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Last Updated: 10/16/23

SPORE for Translational Approaches to Brain Cancer

Northwestern University

Principal Investigator(s):

Maciej S. Lesniak, MD
Maciej S. Lesniak, MD

Principal Investigator(s) Contact Information

Maciej S. Lesniak, MD
Michael J. Marchese Professor of Neurological Surgery
Chair, Department of Neurological Surgery
Feinberg School of Medicine
Program Leader, Neuro-Oncology
Robert H. Lurie Comprehensive Cancer Center
Northwestern University
676 N. St Clair Street
Suite 2210
Chicago, Illinois 60611


The overall objective of the Northwestern Brain Tumor SPORE is to improve outcomes for brain tumor patients. Of the various primary intracerebral neoplasms, glioblastoma (GBM) is the most common. GBM patients that receive standard-of-care treatment have a median survival of 20 months, and 5-year survival is extremely rare. Progress in developing better treatments for this lethal tumor has been disappointing. A major contributor to this lack of therapeutic improvement is the delicate nature of the organ in which this cancer occurs. There are significant limitations to how aggressively GBM patients can be treated surgically, and the efficacy of systemically administered therapies are often compromised due to limited access to the brain. To address the public health problem that is associated with glioblastoma, we have assembled a talented team of investigators with extensive backgrounds in brain tumor research and therapy. All members of this team have professional records indicating success in directing their own programs of research. Together, these faculty initiated group interactions in order to bring a team science approach to bear upon the study and treatment of GBM, and for which a multidisciplinary approach is needed for achieving meaningful progress.

PROJECT 1: Neural Stem Cell Virotherapy for Malignant Glioma

Project Leaders:
Maciej S. Lesniak, MD (Basic Co-Leader)
Roger Stupp, MD (Clinical Co-Leader)
Adam Sonabend, MD (Clinical Co-Leader)

Glioblastoma remains resilient to therapy and recurrence is almost universal. In particular, targeted therapies fail given the heterogeneity in the expression or presence of molecular targets for these therapies across tumors. Oncolytic virotherapy (OV) is an anti-tumoral strategy where viruses selectively replicate and kill tumor cells in the brain and potentially, activate anti-tumoral immune response. Initial studies showed that a bottleneck for the efficacy of OV was poor distribution of virus in the human brain. To overcome this challenge, over the last SPORE funding period, we investigated the feasibility and safety of delivering oncolytic adenovirus to the peri-tumoral brain of malignant glioma patients using neural stem cells (NSC) which can carry OV and migrate to distant tumor pockets infiltrating the brain. We conducted a Phase 1 trial in which we showed the feasibility, safety and established a maximally tolerated dose for this therapy (NCT03072134) and published the results in Lancet Oncology. The next step in this program is to perform a phase II trial to investigate the efficacy of OV using overall survival as an endpoint for efficacy. However, a phase II trial needs to be optimized via additional studies proposed in this continuation of funding by 1) enabling multiple injections over time, to be accomplished through a novel brain parenchymal catheter-based delivery system. 2) maximizing NSC viability and OV production using N-acetylcystein Amide (NACA), which we showed to enhance delivery and efficacy of this therapy, and 3) a priori-identification of patients with tumors that are susceptible to OV. We hypothesize that only a subset of patients might have tumors that are susceptible to OV, and that identification of susceptible tumors will allow elucidation of an efficacy signal.

Specific Aims:

Aim 1: Conduct a phase 1B expansion trial utilizing a novel catheter method to deliver multiple injections of product in newly diagnosed malignant gliomas

Aim 2: Examine the pre-existing tumor microenvironment, the effect of NACA on viral replication, and the immune response during NSC-OV therapy in malignant glioma patients.

