Despite aggressive multimodal therapy and advances in imaging, surgical and radiation techniques, malignant brain tumors (high-grade gliomas) remain incurable, with survival often measured in months. Treatment failure is largely attributable to the diffuse and invasive nature of these brain tumor cells, ineffective delivery of chemotherapeutic agents to tumor sites, and toxic side-effects to the body, which limits the dose of drug that can be given. Therefore, new tumor-selective therapies are critically needed. Neural stem cells (NSCs) offer an unprecedented advantage over conventional treatment approaches because of their unique ability to target tumor cells throughout the brain. This ability allows NSCs to be used to deliver prodrug-activating enzymes to tumors, where these enzymes will generate high concentrations of powerful anti-cancer agents selectively at tumor sites.
We will use an established human NSC line to develop a novel NSC-based product to deliver the enzyme carboxylesterase (CE), which will activate a systemically administered prodrug, CPT-11, to a powerful chemotherapeutic agent, SN-38, selectively at tumor sites, destroying invasive glioma cells while sparing normal tissues. Based on our preliminary data, we hypothesize that CE-expressing NSCs will home to tumor sites in the brain, and, in combination with CPT-11, will generate high concentrations of SN-38 specifically at tumor sites. Thus, in addition to potentially improving lifespan by concentrating the powerful chemotherapeutic agent selectively at tumor sites, this NSC-mediated treatment strategy should significantly decrease toxic side-effects to normal tissues, thus preserving or improving the patient’s quality of life.
Our research, regulatory and clinical teams have the collective expertise and experience to conduct the preclinical studies necessary to optimize the efficacy of this innovative treatment approach. Specifically, we will determine the optimal dose and route of NSC administration; the optimal prodrug dosing regimen; and assess the safety of this treatment approach. We will perform these studies and analyses, generate clinical grade products, and file and obtain all appropriate regulatory documents and approvals. Completion of these activities will lead to the filing of a new Investigational New Drug (IND) proposal to the FDA, for a first-in-human Phase I clinical trial of this pioneering NSC-mediated treatment in patients with recurrent high-grade gliomas.
Importantly, our NSC line can be further modified for tumor-localized delivery of a variety of therapeutic agents, and can be given serially or in combination to maximize therapeutic benefit. Thus, the potential medical impact of this innovative NSC-mediated therapeutic approach may be very far-reaching, as it can be developed for application to other types of malignant brain tumors, as well as for metastatic cancers.
Despite aggressive multimodality therapy and advances in imaging, surgical and radiation techniques, high-grade gliomas remain incurable, with survival often measured in months. Approximately, 22,500 malignant brain tumors are diagnosed annually in the U.S., of which more than 2,600 cases are in California. New therapies are desperately needed to improve both the survival and quality of life of these brain tumor patients and to reduce the economic impact of billions of dollars in related healthcare costs.
We propose to develop a novel neural stem cell (NSC)-based treatment method that will selectively target glioma cells with a potent chemotherapy agent, locally activated by the NSCs at tumor sites to destroy neighboring tumor cells. Our tumor-selective approach also has the advantage of minimizing toxicity to normal tissues, thereby decreasing systemic side effects and damage to normal brain. This new therapeutic strategy, therefore, not only has the potential to improve survival, but, by preserving cognitive function and quality of life, it could also enable adult Californians diagnosed with brain tumors to continue making societal contributions that would benefit all Californians.
Important for clinical translation of this novel therapeutic approach, we have established the NSC line to be used in this study as a fully characterized cGMP Master Cell Bank. The NSC line is thus expandable, easily distributed to other medical centers, and cost-effective, which will allow this therapeutic approach to be quickly adopted. Importantly, this NSC line can be further modified for tumor-localized delivery of a variety of therapeutic agents, which may be given serially or in combination to maximize therapeutic benefit. There is tremendous potential for developing NSC-mediated treatment applications for other types of malignant brain tumors, as well as for metastatic solid tumors throughout the body. Therefore, the impact of these proposed studies to advance NSC-mediated treatment of glioma may be very far-reaching and may significantly contribute to reducing healthcare costs.
Finally, the combined strengths and experience of our research team will enable us to advance this NSC-meditated therapeutic approach in a timely, streamlined, and cost-effective manner to submit a new IND application for initiating first-in-human clinical trials in California, providing benefit to state taxpayers by efficient use of tax dollars and initial access to this novel therapy. In addition, our CIRM Disease Team NSC-mediated cancer treatment studies would stimulate and advance collaborative partnerships and alliances with other cancer centers and affiliates, pharmaceutical companies, academic institutions, and philanthropic societies within California, which would further enhance local and state economies.
