Funding opportunities

Genetically-modified neural stem cells for treatment of high-grade glioma

Funding Type: 
Disease Team Planning
Grant Number: 
DT1-00708
Principle Investigator: 
Funds requested: 
$55 000
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
Our proposal details assembly of a multidisciplinary Disease Team whose goal will be to take into the clinic a novel and promising stem cell-based strategy for selectively targeting invasive tumor cells in high-grade glioma. These tumor cells form small foci scattered throughout the brain that are resistant to standard treatments and are the tumor in large part responsible for the poor prognosis of glioma patients. Therapies to eliminate invasive brain tumor cells while sparing normal brain are urgently needed to address this clinical gap. The therapy we intend to develop is centered on our initial preclinical results demonstrating that neural stem cells (NSCs) can be used to target and deliver chemotherapeutic agents to tumors and infiltrative microfoci. Only cell-based therapies have the capability to actively seek out tumor cells, a property essential to targeting dispersed invasive glioma microfoci. Our fundamental observation and lead approach has been established in pre-clinical glioma models: a well-characterized immortalized human neural stem cell line will localize to tumor sites, track invading tumor cells, and deliver therapeutically effective drug. We are now uniquely poised to take this NSC-based therapeutic concept to the next level. Our goal is refining the this therapeutic approach while identifying and ameliorating potential clinical complications, to be followed by implementation in a clinical trial. We envision team focus on critical therapeutic development areas, with alternative approaches evaluated using a set of strong analytical methods and metrics. Participation of the clinical implementation-oriented members of the disease team in all aspects of therapeutic development and evaluation will ensure that NSCs selected for clinical use will have been derived under conditions where they can directly pass into manufacture and meet regulatory standards.
Statement of Benefit to California: 
Glioma is among the most intractable cancers, in part because invasion of the normal brain by tumor cells makes surgery only palliative. Therapies to eliminate invasive brain tumor cells while sparing normal brain are urgently needed to address this clinical gap. Our proposal details assembly of a multidisciplinary Disease Team whose goal will be to take into the clinic a novel and promising stem cell-based strategy for selectively targeting invasive tumor cells in high-grade glioma. Participation of the clinical implementation-oriented members of the disease team in all aspects of therapeutic development and evaluation will ensure that stem cells selected for clinical use will have been derived under conditions where they can directly pass into manufacture and meet regulatory standards. Our hope is that this novel approach will yield a unique therapy targeting tumor cells that cannot be eliminated by other therapeutic methods. Any progress towards reducing the virulence of glioma will be of immense benefit to the State of California and its citizens.
Review Summary: 
Executive Summary This proposal details assembly of a multidisciplinary Disease Team whose goal will be to take into the clinic a novel and promising stem cell-based strategy for selectively targeting invasive tumor cells in high grade glioma. The therapy that this proposal intends to develop is centered on initial preclinical results demonstrating that neural stem cells (NSCs) can be used to target and deliver chemotherapeutic agents to tumors and infiltrative microfoci. Cell-based therapies have the capability to actively seek out tumor cells, a property essential to targeting dispersed invasive glioma microfoci. Genetic manipulation of NSCs so as to deliver a cytotoxic drug followed by their transplantation into brains affected by gliomas in animal models is proposed. A key goal would be the development of analytical methods and metrics to assess stem cell fate and efficacy following transplantation. Glioma is among the most intractable cancers, in part because invasion of the normal brain by tumor cells makes surgery only palliative. Therapies to eliminate invasive brain tumor cells while sparing normal brain are urgently needed to address this clinical gap. If the approach is successful, it could have a major impact on an extremely common and fatal group of diseases affecting adults. In addition to the potential significance of the work, reviewers were positive about the proposed planning process, and about certain features of the project that increased its feasibility and decreased safety concerns. Reviewers commented that this is a well-designed and well-structured disease planning team. The key areas of basic, pre-clinical and translational research have all been covered with the composition of the core team of three PIs. The aims are clearly defined and the elements necessary for success are identified, i.e. 1) refinement of the therapeutic to be delivered, 2) optimization of delivery regimens, 3) assessment of potential complications. Reviewers cited two key advantages in terms of plausibility for this project: 1) the inbuilt