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Targeting Glioblastoma Cancer Stem Cells Using a Novel Bispecific Antibody

Funding Type: 
Early Translational IV
Grant Number: 
TR4-06787
Funds requested: 
$5 399 676
Funding Recommendations: 
Not recommended
Grant approved: 
No
Public Abstract: 
Glioblastoma multiforme is the most prevalent and aggressive type of brain tumor. Our proposed research focuses on a new theory that brain tumor cells are initiated and maintained by a small fraction of cells with stem cell properties and if this small subset of cancer stem cells could be inactivated, the tumor would cease to grow. We reasoned that cancer-specific genetic alterations in a glioblastoma tumor could be a potential marker for cancer stem cells and zeroing in on these cells could result in targeted therapeutics. CD133 is a marker for normal neural and hematopoietic stem cells and EGFRvlll is a receptor that is genetically altered in glioblastoma tumors. We found that CD133 and the EGFRvIII are both tightly associated in glioblastoma tumors and tumor cells that express both CD133 and EGFRvIII grow more quickly. We have already developed a “bispecific” antibody that recognizes both of these markers and we have shown that this antibody selectively kills the cancer cells in glioblastoma tumors that express both CD133 and EGFRvIII, but not normal stem cells. When we injected glioblastoma cells pre-treated with BsAb into mice or used this to treat established brain tumors, tumor formation was severely inhibited. Our goal is to ready this antibody for the investigational new drug phase and to ultimately generate a human therapeutic effective against glioblastoma.
Statement of Benefit to California: 
As the most populous state in the U.S., more Californians are diagnosed with glioblastoma each year than any other state, with a consequent significant economic toll to the state. We have shown that two markers of cancer stem cells, CD133 and EGFRvIII, are tightly associated in glioblastoma tumors. We created a recombinant bispecific antibody (BsAb) selectively targeting CD133 and EGFRvIII. This antibody selectively kills glioblastoma tumor cells but not normal cells. Our goal is to ready the BsAb for investigational new drug-related development. Californians will benefit from this research project in several significant ways. 1. Most importantly, this research has the promise to dramatically extend the long-term survival rates for Californians with glioblastomas, with potential applications to multiple other human cancers. 2. The research will take place in California with direct benefit to the California economy through the hiring of employees and purchase of supplies and reagents. 3. An investigational new drug application will be the direct next step, requiring employing a local contract research organization to generate clinical grade antibody, requiring additional employees along with associated expenditures. 4. If the therapeutic BsAb generated is commercialized, profits derived from the production of the BsAbs by CIRM policy will result in improved treatments to insured patients and lower cost treatments to the uninsured, thus ultimately benefiting all Californians.
Review Summary: 
The goal of this Development Candidate Award application is to identify a single drug candidate for the treatment of glioblastoma multiforme (GBM) and complete all activities necessary to advance the candidate to IND-enabling preclinical development by the end of the award period. The applicants intend to develop a bispecific antibody (BsAb) that targets CD133, a known Cancer Stem Cell (CSC) marker, and EGFRvIII, a variant of the EGF receptor protein that is highly expressed on the cell surface of GBM cells. The applicants propose that this BsAb will specifically target GBM CSCs for lysis while sparing normal stem cells and will improve on the existing standard of care and on other strategies currently in development. Objective and Milestones - There is a reasonable target product profile and clearly defined milestones. Rationale and Significance - GBM is a clear unmet medical need. However, there was debate as to whether this candidate, if successfully developed, would advance the treatment of GBM and impact patient care. Some reviewers thought the potential existed. Others acknowledged the potential of a bispecific antibody approach but thought it unlikely that this candidate would eliminate a sufficient number of CSCs to impact patient outcomes and thought that any advance may be incremental rather than transformative. - Though the provided preliminary data (PD) are compelling, they are not sufficient to support the rationale and research plan (see next bullet points). -The PD demonstrate that cells expressing both the EGRFvIII receptor and CD133 are tumorigenic and capable of reconstituting the tumor. However, the PD also demonstrate that cells expressing only one of the antigens (EGRFvII or CD133) are also tumorigenic and capable of reconstituting the tumor. This observation undermines the rationale for targeting double positive cells for elimination. - Data provided by the applicant suggest that the BsAb does not target single positive cells for elimination. Because single positive cells can be tumorigenic it becomes unclear whether the BsAb would successfully target sufficient numbers of CSCs to provide clinical benefit. - The applicant provides data, using transfected cells, intended to demonstrate preliminary evidence of efficacy. However, an experimental design based on transfected cells biases the outcome such that it is difficult to ascertain the potential effectiveness of the BsAb in a primary tumor population. - Other more minor concerns included the following: that the BsAb might be toxic to naturally occurring stem cells; that the cell line used to generate the preliminary data does not have sufficient migratory ability to support drawing conclusions as to the efficacy in GBM; that data on EGFRvII from other groups was not considered in the proposal; that the BsAb might not work in all brain tumor sites if the blood-brain barrier is not universally disrupted; and that no rationale was provided for a mechanism of action other than Antibody Dependent Cell-mediated Cytotoxicity (ADCC). Feasibility and Design - Due to the limitations of the PD (described in the previous section), additional efficacy data is needed to justify moving forward with Milestones 1-3 (focused on production of the BsAb and Mechanism of Action). - The development plan is logical and feasible given the available resources and team and can be achieved within the proposed time frame. Qualification of the PI (Co-PI, Partner PI, if applicable) and Research Team - The PI and research team have the appropriate expertise, experience, and track record to conduct the proposed studies and have an adequate communications plan. - It is unclear if the team has sufficient expertise to develop the animal models and the toxicology consultant is minimally involved in the project. - The budget appears appropriate to the proposed activities. Collaborations, Assets, Resources and Environment - The institution, environment, and resources are appropriate to support the team and proposed research. Responsiveness to the RFA - The application is responsive to the RFA and no concerns were discussed.
Conflicts: 

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