Early Translational I
The aim of this proposal is to develop therapeutic monoclonal antibodies specific to the Chronic Myeloid Leukemia (CML) and Acute Myeloid Leukemia (AML) Cancer Stem Cells (CSC). Cancer stem cells arise from normal stem and progenitor cells though a number of gene mutations. CSCs are a small population of cells within the tumor that drives its growth. Most cells in the tumor are derived from the CSC but do not have growth potential. The CSCs are also responsible for the relapse after therapy. Since these cells are very resistant to current chemotherapies, treatment will only be successful if the CSC is directly targeted and eliminated. We have identified several highly specific cell surface targets to CSC which are not on the surface of normal cell types. Monoclonal antibodies will be generated that kill only cells expressing these targets. Due to the limited expression pattern, we believe therapeutic monoclonal antibodies developed to these targets would have less toxicity than current treatments and may offer a cure to these leukemias.
Statement of Benefit to California:
Myeloid leukemias are devastating diseases especially in the elderly who can not tolerate intensive chemotherapeutic treatments. Approximately 3000 cases of myeloid leukemia will be diagnosed in the state of California in 2008 according to National Cancer Institute estimates. With current therapies, the 5 year survival rate for acute myeloid leukemia is 21%. Survival of patients with advanced CML is only 20-40%. Improved cancer treatment would directly benefit the people of California. The aim of this research proposal is to develop therapeutic monoclonal antibodies specific to the acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) cancer stem cells (CSC). CSCs are a rare population of cells within the tumor that are responsible for its growth. CSCs are resistant to chemotherapies and responsible for the reoccurrence of disease following treatment. Monoclonal antibodies bind to and kill only cells expressing a specific target. Development of monoclonal antibodies that bind to and kill only cells expressing a specific target could provide a novel treatment to decrease the relapse and reoccurrence of the diseases.
In this development candidate grant proposal, the applicant proposes to generate therapeutic monoclonal antibodies to chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) cancer stem cells (CSCs). Current therapies are believed to not eliminate CSCs resulting in short remissions or resistant clones; hence, with the occasional exception of allogeneic transplantation, these current therapies are not curative. The applicant’s hypothesis contends that relapse after therapy is due to failure to eliminate the cancer stem cells that recapitulate the disease. Multiple potential antibody targets that are not expressed on normal HSC or other blood cell types have been identified based on broad gene expression array analyses in multiple patients. Hybridomas secreting monoclonal antibodies to some of the targets have been generated using enriched candidate CSC. The proposal focuses on defining those targets most suitable for therapeutic antibody development; generating and characterizing monoclonal antibodies to the best targets and selecting the best antibodies based in vitro and in vivo characterization; and initiating preclinical development studies with top candidates. . Approximately 3,000 new cases of AML occur in California per year, with a 20% five-year survival rate. Current front-line therapies likely do not target leukemic CSC. Hence there is an urgent need to develop new drugs to treat these leukemias. Despite the proposal’s potential impact on treatment of myeloid leukemias, reviewers were not convinced that the objectives of the study would be achieved. The applicant acknowledges qualified CSC specific antigens may be difficult to identify Candidate monoclonal antibodies that are differentially expressed on patient samples and normal hematopoietic cells have been identified. The applicant proposes to identify the target In order to generate additional antibodies for characterization. Reviewers considered the experimental approach to obtain target antigen to be problematic resulting in potential configurational changes in the antigen. Reviewers also expressed frustration that the specific cell lines that the applicant was proposing for target identification were not identified. The frequency of CSCs in these lines is likely low, and hence, the targets may not be readily identified. Reviewers considered the strategy to use gene signatures to identify candidate antigen targets for antibody generation as unlikely to be sufficiently selective. Where the target antigen has functional biology, reviewers felt there was not enough attention devoted to addressing the issue of antigen loss variants as the expression of the target antigen may not be critical for CSC survival. As acknowledged by the applicant, in some cases target antigens may not have critical biology and thus candidate antibodies may not have direct therapeutic responses and require “enhancement” such as effector function or coupling to a cytotoxic payload. Reviewers also considered the preliminary data to be limited. One reviewer criticized the data presented by the applicant on a few candidate CML antibodies as indicative of bulk population staining, not the rare subset that would be expected for CSCs. Another reviewer expressed disappointment over the lack of the gene expression profiling data. The applicant summarized the preliminary data in the context of general categories of target antigens (e.g. complement pathway, cytokine receptor). As noted by one reviewer, these categories do not suggest limited expression patterns, and insufficient attention is paid to antibody specificity and cross reaction with other tissues until late in the selection process. Finally, the proposal did not adequately address potential problems, pitfalls, or alternative strategies for their research approach. The primary applicant has worked in the stem cell field for some time and appears to be scientifically qualified for the project as s/he has a very good track record. Reviewers, however, openly expressed reservations over the primary applicant’s project management experience, a consideration given the significant role of consultants and outsourcing with the project. Although reviewers stated that the resources and environment were adequate, they noted that consultants and the outsourcing through subcontractors utilized a large portion (approximately two-thirds) of the project budget. In summary, the applicant proposes to develop candidate therapeutic monoclonal antibodies for CML and AML CSCs. Despite its laudable goal to attempt to treat these serious diseases, the proposal suffers from deficiencies, including too little attention to antibody specificity and the cross-reactivity with other tissues, a lack of preliminary data, a generic feel to the application, and the primary applicant’s project management inexperience.