safety measure provided by the cytotoxic action on the NSCs themselves, should uncontrolled proliferation occur; and 2) the likelihood that any reduction in tumor bulk would be clinically advantageous; complete eradication is not a necessary end-point. In terms of principal investigator (PI), this applicant states that there will be three co-PIs heading the project. The first PI has extensive administrative and leadership experience in neuroscience, but is not a recognized leader in the SC field. The second PI is a recognized leader in this field however; s/he is also a collaborator on two similar, competing applications for the Disease Team Planning awards. The third PI is also a collaborator on one similar competing application. Some concern was expressed by the review panel as to how they would prioritize their commitments if more than one of these proposals was funded. Reviewers were of mixed opinions regarding the maturity of the project and whether the proposed team could be ready for the clinic in 5 years. One reviewer commented that progress to the clinic could be hastened if the team focused on signaling pathways that are known to be important for high-grade glioma formation and growth. This reviewer also commented that there is very little description or justification of the tumor models that will be used. The reviewer commented that the ability to successfully translate preclinical studies into clinical trials will be dependent, in part, on the fidelity of the tumor models in which these novel approaches are tested. Finally, Good Manufacturing Protocol (GMP) practices and clinical trial design are only addressed in a few lines and no consideration appears to have been given to late translational aspects of the project, such as patient recruitment or numbers of subjects per study. This final concern was ameliorated by the fact that the co-investigators provide substantial experience in GMP work. Reviewers emphasized that it is likely that most of the issues mentioned above can be addressed, and it is still possible that a clinical trial based on these studies is attainable within 5 years. The application of stem cells to brain tumor therapy is undoubtedly a critical medical problem that could advance stem cell therapies. Adult-onset cancers, such as this one, will enable many ethical and other issues to be dealt with effectively and therefore represent a target of high priority for this initiative. Given the strength of the described planning process and the significance of the research area, reviewers were comfortable recommending that this team receive a Disease Team Planning award. Reviewer One Comments Concept: The use of stem cells to track brain tumor cells and deliver a cytotoxic effect has significant support in literature. While these aspects of the proposal are mature, there are at least two issues that are not addressed well enough in the proposal that could impact on the success of stem cell application to malignant glioma cure. a. Targets: The molecular bases for high-grade glioma formation and growth are relatively well-described. EGF and PDGF receptor activation, PTEN mutation as well as inactivation of the Rb and p53 pathways are known to be important. The central role that these genetic alterations play in gliomagenesis has very recently been further advanced by the findings of The Cancer Genome Atlas. This project would be strengthened by efforts to target the pathways identified as important to gliomagenesis. b. Tumor models: The ability to successfully translate these preclinical studies into clinical trials will be dependent, in part, on the fidelity of the tumor models in which these novel approaches are tested. There is little to no description of what models are being utilized and why. These issues can be addressed and it is still possible that a clinical trial based on these studies is attainable within 5 years. The application of stem cells to brain tumor therapy is undoubtedly a critical medical problem that can advance stem cell therapies. Principal Investigator: The proposal states that it will be have three co-principal investigators (co-PIs). The first PI has extensive administrative experience in neuroscience but is not a recognized leader in this field. In fact he/she is co-author (not senior author) on only two stem cell publications. The second PI is a recognized leader in this field however, he/she is also a collaborator on two similar, competing applications to CIRM. The third PI is also a collaborator on 1 similar competing application. One of the competing proposals is a stronger application. It is not clear how they would prioritize their commitments if more than one of these proposals was funded. Planning Approach: The aims are clearly defined and the elements necessary for success are identified, i.e.,1) refinement of the therapeutic to be delivered, 2) optimization of delivery regimens, 3) assessment of potential complications. Limitations include a single stem cell source and no consideration of how alternate orthoptic models, i.,e., xenografts from established tumor cell lines or from CD133 selected primary isolates, could impact on results of the relatedness of findings to clinical applications. The planning process as outlined would likely prepare the team for a Disease Team Application Award. Reviewer Two