Interim Summary Report
The National Heart, Lung, and Blood Institute convened a Working Group of investigators on August 5-6, 2004, in Bethesda, Maryland, to assess the current status of Phase I/II clinical studies of cell based therapies for cardiovascular disease; determine the gaps in knowledge and barriers that prevent the implementation of well designed, safe clinical studies and trials; identify the areas of opportunity for application of cell based therapies for cardiovascular disease; and facilitate the clinical implementation of cell based therapies for cardiovascular disease.
The Working Group consisted of 12 members with broad expertise in cell based therapies, including experts in stem cell biology, cardiovascular physiology, cardiology, clinical research, and regulatory issues. The Working Group began with short presentations by invited speakers summarizing clinical protocols, the types of cells utilized, results that have been generated, and recommendations for future preclinical and clinical studies. Speakers were asked to focus on issues related to opportunities for advancing the science, gaps in knowledge that need to be filled, and barriers to the implementation of cell therapy for cardiovascular disease. Speakers were derived from a broad spectrum of expertise that included US and international investigators.
In their deliberations, the Working Group summarized the information presented, discussed a number of issues related to cardiovascular cell therapy, and formulated specific implementable recommendations. Discussion by the Working Group covered a number of points including current clinical studies and trials, appropriate patient populations or disease states, choice of cell type and mode of delivery, efficacy of treatment, mechanism of benefit, and basic investigations to be pursued. In implementing cell therapies for cardiovascular disease, controversies exist over the specific cells to be utilized, cell dosages and fate, the impact of cell therapy on functional and electrical activity of the myocardium, and the means by which cell therapy improves myocardial function. From the reports of clinical trials conducted in Europe and elsewhere, it appears that cell-based therapy may benefit cardiovascular function. However, whether there will be substantial long-term benefits, particularly in blinded randomized trials, is unclear. There was consensus that acute myocardial infarction patients with ventricular dysfunction (low ejection fraction) and patients with chronic heart failure should be the 2 primary groups targeted for therapy, although it is likely that these conditions will require different therapeutic approaches.
Among the challenges identified to implementation of cardiovascular cell therapy are:
- the identity and characterization of optimal cell(s) for therapy
- appropriate modes of delivery
- fate of engrafted or transplanted cells
- lack of understanding of mechanisms of clinical benefit
- need for a wide array of technical expertise
- suitable animal models that reflect human disease conditions
- regulatory and safety barriers
- lack of commercial interest in early development of cell therapy
In considering how best to translate cardiovascular cell therapy into the clinical arena, the Working Group determined that cell therapy can be implemented more quickly and effectively through an integrated approach. Such an approach would include clinical investigators to conduct clinical trials; basic preclinical investigators to understand and delineate mechanisms, characterize cells and markers, and develop new methodologies, core labs to develop, prepare and sort various study cell types; and imaging specialists to measure efficacy and track the fate of cells in humans. Therefore, the primary recommendation of the Working Group is that the NHLBI establish a cardiovascular cell therapy research network, consisting of a clinical research network component (5-7 primary sites) with an integrated, complementary preclinical investigative component. The intent of the program is to establish a stable infrastructure to conduct safe, efficient cell therapeutic protocols grounded in and adapted by sound preclinical studies to improve outcomes for cardiovascular patients. The clinical research network would initiate short-term Phase I or II cell therapeutic protocols in specific patient populations to determine safety and efficacy. The basic science, preclinical component would comprise stem cell biologists and animal physiologists to conduct basic mechanistic studies, characterize and define cell populations, and analyze tissue that might become available. The overlay of this component is viewed as essential to translating basic science into the clinic, understanding clinical benefit, improving treatments, and developing new treatment strategies. Both components would work in concert so that results from clinical studies will be validated and investigated in the laboratory and basic preclinical studies will be readily translated into the clinical network. Critical resources for the network would include a data and coordinating center, animal and human imaging components, cell processing facilities associated with existing bone marrow transplantation centers, such as the established NHLBI facilities for Production Assistance for Cellular Therapies, and a component to deal with regulatory and safety issues. Key peer review of science and safety would be conducted independently but would be facilitated by standing committees, which might include both industrial and international representation. Through such an integrated and concerted effort, the tools, knowledge, and experience can be developed for the scientific and clinical community to translate cardiovascular cell therapy to practice.
The Working Group also considered that, in the long-term, the best cells for cardiovascular cell therapy are likely to be non-autologous cells, such as embryonic and mesenchymal stem cells. The barriers prohibiting immediate use of such cells are lack of knowledge concerning their immunogenicity, ideal conditions for their differentiation, and mechanisms for their introduction into damaged hearts. Therefore, it is recommended that the NHLBI consider support for basic research on the characterization, differentiation, and immunology of allogeneic stem cells.
The Co-chairs will develop a report of the meeting for publication in an appropriate professional cardiovascular journal. An Executive Summary of the meeting derived from this report will be published on the NHLBI website.
John Fakunding, Ph.D., NHLBI, NIH
Last updated: May 11, 2005