R01CA263500

Developing Safe and Effective GD2-CAR T Cell Therapy for Diffuse Midline Gliomas - Project Summary

Brain tumors are the leading cause of cancer-related death in children. Among these, Diffuse Intrinsic Pontine Glioma (DIPG) and other Histone-3 K27M (H3K27M) mutated Diffuse Midline Gliomas (DMGs) are the most aggressive and universally fatal with current standard therapies. Despite several decades of investigational trials testing dozens of therapeutic approaches, the median overall survival for DIPG is only 11 months.

Chimeric Antigen Receptor (CAR)-expressing T-cells have shown impressive clinical activity in B-cell malignancies, and recent preclinical and early clinical results suggest benefit in CNS malignancies. We have discovered homogeneous, high overexpression of the GD2 ganglioside on H3K27M DMGs and demonstrated impressive antitumor effects in xenograft models of H3K27M-mutant DIPG following treatment with GD2-CAR T cells (GD2-CART, Mount, Nat Med 2018). Significant clinical experience with GD2 targeting CAR T cells, mostly from studies in neuroblastoma, demonstrate safety and some early signals of antitumor activity. Safe and effective translation of these findings to children with DMGs would transform the landscape for this universally lethal pediatric brain tumor.

This bench-to-bedside-to-bench project will conduct three aims in parallel, leveraging a recently launched single institution phase I trial of GD2.BB.Z.ICASP9-CAR T cells administered intravenously following a lymphodepleting preparative regimen in children and young adults with H3K27M DMGs.

The first aim focuses on safety, integrating insights gleaned from our preclinical models into trial design to diminish the risk of tumor inflammation-associated neurotoxicity (TIAN), establish best practices, and develop improved grading and treatment algorithms for this novel toxicity.

The second aim focuses on efficacy, assessing the clinical activity of GD2-CART in DMG and identifying biomarkers and clinical features associated with response. We further address the limitations of standard radiographic imaging in these infiltrative tumors using a novel machine learning-aided MRI radiomics approach to quantify textural changes within the tumor and assess whether such changes correlate with clinical outcome. Additionally, we assess whether GD2-CART induced changes in cerebrospinal fluid (CSF) cell-free DNA can provide a rapid quantitative assessment of antitumor response.

Our third aim is a discovery aim, focused on improving understanding of the biology associated with myeloid cell activation following GD2-CART therapy for DMGs, which we observe in preclinical models and in the first patient treated. Here, we undertake comprehensive single-cell profiling of CSF myeloid cells emerging post-GD2-CART in patients enrolled in the study and in preclinical models. We also perform bedside-to-bench translation using murine models to test the hypotheses that GD2-CART induced CNS myeloid cell expansion/activation limits the efficacy of GD2-CART, is modulated by corticosteroid therapy, and that this obstacle can be overcome by engineering CD47 overexpression in the GD2-CART.

The Leland Stanford Junior University

TO DEVELOP THE MEANS TO CURE AS MANY CANCER PATIENTS AS POSSIBLE AND TO CONTROL THE DISEASE IN THOSE PATIENTS WHO ARE NOT CURED. CANCER TREATMENT RESEARCH INCLUDES THE DEVELOPMENT AND EVALUATION OF IMPROVED METHODS OF CANCER TREATMENT THROUGH THE SUPPORT AND PERFORMANCE OF BOTH FUNDAMENTAL AND APPLIED LABORATORY AND CLINICAL RESEARCH. RESEARCH IS SUPPORTED IN THE DISCOVERY, DEVELOPMENT, AND CLINICAL TESTING OF ALL MODES OF THERAPY INCLUDING: SURGERY, RADIOTHERAPY, CHEMOTHERAPY, AND BIOLOGICAL THERAPY INCLUDING MOLECULARLY TARGETED THERAPIES, BOTH INDIVIDUALLY AND IN COMBINATION. IN ADDITION, RESEARCH IS CARRIED OUT IN AREAS OF NUTRITIONAL SUPPORT, STEM CELL AND BONE MARROW TRANSPLANTATION, IMAGE GUIDED THERAPIES AND STUDIES TO REDUCE TOXICITY OF CYTOTOXIC THERAPIES, AND OTHER METHODS OF SUPPORTIVE CARE THAT MAY SUPPLEMENT AND ENHANCE PRIMARY TREATMENT. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.395 - Cancer Treatment Research

National Cancer Institute (NCI) [HHS - NIH]

Stanford, California 94305 United States

Single Zip Code

National Cancer Institute's Investigator-Initiated Early Phase Clinical Trials for Cancer Treatment and Diagnosis (R01 Clinical Trials Required) (PAR-18-560)

Amendment Since initial award the total obligations have increased 391% from $671,445 to $3,294,656.