Methods of treating t cell exhaustion by inhibiting or modulating t cell receptor signaling

Abstract

Provided herein are compositions and methods for preventing or reversing T cell exhaustion. In particular, the present invention relates to methods of preventing or reversing T cell exhaustion by exposing T cells experiencing T cell exhaustion to particular tyrosine kinase inhibitors (e.g., dasatinib, ponatinib), or by expanding genetically engineered T cells in the presence of particular tyrosine kinase inhibitors (e.g., dasatinib, ponatinib).

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. provisional application Ser. No. 62 / 479,930, filed Mar. 31, 2017, which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION[0002]Provided herein are compositions and methods for preventing or reversing T cell exhaustion. In particular, the present invention relates to methods of preventing or reversing T cell exhaustion by exposing T cells experiencing T cell exhaustion to particular tyrosine kinase inhibitors (e.g., dasatinib, ponatinib), or by expanding genetically engineered T cells in the presence of particular tyrosine kinase inhibitors (e.g., dasatinib, ponatinib).INTRODUCTION[0003]T cells are immune cells that become activated via T cell receptor (TCR) signaling following engagement with antigen. Physiologic activation through the T cell receptor renders T cells capable of mediating potent antitumor or anti-infective effects. During resolution of an acute inflammato...

AI Technical Summary

Benefits of technology

The patent describes a method for preventing or reversing the exhaustion of T cells, which can lead to a reduction in their effectiveness in fighting cancer. The method involves using a specific type of molecular protein called a tyrosine kinase inhibitor, such as dasatinib or ponatinib, which can reduce the expression of markers associated with exhaustion and improve the formation of T cell memory. The patent also describes experiments that demonstrated the effectiveness of this method in reducing toxicity related to genetically engineered T cells in animals treated with this method, and in improving the tumor response and clinical benefit of combination therapies involving the use of these inhibitors and other anticancer drugs or radiation.

Problems solved by technology

Disturbance in TCR signaling can lead to inflammatory and other T cell-related disorders.

Such T cells function poorly as a result of T cell exhaustion, as evidenced by high levels of PD-1, TIM-3, LAG-3, diminished antigen induced cytokine production, and excessive programmed cell death.

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