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850 Selective expansion of anti-tumor CD4 T-cell subsets contributes to oncolytic virotherapeutic efficacy in malignant glioma
  1. Jeffrey M Grimes and
  2. Jianmei W Leavenworth
  1. University of Alabama at Birmingham, Birmingham, AL, USA


Background Malignant glioma, an aggressive type of brain tumor, remains an intractable problem with uniformly fatal outcomes in patients. We engineered herpes simplex virus (HSV)-1 and developed oncolytic HSV (oHSV) to treat brain tumors, given its capacity to selectively kill tumor cells while sparing normal cells, and to boost anti-tumor immunity. Both of our phase I trial and preclinical studies have demonstrated the safety and efficacy of this oHSV-based therapy. However, the nature of anti-tumor immune responses to such therapy remains largely unclear.

Methods An oHSV expressing murine IL-12 (M002) and vehicle control were used to treat immunocompetent mice bearing intracranial glioma. The in vitro cell culture assays, in vivo adoptive transfer approaches and single-cell RNA sequencing coupled with T-cell receptor (TCR) repertoire analysis of intratumoral CD4+ T-cells were performed.

Results We revealed that M002 treatment preferentially induced unique CD4+ T-cell populations in the tumor that were distinct from conventional T helper subsets and displayed less exhausted phenotype but increased effector activity. CD4+ T-cells isolated from M002-treated tumors prolonged mice survival and had better tumor-killing ability than CD4+ T-cells from vehicle-treated control tumors in an MHCII-dependent manner. Notably, M002 treatment reduced the CD4+ T-cell clonal diversity but expanded certain clones.

Conclusions These results suggest that the capacity of oncolytic virotherapy to reshape the CD4+ T-cell repertoire and to enhance their anti-tumor functionality contributes to its improved efficacy. This study has provided insights into the immune-based mechanistic actions of oHSV therapy and has suggested the strategies for the development of better treatments for brain tumor patients.

Acknowledgements This study was supported by DoD W81XH-18–1-0315 and the University of Alabama at Birmingham Faculty Start-up Funds.

Ethics Approval All animal experiments were performed in compliance with federal laws and institutional guidelines as approved by the UAB IACUC.

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