This application proposes to develop a human neural stem cell (NSC) line as a therapy for malignant brain tumors, specifically recurrent high-grade gliomas. The NSCs will be genetically engineered to deliver an enzyme, carboxylesterase (CE), which can convert a systemically administered prodrug, CPT-11, to a potent chemotherapeutic agent, SN-38. The foundation of the approach lies in published preclinical data showing that NSCs migrate to tumors and thus could provide local, selective conversion of CPT-11 to SN-38. The applicant hypothesizes that this selective delivery will result in higher doses of chemotherapy at tumor sites and lower toxicity to normal tissues. A number of preclinical studies are proposed in rodent models, including evaluation of delivery routes and doses of NSCs to maximally target tumor delivery, selection of the CE enzyme source, pharmacokinetics testing, optimization of CPT-11 dosing, and preclinical safety and toxicology. The applicant will also develop the CE-expressing vector to GMP grade, design a clinical human protocol and prepare documents for an Investigational New Drug (IND) filing.
Overall, while reviewers appreciated the scientific rationale and potential impact of this proposal, they raised a number of concerns about the preliminary data that led them to question the project's scientific maturity and feasibility. Specifically, reviewers did not feel that the applicant provided compelling evidence of disease-modifying activity with the proposed therapeutic approach.
Reviewers agreed that scientific rationale for this proposal is sound and described the overall strategy as elegant. They appreciated the advantages offered by local, selective delivery of a chemotherapeutic agent to brain tumors, as delivery of drugs across the blood-brain barrier is typically difficult and requires high doses, which are accompanied by high associated toxicity to non-diseased tissue. Reviewers did question why the CE/CPT-11 approach was chosen over other enzyme/prodrug combinations and would have appreciated discussion of the choice. The significance of this proposal is substantial, as malignant gliomas affect over ten thousand patients annually and in the majority of patients are fatal within one year. These tumors are largely untreatable, so any effective therapy would be clinically competitive and have a major impact for patients.
Reviewers raised a number of issues with the preliminary data, which led them to question the feasibility of the approach. While they found the data demonstrating the tumor tropism of NSCs to be compelling, they were not convinced by the data supporting the prodrug conversion strategy in this system, compared to other enzyme/prodrug combinations that have been studied more extensively. Reviewers noted that levels of the more potent chemotherapeutic agent, SN-38, were undetectable by microdialysis at brain tumor foci unless the samples were pooled over an eight hour period. Furthermore, even these pooled samples only contained SN-38 levels of 1-2% those of CPT-11. Reviewers felt that these data did not support the proposed strategy of delivering high concentrations of SN-38 directly to tumors. Reviewers acknowledged that the applicant presents in vivo imaging data showing tumor regression in a rodent glioma model but found it difficult to assess these results without statistical analysis or histological data.
The reviewers also raised questions about the survival of NSCs in vivo. The applicant cites unpublished data that the NSCs will survive in tumors for at least two weeks, long enough for one treatment round. But reviewers were unsure that one treatment round would be sufficient and commented that the plan may need to accommodate the possibility of multiple doses of NSCs. They also were not convinced that immune rejection would not be an issue and questioned the efficacy of the proposed immunosuppressant. Reviewers recommended testing the lifespan of the genetically engineered NSCs in immunocompetent animals. They also questioned whether transplanted NSCs might be killed prematurely by the locally generated SN-38 and would have appreciated discussion of this possibility.
While reviewers questioned the proposal’s scientific maturity, they praised the maturity of its regulatory strategy. The proposed NSC line has been favorably reviewed by the FDA Recombinant DNA Advisory Committee and is part of an IND currently under review. Reviewers did note that only a limited outline of a Phase I trial was provided and would have preferred more detail (e.g. patient eligibility criteria).
Reviewers found the research plan and milestones to be generally reasonable but had concerns about a number of important details. They felt that the milestones should be reset to allow for generation of compelling preclinical data to support the overall hypothesis. Reviewers recommended in vitro potency assays with SN-38 as well as additional experiments in animal models to provide more quantitative data. They also felt that the efficacy of SN-38 in heterogeneous patient tumors should be demonstrated in vitro before proceeding further. The process of manufacturing and testing this vector is ambitious and should begin earlier in the timeline. Reviewers were concerned that the standard-of-care regimen in recurrent glioma patients could affect the tumor tropism of NSCs; they suggested that the applicant should consider testing NSC tumor tropism in animals that have been subjected to the standard-of-care regimen for glioma patients.
Reviewers found the PI and research team to be generally well-qualified, with appropriate experience, including GMP manufacturing and successful IND filing. Reviewers were concerned by the number of personnel, and described the research team as enormous. It consists of 60 researchers in total, including 39 under the direction of the PI, who will commit 60% effort to the project. Reviewers were surprised that, given the size of the research team, neither the PI, nor two co-PIs, has a senior academic rank; but reviewers did note that several of the project’s teams are lead by senior investigators. Reviewers also felt that the roles of some team members and consultants were not well justified. They recommended combining some of the low percent effort positions to enhance efficiency and conserve resources.
Reviewers agreed that the resources and facilities are more than adequate to complete the proposed project. They noted that the collaborations bring together essential ingredients including imaging and statistical support. The budget was judged appropriate for the overall project, co-PI projects and subcontracts.
Overall, while reviewers agreed that this proposal addresses an important unmet medical need and could potentially have a significant impact, they did not feel the applicant presented sufficient preliminary data to justify the feasibility of the therapeutic approach. As a result, the reviewers were not convinced that the proposal would result in an IND filing within the 4-year timeframe.