326P - Autologous V gamma 9 V delta 2 T cell therapy to target Epstein Barr Virus (EBV)-related malignancies

Background

Analysis of ∼18,000 human tumors across 39 cancers identified tumor infiltrating γδ T cells as the most favorable prognostic immune population. Sharing both innate and adaptive immune properties, γδ T cells are an attractive candidate for direct adoptive cellular therapy as well as utilizing their professional antigen presenting cell (APC) property for ex vivo expansion of antigen-specific CD4⁺and CD8⁺ T cells for subsequent adoptive cellular therapy.

Methods

Here, we report a Good Manufacturing Method (GMP) expansion protocol of Vγ9Vδ2 T cells from human PBMCs and its functional and transcriptomic characterization.

Results

Following cytokine optimization experiments, we found that some combinations of IL-2, IL-15 and IL-21 led to optimal antigen presentation and effector functions. γδ T cells produced in the presence of IL-2 alone or in combination with other cytokines showed increased APC markers compared to IL-15 combinations. In vitro, EBV-LMP2 peptide-pulsed γδ T cells primed a more robust naïve CD3⁺ T cell proliferation than monocyte-derived Dendritic Cells (moDC). Importantly, EBV-LMP2 peptide-pulsed γδ T cells stimulated less T regulatory cells and exhausted CD8⁺ and CD4⁺ T cells compared to moDCs.Through gene expression profiling, we demonstrated that γδ T cells express enhanced levels of markers of cross presentation pathway compared to moDCs which may explain the cross presentation phenotype. Finally, we demonstrated the potential of EBV-LMP2 peptide-pulsed Vγ9Vδ2 T cells as a therapeutic cancer vaccine in an autologous EBV-lymphoblastoid cell line tumor model in vivo. This therapeutic intervention resulted in increased tumor infiltration of gd, CD8⁺ and CD4⁺ T cells and improved control of primary tumor growth and metastasis of EBV LCLs tumor model in vivo.

Conclusions

In summary, we demonstrated in our pre-clinical study γδ T cell APC and effector functions in vitro and in vivo, indicating the potential of γδ T cells as therapeutic immunotherapy against EBV-positive cancers.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Tessa Therapeutics.

Disclosure

P.W.-W. Wang: Advisory / Consultancy: Tessa Therapeutics. H.C. Toh: Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Tessa Therapeutics. All other authors have declared no conflicts of interest.