Cytokine Modification of Adoptive Chimeric Antigen Receptor Immunotherapy for Glioblastoma

Simple Summary Chimeric antigen receptor (CAR) cell-based therapy is a promising treatment approach for glioblastoma, a fatal brain cancer with limited treatment options. Efforts to improve these therapies are currently underway, with one method being cytokine modification. Cytokines are a type of protein created by cells in the body that can change the function of immune cells. In this review, the authors summarize approaches that employ cytokines to improve CAR cell therapies. These include coadministering CAR T-cells or CAR NK-cells with cytokines, antibodies, or oncolytic viruses or via engineering CAR cell therapies to secrete or express cytokines, express a cytokine receptor, or genetically alter cytokine signaling pathways. We hope that providing cytokine support to CAR cell-based therapies will improve their efficacy for patients with glioblastoma.Abstract Chimeric antigen receptor (CAR) cell-based therapies have demonstrated limited success in solid tumors, including glioblastoma (GBM). GBMs exhibit high heterogeneity and create an immunosuppressive tumor microenvironment (TME). In addition, other challenges exist for CAR therapy, including trafficking and infiltration into the tumor site, proliferation, persistence of CARs once in the tumor, and reduced functionality, such as suboptimal cytokine production. Cytokine modification is of interest, as one can enhance therapy efficacy and minimize off-target toxicity by directly combining CAR therapy with cytokines, antibodies, or oncolytic viruses that alter cytokine response pathways. Alternatively, one can genetically modify CAR T-cells or CAR NK-cells to secrete cytokines or express cytokines or cytokine receptors. Finally, CARs can be genetically altered to augment or suppress intracellular cytokine signaling pathways for a more direct approach. Codelivery of cytokines with CARs is the most straightforward method, but it has associated toxicity. Alternatively, combining CAR therapy with antibodies (e.g., anti-IL-6, anti-PD1, and anti-VEGF) or oncolytic viruses has enhanced CAR cell infiltration into GBM tumors and provided proinflammatory signals to the TME. CAR T- or NK-cells secreting cytokines (e.g., IL-12, IL-15, and IL-18) have shown improved efficacy within multiple GBM subtypes. Likewise, expressing cytokine-modulating receptors in CAR cells that promote or inhibit cytokine signaling has enhanced their activity. Finally, gene editing approaches are actively being pursued to directly influence immune signaling pathways in CAR cells. In this review, we summarize these cytokine modification methods and highlight any existing gaps in the hope of catalyzing an improved generation of CAR-based therapies for glioblastoma.