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Compositions and methods for inhibiting T cell exhaustion

A composition and cell technology, applied in chemical instruments and methods, for targeting specific cell fusions, drug combinations, etc., to solve problems such as CART cell exhaustion

Pending Publication Date: 2020-09-29
THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Incorporation of the CD28 endodomain into second-generation CAR T-cell receptors enhanced expansion capacity, but neither in the context of tonic signaling receptors nor in CD19- 28z CAR T cells are prone to CAR T cell exhaustion (Reference 9; the entire contents of which are hereby incorporated by reference)

Method used

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  • Compositions and methods for inhibiting T cell exhaustion
  • Compositions and methods for inhibiting T cell exhaustion
  • Compositions and methods for inhibiting T cell exhaustion

Examples

Experimental program
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Effect test

Embodiment 1

[0222] Gene expression analysis of T cell exhaustion

[0223] Antigen-independent complementary signaling by chimeric antigen receptors (CARs) promotes differentiation and exhaustion of T cells, limiting their potency. For example, GD2-specific CARs have been described to self-aggregate in the absence of antigen, leading to activation of chronic downstream T-cell activation signaling cascades. While GD2-CARs incorporating a CD28 costimulatory domain rapidly developed hallmark features of T cell exhaustion, GD2-CARs incorporating a 4-1BB costimulatory domain, despite similar aggregation and signaling, showed less There was less evidence of T cell exhaustion and greater retention of functionality. Among GD2-28z-expressing T cells, the most prominent features of T-cell exhaustion include increased surface expression of inhibitory receptors (e.g., PD1, TIM3, LAG3, CD39), decreased expression of memory markers (e.g., CD62L and CCR7), As well as decreased production of cytokines (...

Embodiment 2

[0226] Construction of CAR T cells forcibly expressing c-Jun and c-Fos

[0227] To determine whether replacement of AP-1 could alleviate exhaustion symptoms in GD2-28Z CAR T cells, lentiviral expression constructs that forced the expression of c-Jun and c-Fos under constitutive promoters were constructed (see Figure 2a). This construct also encodes a truncated nerve growth factor receptor (NGFR (tNGFR)) expression cassette as a surface marker for T cell transduction. Activated primary human T cells were subsequently transduced with CD19, GD2-BBZ, or high-affinity (HA) GD2-28Z CARs with (AP-1) or without (wo) AP-1 expression vectors.

Embodiment 3

[0229] Expression of c-Jun and c-Fos in CAR T cells

[0230] On day 8 of T cell culture, AP-1-transduced CD4 or CD8 CAR T cells were sorted using NGFR. In CD4 (see Figure 2b) and CD8 (see Figure 2c) CAR T cells, constitutive expression of AP-1 decreased the frequency of exhaustion-associated inhibitory receptors PD1, TIM3, LAG3, and CD39 and elevated memory markers CD62L frequency. CAR T cells were co-cultured with tumor cells expressing CD19 and GD2 antigens with (AP-1) or without (wo) AP-1 cotransduction to assess the function of AP-1-transduced CAR T cells Variety. In most cases, AP-1-transduced CAR T cells released more IL2 (see Figure 2d) and IFNg (see Figure 2e) than CAR T cells without AP-1 transduction.

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Abstract

The present invention relates to T cell compositions and methods of using the same in the context of therapy and treatment. In particular, the invention provides T cells that are modified (e.g., genetically and / or functionally) to maintain functionality under conditions in which unmodified T cells display exhaustion. Compositions and methods disclosed herein find use in preventing exhaustion of engineered (e.g., chimeric antigen receptor (CAR) T cells) as well as non-engineered T cells thereby enhancing T cell function (e.g., activity against cancer or infectious disease).

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application 62 / 738,687, filed September 28, 2018, and U.S. Provisional Application 62 / 599,299, filed December 15, 2017, the entire contents of which are hereby incorporated by reference. technical field [0003] The present invention relates to T cell compositions and methods of their use in therapy and therapeutic settings. In particular, the invention provides T cells modified (eg, genetically and / or functionally modified) to maintain function under conditions in which unmodified T cells are rendered exhausted. The compositions and methods disclosed herein can be used to prevent the exhaustion of engineered (e.g., chimeric antigen receptor (CAR) T cells) as well as unengineered T cells, thereby enhancing T cell function (e.g., against cancer or infection) disease activity). The compositions and methods described herein are useful in clinical and research fields su...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K35/17C12N5/0783C12N5/10A61P35/00
CPCC07K14/7051C07K16/2803C07K16/3084C07K16/32C07K2317/524C07K2317/526C07K2317/622C07K2317/70C07K2319/03C07K2319/33C07K14/4702A61P35/00A61K38/1709A61K2239/47A61K39/464406A61K2239/38A61K39/4611A61K39/464413A61K39/464412A61K39/464471A61K2239/31A61K2239/48A61K39/4631C07K16/2812C07K16/2815A61K35/17A61K39/464424A61K39/0011A61K2039/5156
Inventor 克里斯托·麦考尔瑞秋·琳恩埃文·温伯埃琳娜·索蒂罗
Owner THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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