen Wanek Program for Hypoplastic Left Heart Syndrome at Mayo Clinic, told Cell Therapy Next.

Benefits of cell therapy

Nelson is one of the study’s coauthors, and he explained the anticipated therapeutic benefit of autologous cord blood-derived stem cells in the setting of pediatric congenital heart disease surgery.

“We know that the cells we are injecting from cord blood do not contribute to new heart muscle, so the cells we put in are really a fertilizer. What we have learned is that in a 3-month-old infant’s heart, they are able to have a different effect than in adult hearts,” he said.

Nelson said preclinical studies showed that the 3-month-old human heart maintains its proliferative capacity when these reconstructive surgeries are performed.

“In other words, the cells of the heart muscle are designed to grow and proliferate, and the stem cells we are putting in manufactured from the patient’s own cord blood are causing those heart muscle cells to proliferate, grow and divide to become a stronger heart.”

The narrative is consistent with the cardiac imaging data the researchers have collected in the first 10 patients they treated, Nelson said.

Initial results

The study included 10 patients (aged 4.9 ± 1.4 years, 80% boys, 100% white) who underwent the stage II Fontan procedure for hypoplastic left heart syndrome between October 2013 and January 2018 at one of five participating institutions. Each patient received intramyocardial injections (median 0.6 mL, range 0.5-0.7) of umbilical cord-blood derived mononuclear cells immediately after completion of the surgery before closing the chest.

Nelson said the cells are a minimally processed product with a manufacturing time of about 3 hours to 4 hours from the time they are collected.

“We can usually collect enough cells from a cord blood unit at the time of birth to have sufficient quantity of the product to use for this procedure,” he said.

All patients underwent a successful stage II reconstructive procedure and intramyocardial injection of stem cells, with no operative mortalities. One treatment-related adverse event included injection site bleeding that required a simple oversew.

There was one post-operative mortality that occurred at the 3-month mark but was not considered to be cell therapy-related.

No patient showed evidence of arrythmia, hemodynamic instability or myocardial ischemia after cell therapy injections. None of the trial’s 27 adverse events were considered related to cell therapy or its injection.

The investigators acknowledged the study was limited by its small size and patient population with mostly normal cardiac function. Further, the study was not designed to evaluate the efficacy of intramyocardial umbilical cord-blood derived mononuclear cell treatment.

Continued research

“We are continuing the phase 1 study as an extension study, so to date we have actually treated 23 patients,” Nelson said. His group will continue collecting safety data on these patients and plans to publish these data in a follow-up paper.

Nelson and colleagues have launched a phase 2b study that has so far treated five patients.

“The phase 2 study is designed to look at clinical efficacy end points in a larger cohort that is better controlled, now that the safety and feasilbity have been established,” he told Cell Therapy Next.

Ronald K. Woods
Ronald K. Woods

This study demonstrated both safety and feasibility of stem cell injections during the Fontan procedure, despite the small sample size, according to Ronald K. Woods, MD, PhD, associate professor of surgery in the division of cardiothoracic surgery at Medical College of Wisconsin. He said the data support moving the treatment into a phase 2 study in an accompanying editorial

“If we accept the premise that delivery of the right cell types in the right amount to young infant myocardium will provide durable and clinically meaningful benefit, then this work is important,” Woods wrote.

Yet, how much benefit therapies like this convey to pediatric myocardial growth must be balanced against “what we are willing to pay for these improvements,” Woods observed.

“As this and similar such trials progress, we, as a clinical specialty, and society at large should be prepared for the challenge of defining the success or value of such therapies,” he wrote.

‘The marvel of where we are’

The main takeaway from this phase 1 study may be that intramyocardial stem cell injections during the Fontan procedure are safe and feasible, but the real story for Nelson is the success behind the machinery that made the study possible for a patient population that only amounts to approximately 1,000 infants born annually.

“It took a consortium; it took a philanthropy like the Wanek Family Foundation. It took a unique team that was built from the ground up to be able to execute these types of studies,” he told Cell Therapy Next.

“The marvel of where we are at is really the collaboration, the partnership, and the multi-institutional cooperation focused on a rare disease like congenital heart disease that would otherwise find it difficult to receive corporate investment. This study represents that all of that is feasible, and with that feasibility behind us, we now have a whole series of clinical trials and possibilities that, working together, we can now accelerate behind a rare orphan disease like congenital heart disease.” – by Drew Amorosi

For more information:

Timothy Nelson, MD, PhD, can be reached at Nelson.Timothy@mayo.edu.

Disclosures: Nelson and his institution (Mayo Clinic) report financial interests in ReGen Theranostics. The other authors report no relevant financial disclosures.