Chimeric PD-1:28 receptor upgrades low-avidity T cells and restores effector function of tumor-infiltrating lymphocytes for adoptive cell therapy

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Item Type:	Article
Title:	Chimeric PD-1:28 receptor upgrades low-avidity T cells and restores effector function of tumor-infiltrating lymphocytes for adoptive cell therapy
Creators Name:	Schlenker, R., Olguín-Contreras, L.F., Leisegang, M., Schnappinger, J., Disovic, A., Rühland, S., Nelson, P.J., Leonhardt, H., Harz, H., Wilde, S., Schendel, D.J., Uckert, W., Willimsky, G. and Noessner, E.
Abstract:	Inherent intermediate-to-low affinity T cell receptors (TCR) that develop during the natural course of immune responses may not allow sufficient activation for tumor elimination, making the majority of T cells suboptimal for adoptive T cell therapy (ATT). TCR affinity enhancement has been implemented to provide stronger T cell activity but carries the risk of creating undesired cross-reactivity leading to potential serious adverse effects in clinical application. We demonstrate here that engineering of low-avidity T cells recognizing a naturally processed and presented tumor-associated antigen with a chimeric PD-1:28 receptor increases effector function to levels seen with high-avidity T cells of identical specificity. Upgrading the function of low-avidity T cells without changing the TCR affinity will allow a large arsenal of low-avidity T cells previously thought to be therapeutically inefficient to be considered for ATT. PD-1:28 engineering re-instated Th1 function in tumor-infiltrating lymphocytes (TILs) that had been functionally disabled in the human renal cell carcinoma (RCC) environment without unleashing undesired Th2 cytokines or IL-10. Involved mechanisms may be correlated to restoration of ERK and AKT signaling pathways. In mouse tumor models of ATT, PD-1:28 engineering enabled low-avidity T cells to proliferate stronger and prevented PD-L1 upregulation and Th2 polarization in the tumor milieu. Engineered T cells combined with checkpoint blockade secreted significantly more IFN-{gamma} compared to T cells without PD-1:28, suggesting a beneficial combination with checkpoint blockade therapy or other therapeutic strategies. Altogether, the supportive effects of PD-1:28 engineering on T cell function makes it an attractive tool for ATT.
Keywords:	Adoptive T Cell Therapy, Low-Avidity T Cells, Chimeric PD-1:28, Tumor-Infiltrating Lymphocytes, Cell Engineering, Animals, Mice
Source:	Cancer Research
ISSN:	0008-5472
Publisher:	American Association for Cancer Research
Volume:	77
Number:	13
Page Range:	3577-3590
Date:	1 July 2017
Official Publication:	https://doi.org/10.1158/0008-5472.CAN-16-1922
PubMed:	View item in PubMed

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