CDK4/6 inhibition enhances CAR-T cell therapy in solid tumors
- Author(s)
- Lelliott, EJ; Naddaf, J; Lu, KH; Cummins, KD; Ramsbottom, KM; Reynolds, DS; Taylor, M; Ambani, K; Munoz, I; Jackson, S; Li, J; Chan, CW; Britt, KL; Beavis, PA; Goel, S; Oliaro, J;
- Details
- Publication Year 2026-07-01,Volume 34,Issue #7,Page 4021-4034
- Journal Title
- Molecular Therapy
- Publication Type
- Research article
- Abstract
- CDK4/6 inhibitors promote anti-tumor immunity through diverse mechanisms, positioning them as promising adjuvants to cancer immunotherapies. While CDK4/6 inhibitors have demonstrated strong synergy with immune checkpoint inhibitors across numerous preclinical cancer models, their combination with CAR-T cell therapy remains unexplored. In this study, we examined the efficacy of combined CDK4/6 inhibition (trilaciclib) and CAR-T therapy across a range of preclinical blood and solid cancer models. In vitro, trilaciclib enhanced human CAR-T cell cytotoxicity and metabolic fitness while reducing expansion. In vivo, the combination outperformed single agents against retinoblastoma protein (RB)-proficient, trilaciclib-sensitive CD19+ leukemia. However, in an equivalent RB-deficient model, the combination therapy was no more effective than CAR-T cells alone, suggesting that enhanced CAR-T cell function may be offset by reduced expansion. In contrast, in solid cancer models the combination was consistently more efficacious than either monotherapy. Notably, combination effects were most pronounced in immunocompetent mouse models, including a model with poor sensitivity to trilaciclib as a monotherapy. Mechanistically, CDK4/6 inhibition reduced tumor-infiltrating T-regulatory cells while enhancing CD8+ CAR-T cell persistence, tumor trafficking, and cytotoxic function within the tumor. Together, these findings suggest that trilaciclib and CAR-T cell therapy may be an effective combinatorial treatment for solid cancers.
- Publisher
- Cell Press
- Keywords
- Animals; Humans; *Cyclin-Dependent Kinase 6/antagonists & inhibitors; *Cyclin-Dependent Kinase 4/antagonists & inhibitors; Mice; *Neoplasms/therapy/immunology/metabolism; *Immunotherapy, Adoptive/methods; Cell Line, Tumor; Xenograft Model Antitumor Assays; *Protein Kinase Inhibitors/pharmacology; *Receptors, Chimeric Antigen/metabolism; Disease Models, Animal; Combined Modality Therapy; CAR-T cell therapy; CDK4/6 inhibitor; RB-proficient tumors; T cell metabolism; cancer immunotherapy; combination therapy; hematologic malignancies; preclinical cancer models; solid tumors; trilaciclib
- Department(s)
- Laboratory Research
- Publisher's Version
- https://doi.org/10.1016/j.ymthe.2026.03.024
- Open Access at Publisher's Site
https://doi.org/10.1016/j.ymthe.2026.03.024- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2026-04-07 12:09:45
Last Modified: 2026-08-04 04:43:07