Aim 3: Validate genes that are implicated in glioma susceptibility to oncolytic virus using paired analysis of pre-treatment and during-treatment human glioma specimens

PROJECT 2: STINGing GBM: A First-in-man Clinical Trial in Surgically Resectable Recurrent GBM

Project Leaders:
Amy Heimberger, MD, PhD (Basic Co-Leader)
Rimas V. Lukas, MD (Clinical Co-Leader)
Irina V. Balyasnikova, PhD (Basic Co-Leader)

The glioblastoma (GBM) microenvironment is dominated by myeloid cell infiltrates. Results from multiple studies indicate these tumor-associated myeloid cells (TAMS) as supporting GBM growth. The goal of this project is to reprogram TAMS for immunologic anti-tumor activity. Stimulator of interferon genes (STING) is a widely expressed sensor of cellular stress that is activated by the presence of DNA in the cytoplasm. Distinct from most other immune agonists, STING activation re-educates tumor supportive M2 macrophage TAMS toward a proinflammatory anti-tumor M1 phenotype. Macrophage proinflammatory phenotypic conversion, in turn, promotes cytotoxic T cell infiltration of and activity against tumor. We have developed a high potency stimulator of interferon genes (STING) agonist, IACS-8803, with marked antitumor activity when tested in humanized mice bearing human GBM, and in canines with spontaneously arising high-grade gliomas. This first-in-man Phase I clinical trial will inform regarding the range in IACS-8803 activity that is observed across the cohort of treated patients, with activity results compared against tumor molecular characteristics, and patient clinical data. The clinical trial will include analysis of several unique endpoints, among which are target engagement and longitudinal kinetics of IACS-8803 induced T cell chemokine expression such as CXCL10. In addition, a window-of-opportunity patient cohort will receive direct intratumoral administration of IACS-8803, and whose results will be compared against those from patients that have received systemic administration of standard-of-care therapeutics. This clinical study will ultimately provide sufficient data to make a clear go/no go determination for later-stage clinical trials.

Specific Aims:

Aim 1: Ascertain the clinical potential of [18F]FLT PET in determining IACS-8803 treatment efficacy in preclinical GBM models.

Aim 2: Evaluate the therapeutic synergy of STING agonists with radiation in orthotopic preclinical glioma models, including those resistant to immune checkpoint inhibitors.

Aim 3: Conduct a Phase I dose-escalation study of IACS-8803 in recurrent GBM patients.

Aim 4: Conduct a window-of-opportunity expansion cohort trial to determine the association between tumor STING promoter methylation, tumor immune functional assessment data, and [18F]FLT PET imaging results in GBM patients after administration of IACS-8803.

PROJECT 3: Development of a B-cell Based Vaccine for the Treatment of Newly Diagnosed Glioblastoma

Project Leaders:
Catalina Lee-Chang, PhD (Basic Co-Leader)
Roger Stupp, MD (Clinical Co-Leader)
Maciej S. Lesniak, MD (Clinical Co-Leader)

Immunotherapy has significantly improved the clinical outcome of many cancer patients. However, most glioblastoma (GBM) patients have not, so far, benefited from immunotherapeutic intervention. To explore alternative ways to potentiate the anti-GBM immunity, we've developed a B-cell-based vaccine (BVax) that consists of 4-1BBL+ B cells activated with CD40 agonism, BAFF, and IFNg stimulation. In our preclinical study, BVax migrates to critical secondary lymphoid organs and is proficient at antigen cross-presentation, promoting the survival and functionality of tumor-infiltrating CD8+ T cells. In addition, BVax produces immunoglobulins (humoral immune response) reactive to the tumor. These immunoglobulins elicited a potent therapeutic effect. A combination of radiation, BVax, CD8 T cells and PD-L1 blockade conferred tumor eradication in 80% of treated tumor-bearing animals. This research proposal aims to translate BVax to the clinic to treat newly diagnosed malignant gliomas. To effectively implement this therapy in the clinic, we propose to perform IND-enabling studies to manufacture autologous BVax and CD8 T cells.

Specific Aims:

Aim 1: Upon FDA approval, we aim to conduct a first-in-human BVax trial.

Aim 2: Evaluate the effect on the immune response.

Aim 3: We hypothesize that the proposed autologous cellular therapy is safe and effective at eliciting protective anti-GBM immunity via cellular and humoral immune responses. Overall, our study provides a novel alternative to current immunotherapeutic approaches.

