Disease Team Planning
Glioblastoma is the most common and aggressive brain tumor. Despite surgery, radiation and chemotherapy, the median survival remains approximately 15 months. This project proposes fundamental and clinical goals that are intimately tied: to understand the biology of neural stem cells (NSCs) derived from embryonic stem cells, fetal stem cells, and adult bone marrow derived stem cells and to manipulate these functions for therapy. The limitation of current therapies for glioblastoma stems from their inablility to target infiltrating tumor cells. However, the obstacles to effective therapy match the known biological properties of neural stem cells (NSCs). NSCs display a dramatic property of attraction towards tumors in the adult central nervous system. We have demonstrated the safety and usefulness of fetal NSCs as delivery vehicles as a means of delivering agents to kill infiltrating brain tumor cells and have demonstrated a mechanism of how they are attracted to glioblastoma cells. We also described a rapid culture process whereby neural stem cells can be obtained from bone marrow cells. These findings – taken together with the desperate state-of-affairs in glioblastoma underscore the importance of research that might accelerate the translation of NSC-based adjuvant treatment strategies. This strategy has garnered attention, in part, because of the pioneering efforts and seminal reports from the investigators on this proposal who now hope to advance it rationally towards clinical translation. More recently, our collaborators have derived NSCs from pluripotent embryonic stem cells (ESCs), termed “ESC-derived NSCs” using a human feeder layer. Culturing without an animal feeder layer enables the clinical development of these cells. The use of stable NSC lines derived from embryonic stem cells have the advantage of being well-characterized and readily available in limitless quantities for the earliest phases of a disease or insult. Starting from this point of departure, we will formulate a team of world class investigators that have been at the forefront of stem cell therapies from basic research to translational research into clinical trial development. We will collaborate to develop multi-institutional aims to prepare an IND by developing (a) a long term safety profile for the optimal hNSC with the optimal gene; (b) a protocol for its GMP scale-up; and (c) an hNSC "use" protocol that is compatible with patient standard care.
Statement of Benefit to California:
This proposal addresses the principle aspiration of CIRM: “to use stem cells to cure a variety of diseases.” Our goal and that of CIRM is to advance therapies to early stage clinical trials. This project will have an impact on five of the ten listed goals of CIRM’s Scientific Strategic Plan: Goal I, CIRM grantees will have six therapies based on stem cell research in pre-clinical development – We will advance a novel stem cell based therapy for a devastating neurological disorder, glioblastoma. Goal II: CIRM grantees will have developed new methods of making stem cell lines- We are and will continue to develop efficient means of differentiating ESCs to neural progenitor cells. Goal VII, CIRM will have increased the workforce of stem cell researchers in California-We will recruit two full time trainees to work on this grant. Goal IX and X: CIRM will have established effective partnerships in stem cell research between scientific teams in non-profit and commercial centers and between national and international collaborations in stem cell research- This grant proposal forges a strong collaboration between a large clinical and preclinical entity with investigators that have a proven track record in preclinical development and clinical research and basic embryonic stem cell research with a superb basic stem cell research institute with an investigator that has made seminal contributions in the stem cell therapy field. The development of stem cell therapies for this devastating neurological disorder would make California the leading state for stem cell therapies, attracting both scientific talent and, in the future, investment for commercialization of these therapies.
