Glioblastoma Organoids: Pre-Clinical Applications and Challenges in the Context of Immunotherapy

Abstract

Malignant brain tumors remain uniformly fatal, even with the best-to-date treatment. For Glioblastoma (GBM), the most severe form of brain cancer in adults, the median overall survival is roughly over a year. New therapeutic options are urgently needed, yet recent clinical trials in the field have been largely disappointing. This is partially due to inappropriate preclinical model systems, which do not reflect the complexity of patient tumors. Furthermore, clinically relevant patient-derived models recapitulating the immune compartment are lacking, which represents a bottleneck for adequate immunotherapy testing. Emerging 3D organoid cultures offer innovative possibilities for cancer modeling. Here, we review available GBM organoid models amenable to a large variety of pre-clinical applications including functional bioassays such as proliferation and invasion, drug screening, and the generation of patient-derived orthotopic xenografts (PDOX) for validation of biological responses in vivo. We emphasize advantages and technical challenges in establishing immunocompetent ex vivo models based on co-cultures of GBM organoids and human immune cells. The latter can be isolated either from the tumor or from patient or donor blood as peripheral blood mononuclear cells (PBMCs). We also discuss the challenges to generate GBM PDOXs based on humanized mouse models to validate efficacy of immunotherapies in vivo. A detailed characterization of such models at the cellular and molecular level is needed to understand the potential and limitations for various immune activating strategies. Increasing the availability of immunocompetent GBM models will improve research on emerging immune therapeutic approaches against aggressive brain cancer.

Mouse Models of Experimental Glioblastoma

“…Furthermore, in vitro cell culture does not model human immune cells. This limits exploration of factors regulating tumor-host interactions and immune control (21)(22)(23).…”

Glutamatergic Mechanisms in Glioblastoma and Tumor-Associated Epilepsy

“…In vitro, glioblastoma cells can also be cultivated as 3D spheroids or organoids [ 165 , 166 , 167 , 178 ]. As in 2D cultures, the tumor-surrounding microenvironment is absent.…”

“…As in 2D cultures, the tumor-surrounding microenvironment is absent. Co-culture models and approaches with limited immune components exist, but these may only reflect selected components and are no full replacement for in vivo conditions [ 166 ]. With respect to glutamate-driven processes in glioblastoma, the main focus with these models is on drug screening and as a source for injection in in vivo models or in organotypic brain slices.…”

Precision Oncology Beyond Genomics: The Future Is Here—It Is Just Not Evenly Distributed

“…Dijkstra et al established a co-culture system of autologous tumor organoids and peripheral blood lymphocytes of patients to induce and analyze tumor-specific T cell responses for mismatch repair deficient colorectal cancer and non-small cell lung cancer in a personalized manner [ 118 ]. Klein et al demonstrated the advantages of co-culture systems of GBM organoids and human immune cells, to investigate not only immune–tumor interactions, but also to explore current and novel immunotherapies, such as adoptive T cell transfer, immune checkpoint inhibitors, or oncolytic viruses [ 127 ].…”