PROJECT 4: A Phase 1 Adaptive Dose Escalation Study of Mycophenolate Mofetil in Combination with Temozolomide for Patients with Newly Diagnosed Glioblastoma

Project Leaders:
Atique Ahmed, PhD (Basic Co-Leader)
Priya Kumthekar, MD (Clinical Co-Leader)

We have identified ARL13B as a novel regulator of the purine biosynthesis pathway during chemotherapy through initial analysis. ARL13B, a member of the ADP-ribosylation factor-like family protein accountable for cilia maintenance, directly interacts with inosine monophosphate dehydrogenase 2 (IMPDH2), the rate-limiting enzyme purine biosynthesis. Our initial studies knocking down ARL13B inhibited GBM cells' utilization of the de novo pathway after TMZ treatment and increased utilization of the salvage biosynthesis pathway. The effectiveness of TMZ treatment was also elevated in vitro and in vivo following ARL13B knockdown. We, therefore, proposed that the ARL13B-IMPDH2 regulated switch from the salvage pathway to the de novo purine biosynthesis pathway is necessary for GBM cells' adaptation to alkylating-based chemotherapy. Based on this, we hypothesize that therapeutic transformation in GBM involves interaction between ciliary protein ARL13B and rate-limiting purine biosynthesis enzyme IMPDH2 Mycophenolate mofetil (MMF), an FDA-approved drug in the organ-transplant setting, inhibits IMPDH2 activity and allows for increased the therapeutic efficacy of TMZ and extended the survival of patient-derived xenograft (PDX) models across multiple GBM subtypes. This provides a clinically translatable opportunity to overcome chemoresistance in GBM.

In this proposal, we set to conduct a Phase 1/1b clinical trial of MMF combined with standard chemo- and radiotherapy for newly diagnosed GBM. The primary objectives are to evaluate this novel combination's safety and toxicity and establish the maximally tolerated dose (MTD). Exploratory secondary endpoints include progression-free and overall survival. Furthermore, we intend to investigate mycophenolic acid, an immediate metabolite of MMF that can serve as a biomarker for such therapy.

Specific Aims:

Aim 1: To complete the ongoing Phase I / Ib trial of MMF combined with standard chemo- and radiotherapy for newly diagnosed GBM.

Aim 2: Monitor target engagement of MMF using a window-of-opportunity arm.

Aim 3: Validation of predictive biomarkers implicated in GBM susceptibility to MMF in combination with standard-of-care TMZ therapy.

Administrative Core

Core Co-Directors:
Maciek S. Lesniak, MD
David James, PhD
Amy Heimberger, MD, PhD

The SPORE Administrative Core will provide the structure and oversight that facilitates scientific productivity and innovation and promotes collaborative activities for SPORE investigators. Through its functions and activities, this Core will serve as the central organizational hub for the Projects and Cores that will assist investigators in achieving their translational research objectives. The Administrative Core ensures that the SPORE is fully integrated into the administrative structure of the Robert H. Lurie Comprehensive Cancer Center (LCC) at Northwestern. The Administrative Core will provide strong leadership for all components of the SPORE.

Specific Aims:

Aim 1: Integrate the SPORE within the activities of the Lurie Cancer Center and Feinberg School of Medicine.

Aim 2: Develop, maintain and, as needed, modify the External Advisory and Internal Advisory Boards and Executive committee that provide advice to, as well as oversight of, SPORE research.

Aim 3: Organize and conduct bi-weekly research meetings for frequent evaluation of SPORE progress.

Aim 4: Provide fiscal planning for and oversight of all components of this SPORE.

Aim 5: Organize and conduct patient advocacy activities.

Aim 6: Facilitate collaborations with investigators at the LCC, other SPORE institutions, industry and with other funded programs.

Biospecimen Core

Core Co-Directors:
Craig M. Horbinski, MD, PhD
Daniel J. Brat, MD, PhD

The primary objective of the Biospecimen Core is to facilitate and enhance the impact of brain tumor research conducted by Northwestern University investigators by serving as the source of high-quality and well-annotated biospecimens, and by providing neuropathological consultation. The Core collects approximately 400 new tumors and matching blood every year from surgical procedures at Northwestern. This robust collection, and analytical services provided by the Core, have supported 126 research projects (including 10 clinical trials) from 49 investigators at Northwestern and outside institutions. The Core PI, Dr. Craig Horbinski, and Core Co-Director, Dr. Daniel Brat, have and will continue to oversee Core activities that are of central importance to Northwestern Brain Tumor SPORE productivity. The Biospecimen Core is a vital resource that supports all brain tumor research at Northwestern and is especially important to ensure that all SPORE projects experience clinical translation. Through regular interaction with Project PIs and key investigators, as well as with the Administrative and Biostatistics & Bioinformatics Cores, the Biospecimen Core will help each project achieve its objectives and will have a positive impact on the care of brain tumor patients.

