Characterization of the minimal residual disease state reveals distinct evolutionary trajectories of human glioblastoma.

Recurrence of solid tumors renders patients vulnerable to advanced, treatment-refractory disease state with mutational and oncogenic landscape distinctive from initial diagnosis. Improving outcomes for recurrent cancers requires a better understanding of cell populations that expand from the post-therapy, minimal residual disease (MRD) state. We profile barcoded tumor stem cell populations through therapy at tumor initiation, MRD, and recurrence in our therapy-adapted, patient-derived xenograft models of glioblastoma (GBM).

CD70 as an actionable immunotherapeutic target in recurrent glioblastoma and its microenvironment.

Purpose: Glioblastoma (GBM) patients suffer from a dismal prognosis, with standard of care therapy inevitably leading to therapy-resistant recurrent tumors. The presence of cancer stem cells (CSCs) drives the extensive heterogeneity seen in GBM, prompting the need for novel therapies specifically targeting this subset of tumor-driving cells. Here, we identify CD70 as a potential therapeutic target for recurrent GBM CSCs.

evaluation of CAR-T cells in patient-derived glioblastoma models.

Advances in chimeric antigen receptor (CAR) T cell therapies have led to the modality dominating translational cancer research; however, a standardized protocol for evaluating such therapies is needed. This protocol details the preclinical evaluation of CAR-T cell therapies for glioblastoma (GBM), including target cell cytotoxicity and T cell proliferation, activation, and cytokine release assays. For complete details on the use and execution of this protocol, please refer to Vora et al.

Advances in Immunotherapy for Adult Glioblastoma.

Despite aggressive multimodal therapy, glioblastoma (GBM) remains the most common malignant primary brain tumor in adults. With the advent of therapies that revitalize the anti-tumor immune response, several immunotherapeutic modalities have been developed for treatment of GBM. In this review, we summarize recent clinical and preclinical efforts to evaluate vaccination strategies, immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T cells.

The Strange Case of Jekyll and Hyde: Parallels Between Neural Stem Cells and Glioblastoma-Initiating Cells.

During embryonic development, radial glial precursor cells give rise to neural lineages, and a small proportion persist in the adult mammalian brain to contribute to long-term neuroplasticity. Neural stem cells (NSCs) reside in two neurogenic niches of the adult brain, the hippocampus and the subventricular zone (SVZ). NSCs in the SVZ are endowed with the defining stem cell properties of self-renewal and multipotent differentiation, which are maintained by intrinsic cellular programs, and extrinsic cellular and niche-specific interactions.

Preclinical Testing of CAR T Cells in a Patient-Derived Xenograft Model of Glioblastoma.

Glioblastoma (GBM) is the most common malignant adult brain tumor that is resistant to the standard care therapy. Advances in chimeric antigen receptor (CAR) T cell therapies have spurred renewed interest in developing CAR T cell therapies to target chemoradiotherapy-resistant brain tumor-initiating cells. This protocol shows how to isolate peripheral blood mononuclear cells from healthy donors and generate CAR T cells for the antigens of interest, and how to intracranially inject the CAR T cells into a patient-derived xenograft mouse model of GBM.

Assessing the Safety of a Cell-Based Immunotherapy for Brain Cancers Using a Humanized Model of Hematopoiesis.

Despite a surge in the preclinical development of immunotherapies, current models are unable to predict putative toxicity, particularly the "on-target, off-tumor" effects of these therapeutics. To address this gap, we used a humanized mouse model of hematopoiesis to examine the toxicity profile of CAR-Ts targeting brain tumor-antigens also expressed in the hematopoietic system. In assessing the safety of cell-based therapies, we aim to develop and integrate a preclinical evaluation protocol as a necessary step in the clinical development pathway.

The Rational Development of CD133-Targeting Immunotherapies for Glioblastoma.

CD133 marks self-renewing cancer stem cells (CSCs) in a variety of solid tumors, and CD133+ tumor-initiating cells are known markers of chemo- and radio-resistance in multiple aggressive cancers, including glioblastoma (GBM), that may drive intra-tumoral heterogeneity. Here, we report three immunotherapeutic modalities based on a human anti-CD133 antibody fragment that targets a unique epitope present in glycosylated and non-glycosylated CD133 and studied their effects on targeting CD133+ cells in patient-derived models of GBM. We generated an immunoglobulin G (IgG) (RW03-IgG), a dual-antigen T cell engager (DATE), and a CD133-specific chimeric antigen receptor T cell (CAR-T): CART133.

Salvage therapy for progressive, treatment-refractory or recurrent pediatric medulloblastoma: a systematic review protocol.

Background: Central nervous system tumors remain the leading cause of cancer-related mortality amongst children with solid tumors, with medulloblastoma (MB) representing the most common pediatric brain malignancy. Despite best current therapies, patients with recurrent MB experience have an alarmingly high mortality rate and often have limited therapeutic options beyond inadequate chemotherapy or experimental clinical trials. Therefore, a systematic review of the literature regarding treatment strategies employed in recurrent pediatric MB will evaluate previous salvage therapies in order to guide future clinical trials.

Differentiation of Brain Tumor Initiating Cells.

Differentiation is a central key capability of stem cells. Their ability to be multipotent and undergo self-renewal are key identifying features of stem cells. A differentiation assay allows for study of one of the essential features of stem cells, the ability to differentiate into all of the cell types of its lineage, in order to ensure that the cells cultured and utilized in key experiments indeed have stem cell properties.