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CIRM MAJOR FACILITIES GRANT APPLICATION #FA1-00603-1

Recommendation: Not recommended for further consideration
Element X Score: N/A
Element Y Score: N/A
Element Z Score: —
Use & Contribution Score:—

Public Abstract (provided by applicant)

Children born with sickle cell anemia and thalassemia, caused by defects in genes that make hemoglobin, may have severe anemia as well damage to virtually all the body organs: the damage begins in infancy, and is frequently fatal by early adulthood. These are the most common inherited diseases in the world: because of California’s ethnic diversity they are relatively common here, particularly in underserved populations. Our research program is dedicated to the treatment and, when possible, cure of these devastating diseases. We and others have shown that transplantation of blood stem cells from bone marrow can cure sickle cell anemia and thalassemia, and this type of stem cell therapy also has promise for treating other blood and genetic diseases. Unfortunately, not all individuals are cured after bone marrow transplantation, as this is a risky treatment. We have carried out pioneering work showing that blood from the umbilical cord (“cord blood”) of a newborn sibling can be used to cure blood disease in the affected sibling. As part of this work, we developed a program in which cord blood from newborn siblings of children with blood disease or cancer is collected and stored for later use, and large numbers of children have been cured using cord blood from this program. A significant part of our effort is devoted to discovering ways to improve and extend the use of cord blood for blood cell transplantation and make this treatment less risky. Most recently, we have found that the placenta itself is a rich source of blood stem cells, and possibly also of stem cells for tissues other than blood. We have developed a program of clinical research that is closely associated and integrated with lab research that supports investigations into ways to improve stem cell transplantation and make it available to more people. We now propose to use support from CIRM to develop a laboratory facility that will provide space for clinical and preclinical research dedicated to the improvement of blood stem cell transplantation using cord blood and placental stem cells. This facility will be used to collect, process, and freeze cord blood, and to release it for transplantation as part of the clinical research discussed above. We will explore new methods to increase yields of cord blood stem cells after collection, so that cord blood transplantation can be made available to a broader population of recipients. We will also use the facility to investigate and develop the use of placentally derived blood stem cells in transplantation, which may in the next few years result in the extension of this type of therapy to many more individuals who currently need it but do not have suitable stem cells available. This facility will thus improve and extend the use of blood stem cell transplantation for genetic diseases in California, and contribute significantly to CIRM’s goal of providing new cures for human disease.

Statement of Benefit to California (provided by applicant)

The inherited blood diseases sickle cell anemia and thalassemia afflict significant number of individuals in California, particularly in underserved populations; both require expensive treatment during the life of the patient, and cause severe tissue damage that degrades quality of life and is often fatal. Individuals afflicted with these diseases can be cured by transplantation of blood stem cells. Nevertheless the application of this treatment is limited because the supply of donated bone marrow stem cells is limited, and because it is necessary to match certain characteristics of the donor’s and host’s immune systems. We have carried out pioneering studies demonstrating that umbilical cord blood can be used as a source of cells to cure these genetic diseases, and in some respects is superior to blood stem cells derived from bone marrow. As part of this program we have developed a program that collects, processes, stores, and distributes cord blood cells for use in transplantation. Most recently we have found that the placenta may be a source of much larger numbers of blood stem cells. We propose to develop a lab facility that will support the enlargement and extension of these investigations. We will use the facility to carry out research dedicated to the improvement of methods that use cord blood for blood stem cell transplantation, and to investigate the use of placental cells in place of cord blood. This facility will combine investigations of methods that directly support transplantation studies, and other investigations that may produce advances that will allow many more people to receive this curative therapy. In the course of this research, individuals with inherited blood diseases will receive transplants, and our extensive experience indicates these will be curative in the large majority of cases. The enhanced and extended lives of these individuals will represent a direct benefit; the savings to the health care system as a consequence of their cure is less direct but will benefit all California taxpayers. Ultimately the knowledge and experience produced by the work in the proposed facility will contribute to the goal of making blood stem cell transplantation available to a much broader group of patients, thus greatly extending the benefits to the affected individuals and to the taxpayers of California.

Review Report

Executive Summary

The applicants propose to build a new facility focused on clinical and preclinical research into the use of stem cells derived from umbilical cord blood and, eventually also placenta, to treat patients with inherited hemoglobinopathies. The investigators previously demonstrated that umbilical cord blood (UCB) transplantation from matched related siblings has a very high success rate in ameliorating the signs and symptoms of these diseases. They also established a prototype for a sibling cord blood bank which was used to demonstrate the efficacy of related cord blood transplantation in the setting. They now proposed to extend their prior experience by: 1) continuing clinical investigations through additional UCB transplantation studies for genetic diseases, 2) establishment of a new sibling cord blood and placental banking facility, 3) performing preclinical studies to investigate methods to overcome histocompatibility barriers and to facilitate engraftment after transplantation, and 4) developing processes to increase the yield of stem and progenitor cells harvested from cord blood and placental blood and to further characterize these cells in vitro.

