June 01, 2019
Stem cells, with their unique potential to transdifferentiate into different tissues, have transformed the way researchers think about how the body repairs itself. The first use of cytotherapy dates back to the 1950s, when cells were utilized to treat hematologic malignancies. With initial successes, the paradigm of biologics-based therapies was expanded to include a spectrum of chronic diseases, culminating in the most recent example utilizing T cells engineered with chimeric antigen receptors (CAR-T) to treat refractory cancer.
The cardiac regeneration effort at Mayo Clinic began 20 years ago. This work has since culminated in clinical efforts spanning beyond adult cardiology to also include cardiac surgery, pediatrics and vascular medicine, with active efforts in heart failure, Ebstein's anomaly, hypoplastic left heart syndrome and refractory angina.
Cell therapy in practice
The discovery that stem cells derived from patients with heart failure had variable regenerative potency was a critical landmark. By identifying uniquely activated cues in regenerative subpopulations, cells from patients could be coaxed to adopt a highly regenerative state. Termed cardiopoietic stem cells, this specialized cellular population demonstrated a heightened aptitude toward cardiac repair.
To standardize the assessment of therapeutic potency in the heart, a cardiopoietic index was developed to allow objective assessment of the regenerative potential of patient-derived stem cells. Moreover, clinical-grade production of these cells at scale provided the capability to translate this platform from the bench to the bedside.
Following optimization of manufacturing algorithms for cardiopoietic stem cells, clinical trials (C-CURE and CHART-1) were executed in Europe using this platform developed at Mayo Clinic to test its safety and to obtain signals of efficacy. Indeed, this effort led to the largest published clinical trial to date using cells in patients with chronic heart failure of ischemic origin. These clinical experiences provided unique insight into patient populations who would most benefit from cell-based therapy and offered a blueprint for how stem cells should be delivered.
Dosing and delivery
Traditional small-molecule drugs have well-defined mechanisms of actions and processes of absorption, distribution, metabolism and excretion. The pharmacodynamics and pharmacokinetics that stand behind these actions are well understood. Case in point, oncologists have identified dose-response curves for the treatment of individual malignancies, as well as dose ceilings beyond which toxicity can be expected.
In contrast, biologics-based therapies display intricate and still poorly understood pharmacodynamics and pharmacokinetics, hampering proper dosing. As such, optimal cell dose and delivery frequency can be further refined.
The large cohort of patients treated in CHART-1 allowed post-hoc subgroup analysis to demonstrate a bell-shaped relationship between dose and effect. Results showed that when a minimum threshold dose was exceeded, fewer injections provided improved outcomes. The trial also revealed that despite robust measures to ensure cellular uniformity, interpatient variability remains the biggest hurdle to achieving uniform improvement following application.
Next-generation biologics
The cardiopoietic stem cell experience, along with other efforts within the Center for Regenerative Biotherapeutics by investigators in Cardiovascular Medicine, Cardiovascular Surgery, Pediatrics, Internal Medicine, Transplant, Radiology, Laboratory Medicine, and more broadly across the Mayo Clinic enterprise, has created a team with unique expertise in product development, manufacturing, quality assurance and FDA-regulated clinical trial execution. To this end, the new challenge in this field is to take an inherently variable autologous (from the patient) cell population and engineer new platforms that provide reliability in dosing, potency and efficacy.
With the emergence of automated bioreactor systems in manufacturing, synthetic messenger RNA platforms and increasing expertise in creating allogeneic (from the donor) master cell banks provide the opportunity to engineer allogeneic cell platforms devoid of the variability seen with their autologous counterparts. Beyond cell therapy, with increasing understanding of the mechanistic basis for regeneration in the heart, systems devoid of living cells are increasingly being considered.
Regenerative technologies devoid of cells would have the capability of activating repair-signaling pathways to mimic stem cell action in the heart. Since it is increasingly apparent that stem cell benefit is likely due to a paracrine mechanism of action, rather than direct integration, acellular approaches are of increasing interest. Implementation of a cell-free regenerative paradigm provides additional benefits, including:
- The ability to have clear dosing algorithms
- Assured homogeneity in function
- Elimination of logistical hurdles that often complicate cell-based therapeutic models
The evolution of biologics-based technologies, in tandem with the 21st Century Cures Act, has encouraged a more rapid advancement of regenerative platforms.
Mayo Clinic has built new readiness in this space with dedicated infrastructure to serve as a supply chain for regenerative technologies and address unmet patient need. The Mayo Clinic regenerative portfolio builds on the already robust cellular effort to now implement trials using extracellular vesicles and gene therapy, a next chapter in the evolving regenerative toolkit.
For more information
Center for Regenerative Biotherapeutics. Mayo Clinic.