Specific Aims:

Aim 1: Provide Northwestern brain tumor researchers with annotated biospecimens from brain tumor patients.

Aim 2: Conduct rigorous quality control testing for all collected specimens.

Aim 3: Conduct independent Biospecimen Core research.

Aim 4: Support SPORE projects with biospecimens and neuropathologic analyses.

Biostatistics and Bioinformatics Core

Core Co-Directors:
Hui Zhang, PhD
Feng Yue, PhD

The Biostatistics and Bioinformatics Core (B&B Core) is a central component of the Brain Tumor SPORE, providing state-of-the-art integrated data science support to all Brain Tumor SPORE projects. Database development and maintenance will provide a centralized resource for data tracking for preclinical studies, ensuring efficient reporting and statistical analysis of all experiments. In addition, clinical databases will be developed in conjunction with all project teams to complement existing clinical trial data registries at Northwestern and ensure custom data capture in a highly secure environment. Bioinformatics activities of the B&B Core are central to discovery and will help define new and significant research directions. The large omics data sets that will be generated in the Brain Tumor SPORE Projects require specialized expertise for preprocessing, analysis, and interpretation of molecular and biological consequences of genetic manipulations and treatments. Bioinformatics functionality provided by the B&B Core will provide this crucial assistance for all proposed Brain Tumor SPORE Projects. Biostatistical activities of the B&B Core are central to the concerns of rigor and reproducibility: by providing study design guidance, data management, statistical analysis, and consultation for interpretation of results the core will see that reported results have been rigorously controlled and will be reproducible by others.

Specific Aims:

Aim 1: Establish and maintain database functionality for all preclinical and clinical data.

Aim 2: Provide bioinformatics collaboration and support for pre-processing and analysis of high-dimensional omics data, including array-based and sequencing data.

Aim 3: Provide biostatistical collaboration and support for design of preclinical studies and clinical trials, as well as statistical analyses of all accumulated data.

Developmental Research Program

Program Co-Directors:
Maciek S. Lesniak, MD
Amy Heimberger, MD, PhD
David James, PhD

The Developmental Research Program (DRP) of the Northwestern Brain Tumor SPORE provides yearly funding to 3-4 projects that have promising translational potential. DRP projects that experience outstanding development may replace main projects that are not progressing, or the associated project investigators will be encouraged to secure independent funding in brain cancer research.

Specific Aims:

Aim 1: Solicit, identify and support meritorious translational research projects that are considered as having a high probability of impacting the diagnosis and/or treatment and/or prevention of brain tumors.

Aim 2: Facilitate developmental project maturation into full SPORE project status, or for independent project funding.

Aim 3: Attract outstanding new and experienced investigators currently not working on brain tumors to pursue brain tumor research, with a special emphasis on inclusion of women and minority investigators.

Career Enhancement Program

Program Co-Directors:
Maciek S. Lesniak, MD
Amy Heimberger, MD, PhD
David James, PhD

The Career Enhancement Program is a critical component of the Northwestern Brain Tumor SPORE, in that it ensures that there will be a continuous influx of talented investigators devoted to brain cancer research.

Specific Aims:

Aim 1: Maintain an administrative structure for the Career Enhancement Program.

Aim 2: Solicit and select career enhancement investigators through a highly structured process.

Aim 3: Mentor and continuously evaluate career enhancement investigators through individual meetings with mentors, bi-annual presentations at SPORE investigator work in progress meetings and written progress reports.

Aim 4: Cultivate new faculty to embark on careers in neuro-oncology to ensure a future source of talented investigators committed to brain cancer research.

Institutional SPORE Website