Executive Summary This proposal is based on the concept that neural stem cells (NSCs) have a tropism for individual tumor cells that escape current therapies for glioma. The applicant suggests that the value of stem cell-based therapies may lie in the ability to treat tumors cells that have migrated away from tumor masses and infiltrated the surrounding brain. This project proposes two goals: a) to understand the biology of NSCs derived from embryonic stem cells (ESCs), fetal stem cells (FSCs) and adult bone marrow derived stem cells and compare them in a head-to-head manner in the same model; and b) to manipulate their functions for the treatment of malignant glioma. The argument is that NSCs that are engineered to promote tumor cell death or boost T-cell responses may be therapeutically superior to currently available treatments. Reviewers agreed that the treatment of glioblastoma is extremely important, as it is the most common and aggressive form of brain tumor. The panel also acknowledged significant support in the literature for the use of stem cells to target brain tumor cells and deliver a cytotoxic effect. However, reviewers noted several issues that were not addressed in the proposal that could impact the success of developing stem-cell based treatments for malignant glioma within the five year timeline conditional in this RFA. In addition, the planning process was poorly co-ordinated. Reviewers pointed to several weaknesses in the proposal. First, potential targets are not discussed. The molecular and genetic basis for high-grade glioma formation and growth are relatively well-known, and this project would be strengthened by efforts to target the pathways already identified as important to gliomagenesis. Second, 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 which models the applicant proposes to use, or the rationale for choosing specific models. Reviewers were mixed in their opinions regarding whether achieving a clinical trial within 5 years is possible. Reviewers were mixed in their opinions regarding the adequacy of the planning approach. Reviewers agreed that the aims of the plan are very clearly stated, and the PI plans a very aggressive course of action toward a Phase I clinical trial within five years. This includes the submission of an investigational new drug (IND), good laboratory practice (GLP) and good manufacturing practice (GMP) filings in consideration of preparing cells and transducing virus. However, the preclinical science necessary to achieve these aims is sparsely described. Moreover, there is no note of planning meetings to organize the team, and no discussion of how the potential named members will come together to formulate this plan. The principal investigator (PI) is well-suited to the task of organizing and leading this research effort. While still a relatively junior faculty member, s/he has assumed a leadership position within his/her institution’s community. This has included the development of investigator-initiated clinical trials. However, a main concern is the fact that the PI’s expertise is clearly not in the stem cell aspects of the work, and s/he will very likely have to rely on the collaboration with one of the proposed members of his/her team, who was noted as a collaborator on several other similar applications in this RFA. Overall, reviewers were positive about the proposed team and the area of focus, but noted that the planning process was not as well–coordinated as compared to other submitted applications, and the description of the preclinical work was also not very strong. Reviewer One Comments Concept: The use of stem cells to track brain tumor cells and deliver a cytoxic effect has significant support in literature. While these aspects of the proposal are mature, there are at least two issues that are not addressed 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. The roles of EGF and PDGF receptors and PTEN mutations, as well as inactivation of the Rb and p53 pathways, are well-known and very recently been further advanced by The Cancer genome Atlas. The value of stem cell (SC)-based therapy may lie in the ability to treat tumors cells that have migrated away from tumor masses and infiltrated the surrounding brain. These cells possess these genetic alterations. This project would be strengthened by efforts to target the pathways already 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. For instance, the use of nude mice will preclude any evaluation of adaptive immunity to the anti-tumor effect. 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 principal investigator (PI) is well suited to the task of organizing and leading this research effort. While still a relatively junior faculty member, he/she has assumed a leadership position within his/her Institution’s community. This has included the development of investigator-initiated clinical trials. A concern is the inclusion of some collaborators in this present team that are also included on very similar, competing applications for this same award. Planning Approach: The aims of the plan are very clearly stated. The preclinical science necessary to achieve these aims is sparsely described. For instance, it is stated that one of the collaborators will develop oncolytic fetal NSC therapy. What will he/she focus on? How are targets selected? What models will be used to validate the cytotoxicity of newly developed NSC therapeutics? It is also not clear, who besides the six named individuals will be collaborating to achieve the aims of this proposal. Reviewer Two Comments Concept: The goal here is to use neural stem cells (NSCs) in the treatment of malignant glioma. The cells would be used in one of two ways 1) to express genes involved in direct tumor cytotoxicity, and 2) express immunomodulating genes that provoke an immune response against neoplastic cells. The treatment of malignant glioma is extremely important. The concept is that NSCs have a tropism for individual tumor cells that escape current therapies for glioma. Thus NSCs that are engineered to promote tumor cell death or boost T-cell response may be therapeutically superior. The source of human NSCs have not been compared head-to-head in the same model in their view and will be a major component of their proposal. They plan to compare CNS-derived NSCs from ES cell derived NSCs and also those derived from adult bone marrow. In my view, they are optimistically hoping that this work will lead to a clinical trial within five years. Principal Investigator: The PI is a well trained academic neurosurgeon who leads surgical neuro-oncology at his California based institution. He/She is an experienced clinician who is knowledgeable on planning and organizing clinical trials. He/She has an R01 and an R21. His/Her publication record is moderate. His/Her expertise is clearly not in the stem cell aspects of the work where he/she will rely on the collaboration with one of his collaborators (a very highly recognized SC expert). Planning Approach: The PI plans a very aggressive course of action toward a Phase I clinical trial within five years. This includes the submission of an investigational new drug (IND), good laboratory practice (GLP) and good manufacturing practice (GMP) filings in consideration of preparing cells and transducing virus. In the six month planning period, one of the collaborating institutions will develop NSCs from different sources that are transduced with oncocidal genes. This seems an overly optimistic time-frame. Overall, the planning process seems less well coordinated than many others with no note of planned meetings etc.