Exploiting viral infection/vaccination to focus high-affinity T cell populations into tumors using oncolytic...

Area of Science:

• Immunology
• Oncology
• Virology

Background:

• Immune tolerance limits T cell responses against self-tumor-associated antigens (TAAs), hindering cancer immunotherapy.
• Viral infections prime high-affinity T cells, offering a potential strategy to overcome this limitation.

Purpose of the Study:

• To investigate the use of pre-existing anti-viral T cell memory against SARS-CoV-2 antigens to enhance anti-tumor immunity.
• To explore oncolytic virus (OV) and chimeric antigen receptor (CAR)-T cell delivery of viral antigens for tumor targeting.

Main Methods:

• Heterologous prime and OV/boost strategy using SARS-CoV-2 antigens (Mem or Spike proteins).
• Chimeric antigen receptor (CAR)-T cell therapy delivering SARS-CoV-2 antigen-expressing vectors.
• In vivo boosting of S-specific CAR-T cells with S protein vaccines.

Main Results:

• CD8+ T cell-dependent tumor cures were achieved using SARS-CoV-2 antigens for T cell focusing, with evidence of epitope spreading against TAAs.
• CAR-T cells successfully delivered SARS-CoV-2 antigen vectors to tumors, even in pre-immune mice.
• In vivo boosting of CAR-T cells enhanced anti-tumor activity and persistence.

Conclusions:

• Leveraging pre-existing anti-viral T cell responses via OV or CAR-T cell delivery of viral antigens is a viable strategy to generate high-affinity T cells for cancer immunotherapy.
• This approach offers a therapeutic alternative when high-affinity anti-tumor T cells are not readily available.