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Improving migration, tumour accumulation, and persistence of Tumour-Infiltrating Lymphocytes (TILs) in ovarian cancer

C Guerra(1,2) M Kalaitsidou(2) G Kueberuwa(2) R Edmondson(1) R Hawkins(2)

1:University of Manchester; 2:InstilBio UK

Background: The deprived endogenous co-stimulation and hindered T-cell trafficking into the tumours constitute the principal hurdles for ovarian cancer immunotherapy. This project aims to evaluate the effect of TIL modification with the synthetic co-stimulatory antigen receptor (CoStAR) or chemokine receptors on migration towards ovarian tumours using in vitro and in vivo models.

Methods: Healthy donor (HD) T cells modified with CoStAR and CXCR2 were produced, and cytokine secretion, interleukin-2 (IL-2) and interferon-γ (IFN- γ), killing and migration capacity were measured. The expression of exhaustion and differentiation markers, and chemokine receptors in T cells, TALs (tumour-associated lymphocytes) and TILs was measured by flow cytometry.

Results: The highest chemokine receptor in HD cells was CXCR4 for both CD4 (41.6 ±2.3 %) and CD8 T-cell populations (57.3 ±16.5 %), whereas in TALs CCR5 (53.7 ±28.2 %) and CXCR4 (51.7 ±27.47 %) in the CD4 subset and CCR5 (80.5 ±36.7 %) and CXCR3 (58.6 ±28.3 %) in the CD8 T-cell population were the highest.

CoStAR demonstrated a robust functional activity after being co-cultured with OVCAR3.OKT3 cells in comparison to MOCK T cells and all cells maintain high killing capacity towards OVCAR3.OKT3 cells.

CXCR2 transduced T cells showed superior migration towards IL-8 in comparison to MOCK T cells in vitro.

Conclusion: The superior cytokine production of the CoStAR transduced T cells was demonstrated across donors. Flow panels for phenotypic characterisation of TILs were effectively developed and migration assays optimised. Data generated for CoStAR+, CXCR2+, and CoStAR+CXCR2+ modified HD cells will be compared with upcoming data from modified TILs.

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