Jump-starting the T cell response in established tumors

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.