Funding opportunities

Hematopoietic Stem Cell Transplants for Severe Combined Immune Deficiency and Systemic Sclerosis

Funding Type: 
Disease Team Research I
Grant Number: 
Funds requested: 
$19 676 665
Funding Recommendations: 
Not recommended
Grant approved: 
Public Abstract: 
Blood stem cells, which reside in the bone marrow (BM) can generate every type of blood and immune cell. They are the only cells necessary to re-establish blood formation if the BM is wiped out by disease or by treatments such as radiation or chemotherapy, as is the case for people who undergo a BM transplant. BM transplants have been performed for >50 years as life-saving procedures for many illnesses. However, patients do not receive pure blood stem cells, and the procedure is considered high risk mainly because BM cells received from a donor contain a combination of blood stem cells plus other mature immune cells. These mature cells pose a conundrum to physicians because on the one hand, the donor’s mature cells can be beneficial to the patient by assisting blood stem cells to take root and grow in the recipient as well as potentially helping battle tumors in cancer patients. However on the other hand, these mature donor cells can attack the recipient’s tissues, perceiving them as foreign and causing a syndrome called graft-versus-host disease (GVHD). Unfortunately, 10-20% of patients that undergo a transplant die from the consequences of GVHD. In the last decade technologies were developed to purify blood stem cells eliminating mature immune cells, thereby eliminating the danger of GVHD. However, transplant physicians remained hesitant to use such grafts because of concerns that purified stem cells without the accompanying immune cells would not take and grow in the recipient. Members of this team have therefore worked out new ways in mice that may be used on patients so that they will accept purified blood stem cell grafts without significant side effects. The reagents we will develop belong to a class of proteins called antibodies. The specialized antibodies we will use are biologic tools that allow us to both purify human stem cells, and eliminate blood stem cells in the recipient thereby clearing the BM for donor cells. We plan to adapt the technologies that have worked successfully in mice to treat two different disorders for whom BM transplant can be curative, but if performed by conventional methods is very high risk and can be fatal for the patient. The disorders we aim to cure by this approach are the childhood disease called severe combined immune deficiency (SCID), and the other is an autoimmune disease called systemic sclerosis (SSc). Children born with SCID lack immune cells to fight infections and without treatment die within the first year of life. Patients with severe forms of SSc experience thickening and tightening of the skin, lung and gastrointestinal problems which ultimately results in death after several years of suffering. We intend for these studies to result in superior treatments for these diseases. Since blood stem cell transplants have the capability of curing many other childhood and autoimmune disease, the ultimate impact of our studies will potentially be on a much broader spectrum of diseases.
Statement of Benefit to California: 
In 2004 California citizens passed a historic proposition supporting research that could result in the use of stem cells to cure many diseases. As a result, public and private institutions in California have emerged as leaders in this field, and scientists are now well on the path to producing tissues from primitive embryonic stem cells (ESCs). As scientists learn to direct these cells to become the tissues needed to replace damaged or failing ones, the obstacle of a patient rejecting these new tissues is a problem that must be overcome. The studies proposed by this Team address this issue. Tissues or organs are rejected because they come from donors who are genetically different. Similarly, tissues derived from ESCs will be genetically different from patients who need these tissues and therefore at risk for rejection. In order to prevent tissue rejection, patients that undergo transplants of organs (i.e, heart, kidney, lung) must remain life-long on medications to suppress their white blood cells from rejecting the grafts. There is one group of transplant patients that are routinely taken off their immune suppressive drugs -- bone marrow transplant (BMT) patients. These patients undergo BMT to cure them of severe cancers or inherited blood diseases. However, they can be liberated from their immune suppressive drugs because donor blood forming stem cells that take root in their bodies make the white blood cells that decide which tissues are identified as “foreign” or “self”. New white blood cells re-educate the recipient’s immune system to accept donor tissues as self. Thus, a state of harmony called immune tolerance is achieved so that donor blood is made without difficulty, and, in theory, the recipient can accept transplanted organs from the marrow donor without need for immune suppression. A similar strategy can be adapted to induce immune tolerance to tissues derived from ESCs. Remarkably, BMT also has the capability to cure autoimmune diseases such as multiple sclerosis, juvenile diabetes and many others. The major obstacle to use BMT beyond the treatment cancers has been the dangers associated with the procedure. This Team will take a crucial step to make BMT safer by transplanting only purified blood stem cells. The benefits of these potential advancements to our state are many. First and foremost is the health and well-being of all Californians who face the many diseases treatable by BMT. In addition, it is a simple fact that with every major scientific advancement come immediate economic benefits to the region that generated those advancements. These benefits can manifest in the form of academic donations from sources around the world, service industries that support the medical establishments that practice the procedures, and hi tech companies who receive their funding globally. This activity can all result in greater investment in California and continued job creation that has made California such a desirable place to live.
