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A limiting step for adoptively transferred tumour-specific T cells is their recruitment from the blood circulation to the proximity of tumour cells and subsequent engagement in direct tumour cell contact. We hypothesised that a bispecific antibody recruiting T cells to a target antigen on tumour cells could enhance T-cell-tumour interaction and thus increase the efficacy of adoptively transferred T cells.
Material and methods
A new bispecific murine IgG2a antibody (BsAb) was generated that recognises EpCAM as a tumour antigen and truncated EGFR (D-EGFR) as an inert surface marker protein on transduced T cells. T cells from transgenic mice for TCR specific for the SV40 large T antigen (TCR-1) were retrovirally transduced with D-EGFR. S.c. tumors were induced in C57Bl/6 mice by injecting mGC8 cells derived from a syngeneic large T antigen expressing EpCAM-positive gastric tumor.
In vitro, the BsAb increased (4-fold) binding of transduced T cells to EpCAM positive tumour cells. In the presence of the BsAb, tumour-directed T cells efficiently lysed EpCAM-positive cells (83 % at a 10:1 effector to target ratio). In vivo, the antibody reached EpCAM+ tumour cells as evidenced by immunofluorescence. mGC8 tumour-bearing mice were treated twice with a combination of the BsAb and transduced TCR-I T cells. Tumour growth was significantly reduced for over 30 days (n=12) compared with control groups (transduced T-cells or BsAb alone) and survival was prolonged by > 30 days (p<0.001).
Co-administration of a BsAb bridging adoptively transferred tumour-specific T cells via an inert surface molecule to a tumour-associated surface antigen enhances the efficacy of therapeutic T cell transfer.