Abstract
Vγ2Vδ2 T cell-based immunotherapy has benefited some patients in clinical trials, but the overall efficacy is low for solid tumor patients. In this study, a bispecific antibody against both PD-L1 and CD3 (PD-L1 x CD3), Y111, could efficiently bridge T cells and PD-L1 expressing tumor cells. The Y111 prompted fresh CD8+ T cell-mediated lysis of H358 cells, but spared this effect on the fresh Vδ2+ T cells enriched from the same donors, which suggested that Y111 could bypass the anti-tumor capacity of the fresh Vγ2Vδ2 T cells. As the adoptive transfer of the expanded Vγ2Vδ2 T cells was approved to be safe and well-tolerated in clinical trials, we hypothesized that the combination of the expanded Vγ2Vδ2 T cells with the Y111 would provide an alternative approach of immunotherapy. Y111 induced the activation of the expanded Vγ2Vδ2 T cells in a dose-dependent fashion in the presence of PD-L1 positive tumor cells. Moreover, Y111 increased the cytotoxicity of the expanded Vγ2Vδ2 T cells against various NSCLC-derived tumor cell lines with the releases of granzyme B, IFNγ, and TNFα in vitro. Meanwhile, the adoptive transferred Vγ2Vδ2 T cells together with the Y111 inhibited the growth of the established xenografts in NPG mice. Taken together, our data suggested a clinical potential for the adoptive transferring the Vγ2Vδ2 T cells with the Y111 to treat PD-L1 positive solid tumors.
Highlights
Vg2Vd2 T cells, accounting for about 90% of total gd T cells in the peripheral bloodstreams of healthy adults, appear to be a fast-acting and non-conventional T-cell population that contributes to both innate and adaptive immune responses to microbial infections and cancers [1]
The transfused Vg2Vd2 T cell was redirected into tumor sites by a novel anti-CD3 and anti-programmed death-ligand 1 (PD-L1) bispecific antibodies (bsAbs), Y111
This proof-of-concept study verified the value of the bsAb-based immunotherapy to leverage the potent anti-tumor capacity of Vg2Vd2 T cells, and suggested that the combination of the Vg2Vd2 T cells and Y111 could be applied for PD-L1+ cancer therapies
Summary
Vg2Vd2 T cells, accounting for about 90% of total gd T cells in the peripheral bloodstreams of healthy adults, appear to be a fast-acting and non-conventional T-cell population that contributes to both innate and adaptive immune responses to microbial infections and cancers [1]. An IgG-like bispecific antibody would display better pharmacokinetics comparing to those antibody fragments These studies showed that the gd TCR-based bispecific antibodies displayed modest activities of tumor growth inhibitions with the co-administration of IL2 [7,8,9,10,11,12,13], these approaches seemed less attractive than the exploring of CD3-targeting bsAbs. We hypothesized that a tumor associated antigen and CD3-targeting bispecific antibody, rather than targeting to only gd TCR, would enhance the anti-tumor effects of the transfused Vg2Vd2 T cells even without administration of phosphoantiens and IL2 into the animals
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