Two core labs are proposed, one for clinical cryopreservation and the second for HLA laboratory services. Institutional collaborations with the chief of the department of hematology/oncology are proposed. Three collaborations with outside institutions are also proposed. Plans for growth include recruitment of additional clinical and basic investigators (up to 3) who would utilize this research space for their work and who would contribute to the ongoing development of applications for cord blood and placental stem cells. Specific details for these plans were not provided.

Reviewers noted that one of the investigators has been successful in creating a strong UCB transplant program, and there is every expectation that s/he will be able to continue that success rate in future clinical studies. The application did not have much additional information regarding the overall success of the other Principal Investigators (PIs) to be housed in the facility or in the rest of the institution, and therefore the track record and likelihood of success could not be assessed by reviewers. Reviewers felt there was minimal evidence for interdisciplinary collaboration in the application. In summary, reviewers felt the four programs are all reasonable, but they do not make a cohesive Z Element program, given that two of the proposed projects are preclinical efforts.

The clinical program was reviewed as only incrementally advancing the field and the sibling cord blood bank objective was felt to be met by the HRSA-mandated initiative. Reviewers felt that the two preclinical investigative programs were early stage and were not sufficiently detailed to convince reviewers that objectives could be met. Panelists queried whether plans were in place to expand the research into human embryonic stem cells (hESCs), and asked whether investigators had any previous CIRM funding. Reviewers responded that there was no evidence of current use or planned expansion into the use of hESCs. Placental cells were discussed, but it was felt that the program was not at a comparable level compared to the state-of- the art efforts of other investigative groups. Therefore, reviewers could not justify the dedication of a facility to this effort. In summary, reviewers felt these proposals would be more appropriate for individual translational or clinical research programs.

Detailed Summary

Element Z

Score: —

SCIENTIFIC PROGRAM: Four programs are described in the application. Two build upon existing clinical programs, and two are in newer areas of investigation in preclinical models. Reviewers in general felt that neither of the two existing clinical programs was innovative, nor would these programs advance the field of stem cell science. The first clinical program proposes to expand the patient population for the existing transplant program covering the use of sibling donor umbilical cord blood (UCB) for blood diseases (primarily sickle cell and thalassemia. One reviewer felt that compared to initiatives by the National Cancer Institute/National Heart Lung and Blood Institute (NCI/NHLBI), which also has a protocol for unrelated donors, proposed work was not perceived to advance the field. Reviewers felt that so much could be done in this area (e.g. non-related and reduced impact transplantation), and these were not considered in the proposal.

The second of the two clinical programs, expansion of the sibling cord blood collection and banking program, had the strength of re-establishing and expanding a program that had moved out-of-state to a commercial provider during the last few years, and might fill a need if the current provider chooses not to support the effort. At least one reviewer thought that this might be a realistic scenario. Reviewers noted that a sibling transfer bank is mandated by the Health Resources and Services Administration (HRSA) for infants born into families with a known disorder that can be treated. One reviewer stated that HRSA funding is “not great”, and acknowledged that locating the sibling cord blood bank in California could be a more stable alternative in the long run. However, reviewers noted that the applicant had failed to acknowledge the HRSA and the CW Bill Young Cell Transplantation Program, with which operational and scientific synergies could be achieved. Under this same clinical program, the applicant also proposes to develop a novel cord blood collection device which has been under development at the applicant institution for several years. Insufficient detail was presented as to planned studies with this device.

Reviewers were more enthusiastic about the concepts for the two preclinical investigative programs, but the scientific plans lacked detail and could not be judged with confidence that goals would be achieved. One reviewer noted that the program exploring a new method to decrease the immunogenicity of donor cells could overcome a barrier in haploidentical transplantation. Unfortunately, this initiative was not discussed in sufficient detail to convince the reviewers that the goals would be accomplished. The final investigative program, the isolation of hematopoietic stem cells (HSCs) from placental tissue, was felt to be the most innovative aspect of the proposal as it relates to stem cell research. Reviewers felt that both of these programs are better characterized as preclinical Element Y programs, rather than as Element Z programs as the proposal suggests.

FORMAL INSTITUTIONAL COLLABORATIONS: One of the major strengths of this application is that the applicant institute already has relationships with several of the key players in hematopoietic stem cell transplantation, such as the Center for International Blood and Marrow Transplantation Research (CIBMTR), an international organization which maintains a repository of product characterization and clinical outcomes data. One of the applicant PIs serves as co-chair of a CIBMTR working group, and thus is in a strong position to coordinate multi-center clinical trials in this disease setting. This same applicant PI heads a clinical center (one of 8 in the nation) for the treatment of hemoglobinopathies, and has led efforts to develop unrelated donor protocols through a collaboration between 13 transplant centers. This collaborative group conducts clinical studies to address key questions in transplantation; thus, the applicant program already has access to several clinical networks to facilitate the large-scale clinical trials that will be necessary to carefully evaluate the use of human umbilical cord blood-derived stem cells (and in the future placental stem cells) for the treatment of rare hemoglobin disorders.

