Approaches to Expand CAR T-Cell Therapy to Solid Tumors

Chimeric antigen receptor (CAR) T-cell therapy has been very effective against a growing number of hematologic malignancies, including diffuse large B-cell lymphoma, B-cell acute lymphoblastic leukemia, and multiple myeloma. The medical community hopes to eventually use the technique against solid tumors. A recent review article in the International Journal of Molecular Sciences highlighted the challenges and recent advancements using CAR T-cell therapy for solid tumors.
According to the authors, the main challenges facing efforts to deploy CAR T-cell therapy against solid tumors are:
• a limited array of targetable antigens
• heterogeneous antigen expression in solid tumors
• CAR structure
• challenges inherent in CAR T-cell production
• limited T-cell fitness
• inefficient methods for homing and infiltrating tumor tissue
• the immunosuppressive tumor microenvironment
The authors recommended high-level strategies that can help overcome those challenges, including:
• redesigning CAR structure
• using genome editing on CAR T cells
• knocking out inhibitory molecules
• promoting the inflammatory and proliferative activities of CAR T cells
• trying combination therapy with, for example, chemotherapies, immune checkpoint blockade, natural killer cell therapy
“Combination therapies with immunotherapies and chemotherapies are being developed extensively to obtain meaningful outcomes in clinical trials, especially for solid tumors with no response to the conventional therapies,” the authors wrote. “Technical advancements in genome editing, viral vector construction, and immune cell isolation and expansion have made the novel CAR T-cell therapies more feasible.”
Furthermore, the authors wrote, these strategies might be helpful in lessening the critical adverse events associated with CAR T-cell therapy, specifically cytokine release syndrome and neurotoxicity. They emphasized the need for novel therapeutic strategies that use lower CAR T-cell doses.
“More progression in CAR T-cell therapy and increased understanding of cancer immunology could lead to development of novel therapies and help patients with advanced solid tumors,” wrote the authors, led by Hyunmin Chung of the Korea Research Institute of Bioscience and Biotechnology. “We believe that it is worthwhile because once it works, these living drugs can recognize and further eradicate the remaining cancer cells. With an appropriate combination therapy, CAR T cells could work much better in the body, with increased persistence, reduced exhaustion, and better tumor trafficking.”