Identification of a tumor-specific allo-HLA–restricted γδTCR

Abstract

Key Points We describe a novel allo-tumor–reactive and CD8α-dependent Vγ5Vδ1TCR. The molecular interface with proximity to the peptide-binding groove of HLA-A*24:02 is an essential determinant of recognition.

TEG011 persistence averts extramedullary tumor growth without exerting off-target toxicity against healthy tissues in a humanized HLA-A*24:02 transgenic mice

“…2A). In addition, all mice did not exhibit any observable discomfort and survived throughout the entire study duration 24 . Persistence of TEGs was assessed by measuring viable huCD45 + γδTCR + CD8 + in mouse peripheral blood by flow cytometry (Supporting Information Fig.…”

“…Clinical data for anti‐CD19 chimeric antigen receptor T cell (CART) therapy highlight the correlation of antitumor effects with their in vivo persistence 27‐29 . To assess whether persistence of TEG011, which carries a CD8α‐dependent Vγ5Vδ1TCR, 24 is also key in long‐term tumor control, we studied in more detail CD8 + TEG persistence in tumor‐bearing NSG‐A24:02 mice injected with K562 HLA‐A*24:02 luciferase tumor cells and subsequently treated with either TEG011 or TEG‐LM1 mock cells (experimental outline Fig. 1B).…”

“…Humane endpoint (HEP) was reached when mice experienced a 20% weight loss from the initial weight (measured on day 1) and in the case of GvHD score 2 was reached for an individual GvHD parameter or a total GvHD score of 4. For the tumor‐bearing mouse model, adult NSG‐A24:02 mice (8–11 wk old) received sublethal total body irradiation (1.75 Gy) on day 1 followed by intravenous injection of 1 × 10 5 K562 HLA‐A*24:02 luciferase tumor cells on day 0, and received 2 injections of TEG011 and TEG‐LM1 mock on days 1 and 6 as previously reported 24 . All mice received 0.6 × 10 6 IU of IL‐2 (Proleukin; Novartis) in 100 μl incomplete Freund's adjuvant (IFA) subcutaneously together with the first TEGs injection and every 3 weeks until the end of the experiment.…”

“…Within this context, we previously identified an allo‐HLA‐restricted and CD8α‐dependent Vγ5Vδ1TCR. When this particular receptor was utilized for the TEG concept (later referred as TEG011) selective reactivity toward HLA‐A*24:02 expressing tumor cells, but not healthy tissues was observed 24 . However, safety studies have been so far very limited and also in vivo persistence and expansion profiles have not been assessed but are crucial before first‐in‐men studies.…”

Revisiting the Interaction of γδ T-Cells and B-Cells

“…Similarly, Daudi cells, a human Burkitt s lymphoma cell line, have been extensively studied in the presence of human Vγ9 + Vδ2 + T-cells as they are able to activate specific γδ TCRs [50][51][52]. Interestingly, human Vδ1 + T-cells also seem to be stimulated by activated B-cells isolated from peripheral blood [53,54]. Moreover, the expression of B7 and CD39 molecules on the surface of activated B-cells appears to be important for the activation of human Vδ1 + T-cells [53].…”