NHLBI Working Group
Translation of Cardiovascular Cell Based Therapies
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.
Discussion:
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.
Publication Plans:
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.
NHLBI Contact:
John Fakunding, Ph.D., NHLBI, NIH
FakundiJ@nhlbi.nih.gov
Last updated: May 11, 2005
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