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...

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Benefits of technology

[0032]The present invention contemplates that such methods (e.g., adoptive T cell therapies with genetically engineered T cell populations and compositions comprising particular tyrosine kinase inhibitors (e.g., dasatinib, ponatinib)) (e.g., adoptive T cell therapies with genetically engineered T cell populations that were expanded in the presence of particular tyrosine kinase inhibitors (e.g., dasatinib, ponatinib)) satisfy an unmet need for the treatment of multiple cancer types, either when administered as monotherapy or when administered in a temporal relationship with additional agent(s), such as other cell death-inducing or cell cycle disrupting cancer therapeutic drugs or radiation therapies (combination therapies), so as to render a greater proportion of the cancer cells or supportive cells susceptible to executing the apoptosis program compared to the corresponding proportion of cells in an animal treated only with the cancer therapeutic drug or radiation therapy alone.

[0033]In certain embodiments of the invention, combination treatment of animals with such methods (e.g., adoptive T cell therapies with genetically engineered T cell populations and compositions comprising particular tyrosine kinase inhibitors (e.g., dasatinib, ponatinib)) (e.g., adoptive T cell therapies with genetically engineered T cell populations that were expanded in the presence of particular tyrosine kinase inhibitors (e.g., dasatinib, ponatinib)) produce a greater tumor response and clinical benefit in such animals compared to those treated with the anticancer drugs / radiation alone. Since the doses for all approved anticancer drugs and radiation treatments are known, the present invention contemplates the various combinations of them with such methods.

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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