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Jump-starting the T cell response in established tumors

Tyler R McCaw1, Mingyong Liu1, Christopher D Scharer2

  • 1Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA.

Biorxiv : the Preprint Server for Biology
|June 12, 2026
PubMed

Insights

Entinostat (ENT) combined with checkpoint blockade shows limited success. However, using an oncolytic virus to boost T cell responses before ENT administration restores anti-tumor activity, offering a new strategy for cancer immunotherapy.

Area of Science:

  • Immunology
  • Cancer Biology
  • Pharmacology

Background:

  • Checkpoint blockade immunotherapy is effective in only 10-20% of patients.
  • Combining checkpoint inhibitors with entinostat (ENT), a class I histone deacetylase inhibitor, has shown poor clinical outcomes in breast and ovarian cancers.

Purpose of the Study:

  • To investigate the mechanisms underlying the limited efficacy of ENT and checkpoint blockade.
  • To identify strategies for enhancing the anti-tumor activity of this combination therapy.

Main Methods:

  • Investigated the effect of ENT on CD8+ T cell populations in pre-clinical cancer models.
  • Administered ENT during different phases of T cell activation and exhaustion.
  • Utilized oncolytic viruses to "jump-start" T cell responses prior to ENT and PD1 blockade treatment.

Main Results:

  • ENT enhances CD8+ T cell responses by preserving progenitor-like CD8+ T cells, which sustain effector T cells in tumors.
  • The anti-tumor effects of ENT are observed only when administered within a specific therapeutic window post-T cell activation and pre-exhaustion.
  • Pre-treatment with an oncolytic virus restored the anti-tumor efficacy of ENT and PD1 blockade.

Conclusions:

  • The efficacy of ENT in combination with checkpoint blockade is dependent on precise timing relative to T cell activation and exhaustion.
  • Oncolytic virus pre-treatment can overcome the timing limitations, restoring anti-tumor immunity and providing a generalizable strategy for cancer therapy.

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