Dataset Information

CDK4/6 Inhibition Enhances CAR-T Cell Therapy in Solid Tumors

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 pre-clinical 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 RB-proficient, trilaciclib-sensitive CD19+ leukaemia. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE326798 | GEO | 2026/04/07

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Osteosarcoma (OS) is the most common primary bone cancer in adolescents, young adults (AYA), and children, with up to 25% of patients developing metastatic disease, primarily in the lungs. Despite survival rates being >70% for localized tumors, patients with metastatic OS have <30% survival due to limited effective salvage therapies. OS is characterized by chromosomal instability (CINs) and dysregulated CDK4/6 and PI3K/mTOR pathways. The retinoblastoma protein (RB), a downstream target of CDK4/6, is a key regulator of G1/S cell cycle progression. We validated these targets in OS cell lines, xenografts, and patient-derived xenografts (PDXs), revealing CDK4/6 hyperactivation. While CDK4/6 inhibitors show promise, they are ineffective as monotherapies due to cytostatic effects and resistance from compensatory pathways, such as PI3K/AKT/mTOR. This study investigates dual inhibition of CDK4/6 and PI3K/mTOR using palbociclib and voxtalisib, respectively, in OS models. In RB proficient (RB+) OS lines, the combination therapy exhibited synergistic inhibition of cell growth and G1 arrest, while inducing autophagy without disrupting palbociclib-induced senescence. Prolonged treatment triggered autophagy in treatment-naïve PDXs, with senescence partially reversed in the combination group. Combination therapy enhanced palbociclib efficacy in both pretreated and naïve PDX models, improving survival. Mechanistically, palbociclib reduced CDK1/2 activity, while voxtalisib suppressed CDK1/2 and RB1 phosphorylation, impairing cell cycle progression. The combination significantly reduced metastatic burden and improved survival in OS lung colonization models, inhibiting pre-established metastatic foci. Kinome profiling and proteomic analyses confirmed decreased PI3K and mTOR activity. This study highlights the potential of CDK4/6 and PI3K/mTOR dual inhibition in OS, offering therapeutic promise for overcoming resistance and improving outcomes in pediatric and AYA patients with CDK4/6 hyperactivation.

Project description:A significant challenge for chimeric antigen receptor (CAR) T cell therapy against glioblastoma (GBM) is its immunosuppressive tumor microenvironment (TME), which is densely populated and supported by protumoral glioma-associated microglia and macrophages (GAMs). Targeting CD47, a don't-eat-me signal overexpressed by tumor cells, disrupts the CD47-SIRPalpha axis and induces GAM phagocytic function. However, antibody-mediated CD47 blockade monotherapy is associated with toxicity and low bioavailability in solid tumors. To overcome these limitations, we combined local CAR T cell therapy with paracrine GAM modulation to effectively eliminate GBM. To this end, we engineered a new CAR T cell against epidermal growth factor receptor variant III (EGFRvIII) that constitutively secretes a signal regulatory protein gamma (SIRPgamma)-related protein (SGRP) with high affinity to CD47. Anti-EGFRvIII-SGRP CAR T cells eliminated EGFRvIII+ GBM in a dose-dependent manner in vitro and eradicated orthotopically xenografted EGFRvIII-mosaic GBM by locoregional application in vivo. This resulted in significant tumor-free long-term survival, followed by partial tumor control upon tumor re-challenge. Combining anti-CD47 antibodies with anti-EGFRvIII CAR T cells failed to achieve a similar therapeutic effect, underscoring the importance of sustained paracrine GAM modulation. Multidimensional brain immunofluorescence microscopy and in-depth spectral flow cytometry on GBM-xenografted brains showed that anti-EGFRvIII-SGRP CAR T cells accelerated GBM clearance, increased CD68+ cell trafficking to tumor scar sites and promoted GAM-mediated tumor cell uptake. In a peripheral lymphoma mouse xenograft model, anti-CD19-SGRP CAR T cells had superior efficacy to conventional anti-CD19 CAR T cells. Validation on human GBM explants revealed that anti-EGFRvIII-SGRP CAR T cells had a similar tumor-killing capacity to anti-EGFRvIII CAR monotherapy but showed a slight improvement in the maintenance of tumor-infiltrated CD14+ cells. Thus, local anti-EGFRvIII-SGRP CAR T cell therapy combines the potent antitumor effect of engineered T cells with the modulation of the surrounding innate immune TME. This results in the additive elimination of bystander EGFRvIII- tumor cells in a manner that overcomes the main mechanisms of CAR T cell therapy resistance, including tumor innate immune suppression and antigen escape.

Dataset Information

CDK4/6 Inhibition Enhances CAR-T Cell Therapy in Solid Tumors

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets