The proposed California-based multi-disciplinary team brings combined and complementary strengths and expertise to this novel application that seeks to implement an innovative neural stem cell (NSC) therapy with pediatric brain tumor patients who have exhausted all other treatment options. This therapy combines delivery of an activating enzyme with an extensively tested and used cancer prodrug (irinotecan) to target brain tumor cells in the pediatric population. We will further modify an IND-approved NSC Master Cell Bank (MCB) to increase the tumor killing properties of irinotecan. This approach is being developed for adult patients with high-grade gliomas in a CIRM DT-1 grant. Our proposed trial will develop this therapeutic approach specifically for children with a wide range of malignant brain tumors. NSCs, by virtue of their inherent tumor-tropic properties, offer an unprecedented advantage of therapeutic specificity over conventional cancer treatments. Human NSCs from a well-characterized, clonal MCB will be expanded and further modified to express an activating enzyme (carboxylestarase, CE) that will convert irinotecan to a potent anticancer agent, SN-38 locally at the tumor sites. We propose that in pediatric brain tumor patients, these NSCs will provide a mechanism for tumor-selective delivery of therapeutic agents resulting in localized and preferential killing of dividing tumor cells. Limiting toxicity to normal brain cells by NSC-mediated localized chemotherapy production is especially important in the developing pediatric brain in order to minimize cognitive and functional deficits associated with current therapies. Objectives are to 1) complete the pre-clinical efficacy and IND-enabling safety/toxicity of CE-expressing NSCs in developing brain, comparing routes of administration, alone and in combination with irinotecan, leading to 2) FDA approval for a single investigational new drug (IND) Phase I/II application to the FDA. This proposed trial will consist of two arms: a)a phase I component for clinical trial in pediatric recurrent embryonal and glioma tumor patients who have exhausted standard-of-care treatments and b) a phase I/II component in pediatric patients diagnosed with primary diffuse intrinsic pontine glioma. Key activities for the Planning Grant will include informal pre- pre- and formal pre-IND FDA meetings to guide efficacy and safety/toxicity study trial designs, as well as 1) finalization of team members and external advisory board, and meeting schedules; 2) pre-clinical study plan; 3) collaborative design of the most effective clinical trial strategy and efficient regulatory approval procedure. The milestones will define direction and "go, no-go" decisions regarding routes of administration for particular tumor location and type, defining assessment criteria and values. Potential combination therapies will also be discussed.
Statement of Benefit to California:
Through CIRM funding the promise of stem cell therapies to combat diseases is made available first to the citizens of the State of California. Our innovative therapeutic approach will be made available to the pediatric brain tumor patients from the state of California. Pediatric brain tumors are among the most intractable of 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 cells 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 neural stem cell-based strategy for selectively targeting invasive tumor cells in pediatric brain tumors. The participation of the clinical 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 manufacturing and meet all 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 pediatric brain tumors will be of immense benefit to the State of California and its citizens.
But the benefits of CIRM funding goes beyond the direct benefit to patients, CIRM funding is an important engine for innovation and economic development in California, providing support for development of new therapies through the generation of FDA approved products. These therapeutic approaches based on stem cells like ours create intellectual property owned by entities within California and allow California based researchers to attract outside investment into the state. Outside investment builds the infrastructure of California to the benefit of all Californians. The California based partners in this proposal are responsible for the care of thousands of cancer patients, most from the within the State of California. CIRM funding for this project will strengthen both the clinical enterprises and the research enterprises of two important California based institutions. This project will create jobs and attract top level scientists and clinicians to the State of California to live and work.
The goal of this proposal is to develop and clinically evaluate a new cellular therapeutic for treatment of children with recurrent malignant brain tumors. The development candidate consists of human neural stem cells (hNSC) that have been engineered to express carboxyl esterase (CE), which will be co-administered with the anticancer pro-drug, irinotecan. Upon homing to the tumor site, hNSC will secrete CE, thereby converting irinotecan to its active form and delivering a potent, localized dose of chemotherapy to the affected tissues. Initial project activities are focused on the completion of preclinical safety and efficacy studies for filing an investigational new drug (IND) application. Upon completion of this milestone, the applicant will conduct a clinical trial consisting of two arms: a) a Phase I component for pediatric recurrent embryonal and glioma tumor patients who have exhausted standard-of-care treatments; b) a Phase I/II component in pediatric patients diagnosed with primary diffuse intrinsic pontine glioma (DIPG).
Significance and Impact
- This effort is highly similar to an ongoing CIRM-funded study for treating adults with malignant brain tumors. While distinguished by its focus on pediatric patients, this project is of limited innovation and is unlikely to break new ground.
- The proposed target product profile is appropriate, potentially achievable, and addresses a significant unmet need.
- Standard treatment methods such as surgery, radiation and chemotherapy have proven largely ineffective for resolving high-risk brain tumors. While the proposed approach is not likely to replace these methods altogether, it may prove useful for enhancing their effectiveness. It may also serve to limit the toxicity of systemically administered chemotherapy by enabling localized delivery of drugs to the affected area.
- The applicant describes a single development candidate and proposes activities that are fully within the scope of this RFA. The likelihood of meeting one ore more project goals is high.
Project Rationale and Feasibility
- The rationale for using hNSC to deliver localized chemotherapeutic treatment is compelling, but it is not clear from the study design whether the additive effects of hNSC would be readily distinguished from those of irinotecan alone.
- The extent to which recurrent tumors would prove sensitive to higher levels of chemotherapy is unclear, as it is possible and likely that resistant tumor cells will remain insensitive in spite of localized dosing.
- It is unclear how effective the hNSC delivered CE will prove compared to endogenous esterases that exist throughout the body. The proposal does not adequately address this issue nor whether the systemic action of those enzymes might lead to side effects.
- Since a similar trial is currently being performed in adults, it may be judicious to wait for the completion of those studies before launching a clinical trial in children.
- While irinotecan has proven useful against relapsed glioma in adults, there is published evidence suggesting that Avastin and irinotecan have little to no efficacy for treating recurrent high-grade glioma in pediatric patients. This uncertainty represents a particular risk for those with DIPG, who despite a poor prognosis, often respond to radiation therapy with improved symptoms and quality of life for as long as 9 months. It is not clear whether this potential benefit would be possible for those patients if radiation therapy were to be delayed through their participation in the proposed trial.
- The extent to which rodent studies will inform the optimal route of administration is uncertain.
Principal Investigator (PI) and Planning Leader (PL)
- The PI is an expert in imaging and has participated extensively in translational projects. However, his/her exact role in those studies is unclear, and there is limited evidence of experience in clinical leadership.
- The PL is a recognized expert in translational research and experimental therapeutics for pediatric cancers. He/she is very well qualified to serve in this capacity.