Smoldering oncolysis by foamy virus carrying CD19 as a CAR target escapes CAR T detection by genomic modification

Area of Science:

• Oncology
• Virology
• Immunotherapy

Background:

• Chimeric antigen receptor (CAR) T-cells show limited success against solid tumors.
• Oncolytic viruses (oVs) offer a potential strategy to enhance anti-tumor immunity.

Purpose of the Study:

• To investigate the combination of an oncolytic foamy virus (oFV) engineered to display a CAR T-cell target antigen (CD19) with anti-CD19 CAR T-cells for solid tumor treatment.
• To evaluate the efficiency and stability of viral spread and antigen display.

Main Methods:

• Generation of oFV vectors (oFV-Δbel2 and oFV-bel2) expressing CD19.
• In vitro assessment of CAR T-cell killing.
• In vivo studies using subcutaneous tumor models to evaluate therapeutic efficacy and viral clearance.
• Analysis of viral genome stability and escape mechanisms.

Main Results:

• Both oFV vectors showed equal CAR T-cell killing in vitro.
• In vivo, CAR T-cells reduced oFV bioluminescence, indicating clearance of infected cells.
• High-dose oFV monotherapy was more effective than combination therapy, suggesting CAR T-cells were detrimental.
• Escaped tumors showed oFV with deletions in the CD19 transgene, indicating viral escape.

Conclusions:

• Oncolytic foamy virus acts as a slow-spreading oncolytic agent, generating anti-tumor therapy.
• CAR T-cell therapy can abolish the anti-tumor effects of oFV by clearing infected cells.
• Further development of oFV platforms with enhanced immunotherapeutic strategies may enable effective chronic oncolysis combinations.