Comments Concept: This proposal takes advantage of the ability of transplanted neural stem cells to home to the site of tumors in the central nervous system. Genetic manipulation of neural stem cells so as to deliver a cytotoxic drug followed by their transplantation into brains affected by gliomas in animal models is proposed. A key goal would be the development of analytical methods and metrics to assess stem cell fate and efficacy following transplantation. Plausibility of target This project is based on extremely interesting animal data showing the tumor tropism of transplanted neural stem cells. Two key advantages in terms of plausibility are: 1) The inbuilt safety measure provided by the cytotoxic action on the neural stem cells themselves, should uncontrolled proliferation occur; and 2) The likelihood that any reduction in tumor bulk would be clinically advantageous; complete eradication is not a necessary end-point. Evidence in support of therapeutic concept: The idea, while ingenious and exciting, is based on a relatively small literature at this stage. Can it go to clinic in 5 years? My view would be that more basic and pre-clinical research is required in this area before translational and clinical trial research is justified. This is reflected in the application; the key issues of GMP manufacture and clinical trial design are only addressed in a few lines and no consideration appears to have been given to patient recruitment, numbers etc. The likelihood is that the development of the analytical methods and metrics would take up much, if not all, of the 5 year period. Importance of problem and ability to advance stem cell medicine to the clinic: This is an extremely important area of medicine and a very exciting potential application of stem cells. If it works, it could have a major impact on an extremely common and fatal group of diseases affecting adults. Adult-onset cancers represent disease targets that enable many ethical and other issues to be dealt with effectively and therefore represent a target of high priority for this initiative. Principal Investigator: Track record of Principal Investigator: A lack of recent publications and clinical expertise is evident. Translational expertise of Principal Investigator: Not apparent, although the co-investigators provide more experience in animal models and GMP work. Leadership qualities of Principal Investigator Appropriate. Planning Approach: Merit of planning process proposed; is it well thought out? The key areas of basic, pre-clinical and translational research have all been considered with the composition of the core team of three PIs. It is not clear; however, how this team will bring cell-based therapy to clinical trial within 4 years as the expertise appears to be based in the areas of basic research and also in regulatory issues. The key issues of in vivo analysis, clinical trial planning and design are not considered in any length. How good is the team? The team appears to be rather weak in clinical implementation. Will an award enable the team to prepare a competitive application? Only if significant attention is given to the issues I have highlighted above. Reviewer Three Comments Concept: The investigator proposes a detailed assembly of a multidisciplinary disease team whose goal will be to take into clinic a novel and promising stem cell-based strategy for selectively targeting invasive tumor cells in high-grade glioma. These tumor cells tend to form microfoci scattered throughout the brain that are refractory to surgical resection, radiation and chemotherapy. The plan of this proposal will be to address the lack of effective therapies for primarily brain tumors due to the inability of current treatment strategies to eliminating infiltrating glioma cells while avoiding toxicity to normal brain. The therapy they intend to develop is centered on their preclinical results demonstrating that NSCs can be used to target and deliver chemotherapeutic agents to tumors and microfoci tumors. A proposed disease team adopted a set of strong analytical methods and metrics which will be critical for the assessment of relative therapeutic efficacies of various alternative therapies especially involving a clone human neuron stem-cell line “HDI-F3” that can be modified to express therapeutic tumorigenesis. Ultimately, a suite of standard in vitro and in vivo models would be required for quantitative measures as well as real-time tracking of administered cells. Principal Investigator: fine Planning Approach: This is a well designed, well structured disease planning team proposal and the actual therapeutic development process from initial concept from implantation.In addition the investigators nicely put together a well defined team that would have responsibility for both guidance coordination, writing a grant, and the preclinical investigations and ultimately the implantation with individuals identifying each of the realms for such ultimate a disease approach. In addition they have very well outlined a time table for how this team would get together, the roles of members and responsibilities of each meeting towards the submission of final proposal by the end of 2008. This is a well defined team and well defined target and a model grant proposal.
Conflicts: 

© 2013 California Institute for Regenerative Medicine