Bispecific T cell engager (BiTE)-based cancer therapies that activate the cytotoxic T cells of a patient's own immune system have gained momentum with the recent FDA approval of Blinatumomab for treating B cell malignancies. However, this approach has had limited success in targeting solid tumors. Here, we report the development of BiTE-sialidase fusion proteins that enhance tumor cell susceptibility to BiTE-mediated cytolysis by T cells via selective desialylation at the T cell-tumor cell interface that results in better immunological synapse formation. We show that a BiTE-sialidase fusion protein targeting human epidermal growth factor receptor 2 (HER2) exhibits remarkably increased efficacy in terms of killing HER2 positive tumor cells when compared to the BiTE alone. This enhanced function is seen both in vitro and in an in vivo xenograft solid tumor model. We feel that BiTE-sialidase fusion proteins have great potential as candidates for the development of next generation bispecific T-cell engaging molecules for cancer immunotherapy.
The histone methyltransferase enhancer of zeste homolog 2 (EZH2)-mediated epigenetic regulation of T cell differentiation in acute infection has been extensively investigated. However, the role of EZH2 in T cell exhaustion remains under-explored. Here, using in vitro exhaustion models, we demonstrated that transient inhibition of EZH2 in T cells before the phenotypic onset of exhaustion with a clinically approved inhibitor, Tazemetastat, delayed their dysfunctional progression and maintained T cell stemness and polyfunctionality while having no negative impact on cell proliferation. Tazemetestat induced T cell epigenetic reprogramming and increased the expression of the self-renewing T cell transcription factor TCF1 by reducing its promoter H3K27 methylation preferentially in rapidly dividing T cells. In a murine melanoma model, T cells pre-treated with tazemetastat exhibited a superior response to anti-PD-1 blockade therapy after adoptive transfer. Collectively, these data unveil the potential of transient epigenetic reprogramming as a potential intervention to be combined with checkpoint blockade for immune therapy.
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