Funding opportunities

Funding Type: 
Disease Team Research I
Grant Number: 
Principle Investigator: 
Funds requested: 
$19 999 996
Funding Recommendations: 
Not recommended
Grant approved: 
Public Abstract: 
Acute myeloid leukemia (AML) is a cancer of the blood and bone marrow that is rapidly fatal within months if untreated. Even with aggressive treatment, including chemotherapy and bone marrow transplantation, five-year overall survival rates range between 30-40%. Evidence indicates that not all cells in this cancer are the same, and that there is a rare population of leukemia stem cells (LSC) that are responsible for maintaining the disease. Thus, in order to cure this cancer, all LSC must be eliminated, while at the same time sparing the normal blood forming stem cells in the bone marrow. We propose to develop therapeutic antibodies directed against surface markers present in much larger amounts on LSC than on the surface of normal blood forming stem cells. We recently identified and validated several such protein markers including CD47, which we determined contributes to leukemia development by blocking the ingestion and removal of leukemia cells by immune system cells called macrophages. In this way, CD47 acts as a “don’t eat me” signal on LSC. Moreover, we determined that monoclonal antibodies (mAbs) directed against CD47, able to block its interaction with macrophages, mask the “don’t eat me” signal resulting in ingestion and elimination of leukemia in mouse pre-clinical models. We propose a combination of clinical studies, basic research, and pre-clinical development to prepare a therapeutic antibody directed against CD47 and/or other LSC-specific proteins for Initial New Drug (IND) filing with the FDA, and then a Phase I clinical trial to be conducted at {REDACTED} and in the Collaborative Funding Partner country. In collaboration with the pioneering Collaborative Funding Partner country AML Working Group, we will track expression of the LSC proteins in patient samples and correlate with clinical outcomes. This will allow us to identify particular LSC proteins that must be targeted to achieve cure, thereby prioritizing candidate therapeutic antibodies for clinical development. Concurrently, we will conduct basic research and pre-clinical development to prepare these candidates. Basic research during years 1 and 2 will focus on the characterization of anti-CD47 mAb efficacy, investigation of mAb targeting of additional LSC molecules, and determination of efficacy in combinations with anti-CD47. Pre-clinical development during years 1 and 2 will focus on blocking anti-CD47 mAbs, including antibody humanization and large animal model pharmacologic and toxicity studies. Similar studies will be conducted with the most promising antibodies resulting from our basic research. During years 3-4, we will proceed with GMP grade production of the best candidate, followed by efficacy testing in mouse models and large animal models. Finally, in year 4, we will prepare an IND filing with the FDA/MHRA and develop a Phase I clinical trial with this antibody for the treatment of AML. Ultimately, therapeutic antibodies specifically targeting AML LSC offer the possibility of less toxicity with the potential for cure.
Statement of Benefit to California: 
Acute myeloid leukemia (AML) is an aggressive malignancy of the bone marrow with nearly 13,000 new diagnoses annually in the US and 2,200 in the Collaborative Funding Partner country. Current standard of care for medically fit patients consists of several cycles of high dose chemotherapy, and often includes allogeneic hematopoietic cell transplantation. Even with these aggressive treatments, which cause significant morbidity and mortality, relapse is common and the five-year overall survival is 30-40%, but
Review Summary: 
This proposal is focused on the development of a novel treatment for acute myeloid leukemia (AML). This treatment is based on a therapeutic monoclonal antibody that targets a cell surface molecule, CD47, preferentially expressed on leukemia stem cells (LSCs). These cells are thought to drive leukemia growth and to display elevated resistance to conventional chemotherapeutic agents. Antibody binding to CD47 (or to additional cell surface molecules) is expected to facilitate macrophage phagocytosis and removal of LSCs. The applicant team will develop a humanized blocking anti-CD47 monoclonal antibody and test its efficacy in a mouse xenotransplantation model system. They will also identify other potential cell surface targets on AML LSCs and evaluate the therapeutic value of antibodies specific to these molecules. In later stages of the study, GMP-grade production of the most promising antibodies followed by efficacy and safety testing in appropriate in vivo models will precede preparation of IND filing. The proposed research is focused on a significant and unmet medical need, as AML is often a rapidly fatal disease with five-year survival rates between 30-40%. Reviewers acknowledged the need for the development and implementation of novel and improved therapeutic strategies. They also believed that the rationale of targeting LSCs was appropriate for AML, particularly since evidence for cancer stem cells in this disease is very strong and widely accepted. Additionally, monoclonal antibody therapies are currently demonstrating efficacy in treatment of a broad range of tumors. The major focus of the application is on developing potential candidate therapeutic antibodies specific for CD47. Reviewers noted that the applicant did not discuss within the scientific rationale that the central implication of a strategy targeting