Review Summary: 
The primary objective of this proposal is to develop a strategy that will enhance the outcome of allogeneic hematopoietic stem cell (HSC) engraftment for the treatment of severe combined immunodeficiency (SCID) and systemic sclerosis (SSc), a severe autoimmune disease. To accomplish this goal, the applicant proposes to develop clinical grade monoclonal antibodies for two purposes. First, certain antibodies will be used to purify the donor HSC population from mobilized peripheral blood, thereby reducing the risk of graft versus host disease (GvHD). Second, an antibody that targets HSC will be used to open niche space in the recipient, thereby improving stable donor HSC engraftment. In conjunction with additional conditioning regimens that are already in clinical use, the approach will be tested in mouse models of SCID and SSc and will be complemented by pharmacokinetic and toxicity studies in large animal models. Additional proposed activities include the optimization of regimens currently used to enhance HSC engraftment, optimization of a newborn SCID screening assay to identify SCID patients soon after birth when treatment with HSC would be optimal, and development of a customized proteomic microarray for identifying new autoantigens in SSc patients. These studies will provide the rationale for the proposed treatment plan for patients with SCID and SSc in future years. Overall, reviewers were not enthusiastic about this proposal. Although supported by an excellent team, they found the proposal to be unfocused, as it targets two rather different disease indications, it includes several projects irrelevant to achieving regulatory filings, and it lacks novelty. The project’s one innovative aspect, the development of less toxic conditioning regimens based on recipient HSC ablation, was supported by some convincing data in mouse models, but the most relevant mouse model has yet to be tested. Based on these deficiencies, reviewers were unable to recommend this application for funding. Reviewers agreed that there are definite unmet medical needs in the treatment of SCID and SSc and the significance of this proposal lies in providing alternatives and developing less toxic therapies of greater efficacy. The current treatment, allogeneic HSC transplantation, is associated with high risk of morbidity and mortality, and if one of the conditioning modalities proposed will be found to be effective and without marked toxicity, reviewers felt it could advance the current clinical outcome in SCID, but the potential advantage for SSc patients is highly speculative at this stage. The allogeneic stem cell transplantation experience for SSc treatment remains essentially anecdotal at this time with added complexity due to similarities between GvHD and SSc. Potential broader significance for this proposal derives from the applicant’s claim that success in developing non-morbid regimens to achieve stable HSC engraftment will be applicable to the treatment of other diseases that can benefit from bone marrow transplantation. Some reviewers agreed with this view, but others argued that specific diseases require specific tailor-made therapies, and although the results of this project will be of great interest, they will not be immediately applicable to other much more common diseases. The rationale for using the anti-HSC antibody to provide less-intense conditioning is logical given that it targets a receptor known to be crucial in maintaining hematopoiesis. Reviewers judged this aspect of the proposal to be innovative, but they perceived a lack of novelty regarding the remainder of the therapeutic strategy. For instance, fast cell sorting of human HSC is already extensively and successfully used in clinical bone marrow transplants, and thus a major effort in this area is not justified, although some reviewers noted that the proposed HSC purification strategy has the potential to address problems associated with subclinical GvHD. Further, reviewers would have appreciated an explanation why the use of some of the proposed combinations of already existing treatments had not already been achieved in the clinic, and pointed out that much of what is being proposed has already been under investigation for several decades. Reviewers strongly criticized the proposal’s lack of focus, the applicant pursues two separate disease targets that are only connected by the fact that they are both potentially curable by allogeneic HSC transplantation, but otherwise share little in terms of rationale and approach. Reviewers supported the rationale for targeting SCID with the proposed strategies, but judged the SSc portion of the proposal to be extraneous. Furthermore, several components of the proposal, such as SCID screening assays and SSc autoantigen discovery are valuable ideas in themselves but do not impact on a successful investigational new drug (IND) application. Thus, the overall plan was judged to be quite diffuse. With regard to clinical competitiveness, reviewers pointed out that gene therapy using autologous HSCs could become the standard of care for immune deficiencies such as SCID while this project would be underway. Similarly, the field of SSc therapeutics is presently extremely active, and other interventions under current investigation enjoy a robust supportive scientific platform. The mouse models developed and validated over many years both in terms of normal HSC transplantation and in multiple immunodeficient mutant mice, were generally considered a strength of this proposal. Reviewers lauded solid preliminary data using these models, suggesting that a low dose of HSCs administered