Pd1-specific chimeric antigen receptor as immunotherapy

A chimeric antigen receptor and specific technology, applied in antibody mimics/scaffolds, immunoglobulin superfamily, blood/immune system cells, etc., can solve problems such as limiting CART cell response and efficacy

Inactive Publication Date: 2020-07-17
朗沃德大学
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, upregulation of inhibitory receptor expression on T cells and expression of inhibitory ligands in the tumor microenvironment limit CAR T cell responses and efficacy

Method used

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  • Pd1-specific chimeric antigen receptor as immunotherapy
  • Pd1-specific chimeric antigen receptor as immunotherapy
  • Pd1-specific chimeric antigen receptor as immunotherapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] Example 1: Adoptive transfer of murine T cells expressing chimeric PD1-Dap10 receptors as immunotherapy for lymphoma.

[0078] summary

[0079] Adoptive transfer of T cells is a promising cancer therapy, and expression of chimeric antigen receptors enhances tumor recognition and T cell effector functions. Provided herein is a murine chimeric PD1 receptor (chPD1) comprising a PD1 extracellular domain fused to the cytoplasmic domain of CD3delta. In addition, chimeric antigen receptor therapies use various co-stimulatory domains to enhance efficacy. Therefore, inclusion of the Dap10 or CD28 co-stimulatory domain in the chPD1 receptor was compared to determine which domain induces the best antitumor immunity in a mouse lymphoma model. chPD1 T cells secrete pro-inflammatory cytokines and lyse RMA lymphoma cells. Adoptive transfer of chPD1T cells significantly reduced established tumors and resulted in tumor-free survival in lymphoma mice. When comparing chPD1 receptors c...

Embodiment 2

[0121] Example 2: Human T cells expressing chimeric PD1-Dap10 receptors as immunotherapy.

[0122] Adoptive transfer of tumor-reactive T cells is a promising antitumor therapy against many cancers. To enhance tumor recognition by T cells, chimeric antigen receptors (CARs), which consist of a signaling domain fused to a receptor that recognizes tumor antigens, can be produced and expressed in T cells. As shown in Example 1, since ligands for the PD1 receptor are expressed in many cancer types, PD1 is a target for novel chimeric antigen receptors. In this study, a human chimeric PD1 receptor (chPD1) consisting of the PD1 receptor extracellular domain and the CD3δ activation domain was developed. As described in Example 1, the Dap10 co-stimulatory domain is also included in the chPD1 receptor. The nucleic acid sequence of CAR is shown in SEQ ID NO: 2, and the amino acid sequence is shown in SEQ ID NO: 3. To determine whether this novel CAR could target multiple tumors, the ant...

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Abstract

Provided herein are methods and compositions useful for treating PDL1 and / or PDL2 positive cancers through adoptive cell transfer of T cells genetically engineered to express a PD1-specific chimeric antigen receptor. Co-stimulatory domains such as Dap 10 may be included to enhance efficacy.

Description

technical field [0001] The present disclosure generally relates to chimeric antigen receptors targeting PDl ligands, and genetically engineered T cells expressing the receptors, for the treatment of cancer. In particular, chimeric antigen receptors may comprise co-stimulatory domains (eg Dap10) to enhance therapeutic efficacy. Background technique [0002] Engineering T cells with chimeric antigen receptors (CARs) is one approach to improve T cell efficacy against tumors. CARs are used to redirect T cell specificity and allow MHC-independent recognition of tumor-associated antigens, thereby enhancing tumor targeting. Advantages of using CAR-modified T cells for cancer therapy include the ability to recognize multiple tumor types, overcome mechanisms that tumors use to evade immune detection, and enhance T cell function. However, upregulation of inhibitory receptor expression on T cells and expression of inhibitory ligands in the tumor microenvironment limit CAR T cell resp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N5/0783C07K14/705C07K14/725C07K16/28C07K16/30
CPCC07K14/705C07K14/70503C07K14/7051C07K14/70521C07K2319/00C07K2319/03C07K2319/33A61K2039/5156A61K2039/585C12N5/0636A61P35/00A61K35/17C12N2510/00A61K45/06C07K14/70532C12N15/63
Inventor A·巴伯
Owner 朗沃德大学
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