The cord blood banking effort is supported by several collaborations. The applicant institution has an ongoing formal collaboration with a for-profit cord blood banking program. The plan is to continue working with the for-profit collaborator, but the cell therapy program will be based in the new facility at the applicant institution. Research collaborations exist with two nearby universities, and the applicant institution has formalized relationships with those institutions. However, the exact benefit of those relationships to the overall applicant program was not clear in the application.

The lack of more clearly defined collaborations with stronger stem cell programs is one weakness of this proposal. Such collaborations would be extremely beneficial to a careful evaluation of the newly-described stem and progenitor cells, especially in terms of accurately assessing engraftment and differentiation potential in a variety of preclinical models. Also helpful would be industry partnerships for the development and possible marketing of the necessary devices for this treatment modality.

Finally, it would have been helpful to describe the exact relationship with a particular corporate collaborator on one of the main preclinical aspects of this application. Similarly, the collaboration with another corporate partner on the development of specific cell surface marker antibodies should have been described.

CORE SERVICES: Two core laboratories are proposed, a clinical cryopreservation laboratory and the HLA laboratory. The core clinical cryopreservation laboratory is currently located at another site and will be moved to the proposed facility. The GLP/GMP cryopreservation laboratory has expertise in processing, cryopreserving, and thawing of umbilical cord blood for clinical use. It also has electronic database management, and is approved by the Foundation for the Accreditation of Cellular Therapy (FACT). It is not clear whether the HLA laboratory would also be housed in the proposed facility. The core facilities available through the proposed program will provide state-of-the-art, standard support for the clinical transplantation effort, and also for a transplantation program at a nearby affiliated hospital. The applicant institution will provide umbilical cord blood stem cells for research to outside collaborators housed at two nearby universities.

The operational plans for the collection, storage, and distribution of cells collected for California families were not clear. It is possible that these activities will occur through a storage collaborator located out-of-state. However, if the banking will take place in the CIRM facility, it would have been helpful if the applicant had addressed the recent FDA guidelines regarding the requirements for licensure and GMP approval of these public banks.

An affiliated local hospital was viewed as a strength to support the clinical transplantation program at the applicant institution. These core support services are already part of an existing facility with a proven track record of support.

On a final note, no discussion was provided in the application regarding intellectual property or technology transfer.

PLANS FOR GROWTH: General plans for growth mention recruitment of additional faculty, up to 3 new investigators who will utilize space in the new CIRM facility at the applicant institution to conduct stem cell research. The focus of the program will be on preclinical and clinical applications of hematopoietic stem cell therapies using cells derived from cord blood, placenta, and bone marrow. Especially if placental-derived cells can be used, this is likely to drive significant growth because the applicants believe they can provide hematopoietic cell transplantation to many more effected individuals. Potential uses of cord blood in the treatment of autoimmune diseases, diabetes, neonatal hypoxic encephalopathy and necrotizing enterocolitis are mentioned but no specifics are discussed. In general, there is a lack of focus and vision for the use of the facility and expansion of research efforts overall.

DISCUSSION: Panelists queried whether plans were in place to expand the research into human embryonic stem cells (hESCs), and asked whether investigators had any previous CIRM funding. Reviewers responded that no evidence of current use or planned expansion into the use of hESCs was discussed in the application. Efforts focused on placental cells were discussed, but it was felt that this preclinical research work was not at the same state-of-the-art level compared to work done by others. The proposal is basically to develop a facility to enable cord blood transplantation and to conduct preclinical research to expand such transplantation capability and to house at least one of the proposed core services which is currently located at another site. Reviewers could not justify the dedication of CIRM facility funds to this effort, but thought the projects could be appropriate for a translational or clinical research award.

Use & Contribution

Score: —

This is a relatively small program, but these research projects represent the breadth of the current efforts at the applicant institution. The proposed preclinical projects were chosen specifically because of their high likelihood of rapid and successful translation into clinical trial evaluation. The CIRM facility will be in close proximity to the animal resource facility (one floor below), which will help facilitate the preclinical evaluation of candidate cord blood and other cell populations. One strength is the proven track record of one applicant PI to organize and carry out complex clinical trials. This guarantees that clinical applications and studies using cord blood stem cells will progress rapidly, and this proposed facility will help to ensure that growth of that program continues.

The proposed facility will allow for the development of a cryopreservation laboratory on site, additional research lab space, and room for recruitment of clinical and research faculty. This will allow the applicant institution to bring together the primary investigators involved in existing preclinical research and the clinical cord blood transplant program under one roof, and permit closer cooperation with greater synergy and efficiency. However, it is not possible to envision from the information presented this application how the space to be developed will allow for development of a focused research program. For example, the clinical trials proposed will require multi-institutional participation, yet no mention is made of statistical or operational support. There is no clear vision or strategic plan presented for the use of the facility in the present or growth phases of the program.

The following Working Group members had a conflict of interest with this application and were therefore recused from participating in review of, discussion of, and voting on the application:

• Feit, Marcy