over an extended period of time may be superior to a single bolus injection. Similarly, the effectiveness of antibody-mediated recipient HSC ablation in improving donor HSC engraftment is supported by convincing data on mouse and human HSC in relevant mouse models, although the approach would have been strengthened with a plan for evaluating immune recovery and not just engraftment. One reviewer raised questions about the validity of the proposed mouse models, since they exhibit low levels of T cells, B cells, and natural killer cells and do not mimic the SCID patients who harbor non-functional B cells. The applicant proposes to interrogate this clinical paradigm in two additional mouse models in the first two years of the proposed study. However, in one of these models, the barrier to engraftment is likely mediated by natural killer cells and thus it was unclear how the recipient HSC ablation would help overcome immune barriers. The reviewers thought that the other proposed model is more appropriate as it is suited to address the pathophysiology observed in many human SCID patients. However, if these proposed studies prove unsuccessful, the entire rationale for developing the anti-HSC strategy for use in SCID will be questionable. Similar questions arose with regard to the preclinical data for SSc applications. Without more substantial mouse data from relevant models in the context of relevant treatment modalities, reviewers were unsure whether an IND application could be filed within four years. However, if studies are successful in such models, the timelines for the generation of proposed antibodies were considered reasonable. Overall, the developmental component of the proposal is likely feasible and sufficiently mature, as many aspects of the plan are either in practice today or have been developed previously. Since allogeneic HSC transplant studies have been attempted in both SCID and SSc patients, there is a large database of medical knowledge to build upon in order to develop appropriate clinical trial designs. The plan to develop the antibody reagents is clearly set out and the steps have been well defined including design of large animal pharmacokinetic studies by a contract research organization, followed by purification schemes and process development. The principal investigator (PI) recognizes multiple interactions with the FDA will be needed to get both the purified HSCs and the conditioning anti-HSC antibody ready for use in clinical studies. However, the reviewers questioned the need for the development of Good Manufacturing Practice (GMP)-grade antibodies for HSC purification and suggested that the PI should discuss with the relevant commercial provider the possibility of obtaining their existing GMP–grade antibodies, saving substantial time and cost. Similarly, obtaining a license or other agreement for the conditioning antibody would be a more straightforward approach and lower risk than novel development routes. Although tangential to the goal of filing an IND, the developmental plan aimed at establishing newborn screening to identify SCID in California or defining the custom array of SSc-relevant antigens is well designed. A reviewer pointed out that it seems premature to develop a Californian state wide screening program prior to the results becoming available from two other states that have already established pilot screening programs. Milestones were judged to be achievable but the timeframe may be very tight. The milestones are meaningful but lacked specific criteria that would be used to identify optimal approaches. For example, reviewers were unclear how the relative effectiveness of various treatments in the mouse models would be judged and what endpoints will be considered meaningful in the large animal studies. The PI has extensive knowledge of HSC cell biology and transplantation, and is highly qualified to lead the proposed program. This leadership is proven in terms of track record and ability to deliver meaningful outcomes to patients. The two co-PIs offer crucial support and complementary strengths, and the whole leadership team is most suitable to direct the preclinical studies proposed. In addition, a large team of experienced investigators has been carefully assembled. Given the track record of working together it would seem that the team will be able to work efficiently towards its goals. Reasonable attention has been paid to conflict resolution and structuring of communications to ensure productivity and focus, and the composition of the external advisory board is impressive, involving many of the leaders of HSC transplantation in the United States. Reviewers felt that the proposed budget is excessive, justification is often lacking sufficient detail for evaluation, the necessity for certain equipment and consulting input was questioned, and duplicating efforts were noted. The collaborators, resources, and environment are exceptional and capable of supporting the proposed work. The proposed collaborations are essential to completing the projects; they are well secured via letters of intent, and there is no doubt regarding the commitment to this project by the two involved academic institutions and the considerable depth of resources available at each campus. The time allocations are appropriate for each of the team members and in particular the leadership. In conclusion, although supportive of the assembled team, the reviewers did not recommend this application for funding since they judged it to be unfocused and felt that it lacked novelty.
  • Andrew Balber
  • Rainer Storb

© 2013 California Institute for Regenerative Medicine