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Overcoming CAR T-Cell Exhaustion Remains a Challenge, Especially in Solid Tumors


Despite progress in chimeric antigen receptor (CAR) T-cell therapy, further research is needed to fully understand and overcome CAR T-cell exhaustion and improve outcomes.

Chimeric antigen receptor (CAR) T-cell therapy is a promising type of immunotherapy with positive results and FDA approvals of 5 treatments in several hematological malignancies, but solid tumors have proved to be more difficult targets. One limitation to the therapy’s efficacy is CAR T-cell exhaustion, especially in solid tumors. A recent review in eBioMedicine highlighted potential strategies to prevent or reverse exhaustion and, hopefully, improve outcomes of CAR T-cell therapy going forward.

CAR T-cell therapy is an adoptive cellular therapy (ACT) during which either allogeneic or autologous T cells are isolated and modified to attack a target antigen or antigens. The modified cells are administered via infusion and incite an immune response to those antigens. Despite positive results with initial treatment, however, relapse occurs in up to 75% of patients treated with CD19- or CD22-targeted CAR T-cell therapy.

Relapse has various causes, the most common of which is antigen escape. When this occurs, antigen-negative tumors develop due to selection pressure as CAR T cells target antigens. Patients with antigen-positive disease also relapse, however, suggesting intrinsic CAR T-cell traits may also have to do with disease response.

CAR T-cell therapy’s less robust efficacy in solid tumors also has to do with the cells’ limited ability to infiltrate tumors and target cells in the tumor microenvironment (TME). Accumulated immunosuppressive cells within the TME also inhibit CAR T-cell therapy efficacy in solid tumors, and T-cell exhaustion is another factor that can contribute to resistance or relapse.

T-cell exhaustion is thought to occur when T cells are persistently exposed to disease-specific antigens and enter a dysfunctional state of reduced proliferative capacity and effector function. Because CAR T cells are unable to kill target cells when resistance develops, formulating strategies to counteract exhaustion are crucial to the treatment’s efficacy.

One potential strategy to overcome exhaustion in CAR T-cell therapy is to target intrinsic T-cell pathways such as programmed death-1 (PD-1) receptors, TOX, Nr4a, transforming growth factor beta, or Casitas B-lineage lymphoma-b (CBL-B).

Both antibody and cell-intrinsic blockades of PD-1 signaling are promising methods to augment the efficacy of CAR T-cell therapy, although the review authors highlight the potential for immunotoxicity when trying to mitigate CAR T-cell therapy resistance via blockades.

“Although PD-1 blockade enhances CAR T-cell therapy, it is associated with T-cell autoreactivity, which can enhance tumor growth,” they wrote. “Similarly, CBL-B is essential for the regulation of immune tolerance and preventing autoimmunity.” For this reason, suicide or safety switches that can efficiently include apoptosis in CAR T cells are crucial to mitigate adverse events if necessary.

Different approaches to CAR engineering, such as modulating their surface expression or uncoupling their antigen recognition domain from the activation domain, are also potential avenues for improvement. The former method aims to overcome CAR T-cell exhaustion by limiting CAR-antigen interaction and the latter combats prolonged antigen stimulation of CAR T cells, which is thought to contribute to cell exhaustion.

Another factor affecting CAR T-cell therapy efficacy is the antigen density of the CAR target, and making CAR T-cell therapy more effective without additional toxicity when antigen density is low remains a challenge. Armored T cells, which have protective effects in the TME, are also being researched in solid tumor settings.

The review authors conclude that despite advancements in recent years, preventing and reversing CAR T-cell exhaustion is a crucial area of research to improve outcomes, especially in solid tumors. Gaining further understanding of the mechanisms of exhaustion is a key aspect of making progress.

“This would promote the development of more precise and effective methods of inhibiting T-cell differentiation and hyporesponsiveness by targeting the intrinsic mechanisms of T-cell exhaustion,” the authors wrote. “Lastly, the safety of these methods must be exhaustively investigated, as removing the brakes of the immune system could have devastating consequences.”


Gumber D, Wang LD. Improving CAR-T immunotherapy: overcoming the challenges of T cell exhaustion. EBioMedicine. Published online March 14, 2022. doi:10.1016/j.ebiom.2022.103941

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