CDK4/6 inhibitor-armed oncolytic adenovirus, ADV-PTD4-D3, reverses T cell exhaustion and boosts anti-PD-1/CAR-T efficacy in colorectal cancer.

The efficacy of oncolytic adenoviruses in colorectal cancer is often limited by treatment-induced T cell exhaustion. High-dose, repetitive administration of these viruses can lead to chronic antigen exposure and tumor microenvironmental stress, driving CD8+ T cells into a dysfunctional state. This exhaustion, coupled with inadequate T cell infiltration, represents a significant barrier to effective T-cell-based immunotherapies like PD-1 blockade and CAR-T cell therapy. Addressing these dual challenges is crucial for improving patient outcomes in advanced cancers.

Researchers engineered an oncolytic adenovirus, ADV-PTD4-D3, designed for intratumoral expression of a peptide inhibitor of CDK4/6. This local delivery strategy aimed to maximize immunomodulatory effects while minimizing systemic exposure. The study utilized syngeneic murine models to assess tumor control and immunological memory, focusing on the role of CD8+ T cells. Additionally, the antitumor activity and potential off-target toxicity of ADV-PTD4-D3 were evaluated in a humanized xenograft model and immunocompetent hosts, respectively, to gauge its translational potential.

ADV-PTD4-D3 significantly improved tumor control and induced robust, antigen-specific immunological memory in murine models, with its therapeutic effect being primarily dependent on CD8+ T cells. It also demonstrated potent antitumor activity in a humanized xenograft model and showed no evidence of significant off-target toxicity. The core mechanism involves a novel signaling axis: viral-mediated CDK4/6 inhibition reduces retinoblastoma (Rb) protein phosphorylation. This decrease relieves Rb-mediated sequestration of the NF-κB p65 subunit, allowing p65 nuclear translocation and transcriptional upregulation of the T-cell chemoattractant CCL5.