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.