CD47 suggests that a major, if not the major, determinant of leukemic stem cell maintenance is a failure of innate immunity (macrophage phagocytosis). This is contrary to a very large body of work that suggests the failure in AML occurs predominantly in the acquired immune system, thereby providing a rationale for the well-established allogeneic hematopoietic stem cell (bone marrow) transplantation therapy and the graft versus leukemia effect. In addition, reviewers expressed serious concerns about this target. In particular, they felt that the preliminary data (much of which was recently published) raised considerable questions regarding the validation of CD47 as a compelling target for therapy. A key concern shared by the reviewers was that CD47 expression was shown to be only approximately two-fold higher on AML than normal hematopoietic stem cells (HSC), providing only a very small therapeutic window for targeting cancer cells specifically. In addition, there was little apparent difference in expression level between bulk AML cells and LSCs, again suggesting no ability to specifically target the cancer stem cells. Moreover, reviewers noted that CD47 is apparently expressed at significant levels on many normal tissues, and this could lead to adverse, secondary events or, minimally, interfere with antibody therapy by serving as a considerable antigen sink. Reviewers were encouraged by studies demonstrating that anti-human CD47 antibodies administered to mice engrafted with LSCs led to depletion of AML, but they were not confident that this xenotransplantion model would accurately predict therapeutic responses in human patients. Another significant reviewer concern about the project’s feasibility was related to the proposition that treatment with anti-CD47 antibodies will lead to eradication of AML cells via macrophage phagocytosis. This plan is dependent on patients having normal, robust macrophage activity, but reviewers considered this unlikely in patient populations with later stages of disease who likely have been exposed to prior chemotherapy. The applicant did not address this complication. Reviewers found the research and development plan to be logically organized but were of mixed opinions as to whether an IND was possible within the proposed time frame even for an anti-CD47 monoclonal antibody. Some reviewers felt that plans to define a critical antigenic LSC profile using serial patient samples to correlate with clinical outcomes was a particular strength of the proposal; others considered this component to be largely superfluous and not needed for the development of an IND application particularly given the sample numbers contemplated for analysis. Another concern was that the proposal lacked adequate discussion of potential pitfalls and alternate plans should substantial roadblocks be encountered, and problems noted in the previous development of other therapeutic antibodies were not discussed. Program milestones were viewed as meaningful and the timeline generally feasible. However, the critical decision for the entire project will be which particular anti-CD47 antibody (or other antibody) to produce for clinical development, and the absence of clearly stated criteria for this decision raised additional concerns about the project’s feasibility. Reviewers viewed the PI, a recognized leader who has made outstanding contributions to the fields of hematopoiesis research and stem cell biology, as a predominant strength of the proposal. The PI’s expertise, track record, and capacity to lead the project were strongly acknowledged. Reviewers had serious reservations about qualifications of the Co-PI, a recently appointed junior faculty member with no apparent experience directing large research projects. The Partner PI was recognized as an extremely strong clinical researcher with outstanding experience appropriate to the proposed project. The leadership plan was sufficiently well formulated to ensure coordinated activities across the team, to monitor progress, implement strategic decisions and to resolve any potential conflicts. The environment and available resources for the proposed studies were considered excellent. Reviewers also viewed the collaboration between the extraordinarily productive groups led by the PI and Partner PI, respectively, as one of the greatest strengths of the application. Collectively, the multidisciplinary research team assembled represents an appropriate mix of basic research, clinical and management skills to ensure successful completion of the project. Reviewers considered the equipment costs for PI and Co-PI to be excessive and felt that the extent and redundancy of equipment requests were unjustified. This application describes a project to develop therapeutic monoclonal antibodies targeted to LSCs to treat AML. Strengths of the proposal include the outstanding qualifications of the PI and Partner PI, the complementary and well-established collaboration, and the medical need of better treatments for AML. Weaknesses include serious concerns about the validity of the proposed therapeutic target and other issues with project feasibility. PROGRAMMATIC REVIEW A motion was made to move the proposal into Tier 1. Key strengths and weaknesses of the proposal were reviewed. Proponents considered the focus on cancer stem cells an important therapeutic advance. Opponents were concerned with the project’s feasibility, considered the approach to be an extremely high risk one, and asserted that other applications focused on leukemia have been rated highly. The motion failed. A subsequent motion to move the proposal down to tier 3 carried.
  • Ivar Mendez