The NCI Glioblastoma Therapeutics Network (GTN)

Background

Limited progress has been made in the treatment of adult glioblastoma (GBM) despite substantial public and private investments into basic, translational, and clinical research. Notwithstanding its extensive clinical trials capabilities, National Cancer Institute’s (NCI’s) current research infrastructure needs to expand in an all-out effort for development and testing of new GBM therapeutic strategies.¹ Numerous distinct challenges can explain the lack of progress in GBM treatment. These include infiltration of malignant cells beyond the resected contrast enhancing tumor; surgical resection that cannot be extended to obtain a tumor free margin; limited passage of therapeutic agents through the blood-brain-barrier (BBB); reduced radiation therapy (RT) tolerance of the normal brain that limits RT dose; intratumoral genetic heterogeneity and plasticity; and an immunosuppressive tumor microenvironment. Therefore, the development and selection of specific agents for GBM needs to break new ground if effective treatments are to be found for this disease.

To address these challenges, NCI Leadership established a GBM Working Group (WG) of the Clinical Trials and Translational Research Advisory Committee (CTAC). The WG was charged to identify critical research gaps and to define opportunities for improved therapeutic efficacy and clinical outcomes of GBM patients. The focus selected by the WG was therapeutics of adult GBM. Its members recognized that development of effective GBM therapies would require a well-integrated, sustained national effort extending from pre-clinical to early phase clinical trials with potential to transition seamlessly to late phase clinical trials supported by other NCI funding mechanisms. The WG recommended the establishment of a national infrastructure to support the discovery and development of novel, effective GBM therapeutics. Moreover, the WG report² detailed recommendations on the design and conduct of pre-clinical and early phase clinical trials to optimize GBM therapeutics development to include: (1) pre-clinical qualification of new agents, (2) clinical trials driven by molecular pharmacodynamics (PD) and imaging, (3) immunotherapy, (4) improving radiation sensitivity and overcoming radiation resistance, and (5) improving the quality of life of patients. From these recommendations, NCI established the Glioblastoma Therapeutics Network (GTN, RFA-CA-20-047)^3,4 as a distinct effort from the NCI Brain SPORE grant program and the Adult Brain Tumor Consortium in several aspects: (1) the GTN structure leverages the knowledge and resources of an extensive collaborative network and, (2) the GTN uniquely focuses on late pre-clinical to early phase clinical studies of novel agents or combinations not previously tested in GBM.

The Glioblastoma Therapeutics Network (GTN): Structure and Function

The GTN consists of five multi-institutional Centers (Figure 1) funded through the NIH U19 cooperative agreement mechanism, which supports multidisciplinary collaborative team science facilitated by government staff working toward a shared goal. The overall goal of the GTN is to improve the treatment of adult GBM by developing novel effective agents in an integrated team setting to address known challenges associated with GBM treatment and testing these agents in early-stage clinical trials within one or several U19 Centers. Each U19 Center aims to move a therapeutic agent(s) from pre-clinical development and IND studies to pilot clinical studies driven by molecular PD. Three structural aspects of the GTN underpin integration of the U19 Centers. First, to facilitate the harmonization of GTN administrative, scientific, and clinical functions, one U19 Center includes the Network Coordination Center (NCC). The NCC, located at the Mayo Clinic in Rochester, MN, functions independently of all U19 Centers. Second, a Steering Committee assesses the readiness of GBM therapeutic candidates from the GTN (or other NIH programs) to enter clinical studies. The Steering Committee includes representatives from each U19 Center, the Network Coordination Center (NCC), NCI staff, and outside experts in GBM.⁴ Third, to harness the unique and complementary strengths of each team, the U19 Centers have budgeted $50, 000 in direct costs per year to develop Collaborative Pilot Projects, including sharing of reagents, assays, and patient samples. Importantly, the U19 Centers have expressed willingness to participate as secondary sites in clinical testing of agent(s) developed by the other U19 Centers.

Figure 1.

Structure of the Glioblastoma Therapeutics Network (GTN): five U19 Center grants include two or three Projects (red discs), one or two Cores (blue discs), and an Administrative Core (lavender disc). Light blue boxes next to each U19 Center include names of PI(s) and their institutions (red) and the title of the U19 grant. The Network Coordination Center (NCC, gray disc) is located at Mayo Rochester. The NCC interacts administratively with all U19 Centers (green arrows). Cross-U19 activities (black arrows) include Collaborative Pilot Projects, sharing of resources, and shared clinical studies. The Steering Committee is central in assessing transit of therapeutic agents from pre-clinical to clinical studies.

Each GTN U19 Center includes at least two Research Projects, at least one Shared Resources Core, and an Administrative Core. Collectively, the five U19 Centers encompass a range of therapeutic agents that are supported by strong pre-clinical data and have not been previously tested in adult GBM patients. Therapeutic agents in U19 Centers span small molecule and biological agents including new and repurposed BBB-penetrant small molecules targeting DNA damage response ATM and ATR kinases, de novo pyrimidine nucleotide biosynthesis, EGFR, neuron-GBM interactions, and telomere mutations; HSV oncolytic vectors bearing anti-CD47; immunomodulators; and novel syn-Notch CAR T cells. Combinations of new agents with standard- or non-standard-of-care agents are proposed.

Unique technologies included in the U19 GTN Centers are intracerebral microdialysis, BBB disruption with ultrasound and microbubbles, and freshly resected GBM tissue slice assays. Applications include plans for testing of PK, PD, safety, and toxicity in Phase 0/1 clinical trials. The U19 Centers represent complementary expertise, disciplines, and geographical distribution, increasing the potential for patient recruitment. Each U19 Center includes at least two clinical sites with non-overlapping patient populations. Overall, the five U19 Centers comprise a balanced set of therapeutic modalities, technologies, and expertise to meet the goal of identifying and testing novel therapies for GBM.

At the end of 5 years, a successful GTN will be prepared to move to Phase 2 studies with at least one agent supported by cross-GTN pre-clinical data, tested in cross-GTN Phase 1 studies, and substantiated by defined Phase 1 PD outcomes.

Participation by the GBM Community

Depending on the expertise required, the GTN Steering Committee will solicit advice and participation from brain cancer experts in the research community outside of the GTN. Groups from outside of the GTN Centers may become associate members by meeting GTN Steering Committee criteria for therapeutic agent readiness to enter the clinic, and participating in GTN-led clinical trials, subject to budgetary considerations. By engaging GTN members and associate members, NCI intends for the GTN to be a hub for pre-clinical to clinical transit and testing of novel agents for adult GBM.

Funding

The text is the sole product of the authors; no third party had input or gave support to the writing of this editorial. Funded by the National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Conflict of Interest:

The authors declare no conflicts of interest. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.