While current treatment strategies for high-grade glioma can yield short term benefits, their inability to eradicate the highly tumorigenic cancer stem cell population results in disease recurrence in the vast majority of patients. Stem cells and some cancer cells (the targets of our therapy) share many common characteristics, including the ability to self-renew and grow indefinitely. These cancer stem cells are also resistant to many standard therapies including radiation and chemotherapy, creating a critical need for novel therapies that will efficiently eliminate this cell population. We propose here to develop and optimize a therapeutic strategy, termed “adoptive T cell therapy", that will eliminate the brain tumor stem cell population by re-directing a patient’s immune cells, specifically T cells, to recognize and destroy tumor stem cells. Our goal is a therapy in which a single administration of tumor-specific T cells results in long-term anti-glioma protection. Our approach builds on previous findings that T cells, when reprogrammed, can potently kill glioma stem cells. Furthermore, we will exploit the self-renewing stem cell-like properties of a defined T cell population (central memory T cells) to establish reservoirs of long-lasting tumor-directed T cells in patients with glioma, and thereby achieve durable tumor regression with a glioma-specific T cell product. Our findings can then be applied to cancers besides glioma, including tumors that metastasize to brain.
The goal of this project is to develop a novel and promising immunotherapy utilizing genetically modified T cells to target glioma stem cells in order to improve cure rates for patients with high-grade malignant glioma. Our strategy, in which a single administration of tumor-specific T cells results in long-term anti-glioma protection, has the potential to provide significant therapeutic benefit to patients with brain tumors, for which there is a dearth of effective treatment options. Further, the tumor-specificity of this therapy is intended to improve the quality of life for patients with high-grade gliomas by reducing treatment related side-effects of conventional therapies. Moreover, due to the high cost hospital stays and treatments usually required for patients with advanced disease, this therapy, by generating long-lasting anti-cancer immunity, has the potential to significantly reduce the costs of health care to California and its citizens. Carrying out these proposed studies will have further economic benefit for California through the creation and maintenance of skilled jobs, along with the purchasing of equipment and supplies from in-state companies. This project will also yield long-reaching benefit through continuing to build the larger CIRM community that is establishing California as a leader in stem-cell and biomedical research both nationally and internationally.
The overall objective of this Development Candidate (DC) Award proposal is to engineer a novel adoptive T cell therapy (ACT) for treating glioblastoma multiforme (GBM), a highly malignant form of brain cancer. In this approach, a patient’s own immune system will be reprogrammed to produce a lasting pool of T cells that can recognize and destroy tumor stem cells and prevent their recurrence. The DC product consists of a combined population of self-renewing memory T cells (Tcm) expressing improved chimeric antigen receptors (CAR) targeting three proteins expressed by glioma cells. Project goals are designed to overcome shortcomings encountered in previous clinical studies including limited T cell persistence, potency, and the ability of tumor cells to evade immune response. A series of 4 milestones has been proposed: 1) to optimize the route of delivery for maximal T cell persistence and tumor targeting; 2) determine the best combination of CAR + Tcm to limit tumor initiating activity; 3) establish good manufacturing practice (GMP)-compatible production of cell product and 4) demonstrate proof of concept for efficacy against established gliomas.
Objectives and Milestones
- The objectives for developing each key attribute of the proposed therapeutic are succinctly stated. The Target Product Profile is clinically sound.
- Milestones are very straightforward and readily achievable in the time frames indicated. Criteria for success are feasible and meticulously enumerated.
Rationale and Significance
- The rationale for this approach is sound and rigorous, addressing key limitations that have been encountered in current and past attempts with ACT for glioblastoma.
- This proposal represents a novel approach to targeting glioma stem cells through ACT and has substantial potential for impact. Despite the limited size of the targeted patient population, the approach would provide critical proof of concept for other ACT approaches in cancer therapy.
- Glioblastoma represents a significant unmet medical need despite the various, multimodal strategies under development.
Research Project Feasibility and Design
- The proposal builds on a very strong foundation of existing preliminary data, including prior clinical experience of the applicant team with analogous approaches. These data support their ability to produce the therapeutic and test its safety and efficacy.
- Processes for GMP manufacturing of engineered T cells are largely in place. An excellent discussion of lessons learned from prior studies informs the well-considered research plan.
- Reviewers noted that antigen escape could still be a problem if the three chosen antigens exhibit non-overlapping expression patterns in glioblastoma populations. They also questioned the extent to which these antigens would specifically target cancer stem cells over the bulk glioblastoma population.
- The relevance of the animal model to the clinical setting is not ideal. Similarly, the chosen cancer stem cell line behaves more like sarcoma than true glioma. Despite these minor concerns, reviewer enthusiasm for this proposal remained high.
Qualification of the PI (Co-PI and Partner PI, if applicable) and
- The PI is a leader in T cell therapeutics and has extensive relevant experience with Investigational New Drug submissions for T cell therapies. The Co-PI has several years experience as a lead scientist and substantive record of achievement.
- The research team is well qualified with a successful record of past collaboration.
- Reviewers felt the plan to meet 4 times/year and costs associated were somewhat excessive. They also felt the budget allocations for pathology to both PI and Co-PI ($70,000/yr combined) were too high.
Collaborations, Assets, Resources and Environment
- Assets, resources and environment are excellent and represent a major strength of this application.
Responsiveness to the RFA
- While CIRM currently funds a few other glioblastoma therapy projects, the strategy outlined in this proposal is distinguished by its novelty and feasibility.
- Reviewers debated the extent to which Tcm are considered stem cells, and whether the approach definitively targets a cancer stem cell. Ultimately they concluded that the proposal is responsive to the RFA.