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Generation of CAR T Cells for Adoptive Therapy in the Context of Glioblastoma Standard of Care
Published on: February 16, 2015
Cytokine Modification of Adoptive Chimeric Antigen Receptor Immunotherapy for Glioblastoma
Kristen D Pawlowski1, Joseph T Duffy2,3, Stephen Gottschalk4
1Department of Neurological Surgery, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA.
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.
Insights
Chimeric antigen receptor (CAR) T-cell therapies face challenges in glioblastoma (GBM). Modifying cytokine pathways in CAR cells or the tumor microenvironment (TME) shows promise for improving CAR therapy efficacy against GBM.
Area of Science:
- Immunotherapy
- Oncology
- Cellular Therapy
Background:
- Chimeric antigen receptor (CAR) cell therapy shows limited efficacy in solid tumors like glioblastoma (GBM).
- Glioblastoma presents challenges including tumor heterogeneity, an immunosuppressive tumor microenvironment (TME), and issues with CAR cell trafficking, infiltration, persistence, and function.
- CAR therapy efficacy is often limited by suboptimal cytokine production and signaling within the TME.
Purpose of the Study:
- To review and summarize various cytokine modification strategies aimed at enhancing CAR-based therapies for glioblastoma.
- To highlight existing gaps in current approaches and catalyze the development of improved CAR therapies for GBM.
Main Methods:
- Review of strategies involving direct cytokine codelivery, combination with antibodies or oncolytic viruses, genetic modification of CAR T- or NK-cells to secrete cytokines or express cytokine receptors, and gene editing of intracellular cytokine signaling pathways.
- Analysis of how these modifications impact CAR cell infiltration, proliferation, persistence, and functionality in the GBM TME.
Main Results:
- Combining CAR therapy with antibodies (anti-IL-6, anti-PD1, anti-VEGF) or oncolytic viruses enhances CAR cell infiltration and promotes a proinflammatory TME.
- CAR T- or NK-cells engineered to secrete cytokines (IL-12, IL-15, IL-18) demonstrate improved efficacy across GBM subtypes.
- Modulating cytokine signaling pathways through engineered receptors or gene editing enhances CAR cell activity.
Conclusions:
- Cytokine modification represents a critical avenue for overcoming the limitations of CAR cell therapy in glioblastoma.
- Strategic manipulation of cytokine pathways offers potential to improve CAR cell trafficking, function, and overall therapeutic efficacy against GBM.
- Further research into these cytokine-centric approaches is essential for advancing next-generation CAR-based glioblastoma treatments.
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