Glioblastoma (GBM) is the most prevalent primary brain tumor in adults with extremely poorsurvival rates and largely unchanged standard of care. While there are many challenges todeveloping better GBM treatments, one of the major challenges is the immune-suppressiveenvironment commonly found within GBM tumors. This immune-suppressive nature results in atumor that is not suitable for mounting an immune response to GBM cells, rendering emergingimmunotherapies ineffective. To address this issue, suitable models that can interrogate thecomplex interactions between GBM cancer cells and microglia and peripherally derivedmacrophages would be invaluable for target identification, screening of novel therapeutics and formode of action studies. Tumor-associated microglia and macrophages are of particular interestdue to their primary role in shaping the immunological environment of GBM tumors. Humanorganoid technology is well-suited for modeling complex, multicellular interactions in a humantissue-like environment. Stem Pharm's hydrogel-enabled neural organoids allow for incorporationof non-neural populations such as microglia and macrophages in a reproducible, 96-well plateformat amenable to screening applications. Therefore, work in this proposal will develop andvalidate a human in vitro glioblastoma organoid model through incorporation of microglia,macrophages, and patient derived GBM cells in our neural organoids. Specific aims will 1)characterize organoids incorporating GBM, evaluate GBM survival, invasion, and proliferation;and characterize cell-type specific transcriptional responses to GBM and compare them to parenttumors and publicly available data sets. 2) demonstrate immunosuppressive activation ofmicroglia and macrophages within the neural organoid in response to infiltrating GBM cells.Multiplex cytokine panels, co-stimulatory and checkpoint molecule expression, and a directimmunosuppression assay with peripheral blood mononuclear cell-derived T-cells will be used toevaluate microglia and macrophage immunosuppression. Finally, treatment with three smallmolecules known to modulate macrophage activation will be assessed within the organoids todemonstrate the ability to regulate the microglial and macrophage response to GBM cells.Successful completion of these specific aims will result in a robust in vitro organoid model withnovel capabilities to interrogate GBM invasion and subsequent microglia and macrophageimmunosuppression. This will provide pharma partners with the ability to study therapies thatpreviously failed due to this immunosuppressive environment, and test new therapeuticapproaches. Phase II studies will expand the number of available patient-derived samples tobetter capture the diversity and heterogeneity of GBM tumors, explore sex-linked differences, andevaluate the effectiveness of CAR-Ts and combination therapies within the GBM model with thegoal of bringing better treatment options to patients for this devastating condition.
Public Health Relevance Statement: This project will apply Stem Pharm's human neural organoids for the development of
glioblastoma models that are amenable to screening for drug discovery applications. Through
inclusion of patient-derived glioblastoma cancer cells, microglia, and peripherally derived
macrophages, we aim to develop a model that better represents the immunosuppressive
environment of glioblastoma tumors for evaluating emerging therapeutics to eliminate cancers.
Project Terms: <21+ years old>
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