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Il-33 secreting immunoresponsive cells and uses thereof

A technology of immune response cells and cells, applied in the direction of blood/immune system cells, genetically modified cells, medical preparations containing active ingredients, etc.

Pending Publication Date: 2020-08-28
MEMORIAL SLOAN KETTERING CANCER CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This "hostile" tumor microenvironment poses a challenge for therapeutic approaches involving stimulating immune responses, such as targeted T-cell therapy

Method used

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  • Il-33 secreting immunoresponsive cells and uses thereof
  • Il-33 secreting immunoresponsive cells and uses thereof
  • Il-33 secreting immunoresponsive cells and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0329] Example 1 - CAR-T cells that secrete interleukin 33 (IL-33)

[0330] introduce

[0331] Genetically modified T cells expressing either a first-generation anti-CD19 CAR and a secretable IL-33 polypeptide or a second-generation anti-CD19 CAR and a secretable murine IL-33 polypeptide were generated. IL-33-secreting CAR-T cells exhibited improvement compared to control anti-CD19 CAR-T cells that did not contain a secretable IL-33 polypeptide. IL-33-secreting CAR-T cells exhibited prolonged survival curves in murine models.

[0332] result

[0333] CAR construct

[0334] Construction of various anti-CD19CAR constructs with or without secretable murine IL-33 polypeptide in the SFG retroviral vector backbone, e.g. ,Such as Figure 1A shown. Figure 1B A construct showing the first generation anti-mouse CD19myc-tag CAR incorporating constitutively secreted murine IL-33, wherein the amino acid sequence of the mature peptide of murine IL-33 used in the construct is shown ...

Embodiment 2

[0349] Example 2 - CAR-T cells secreting interleukin 33 (IL-33) in a mouse model

[0350] CAR construct that secretes murine IL-33

[0351] The biological role of IL-33-secreting CAR-T cells was analyzed in a mouse model. Such as Figure 8 Various anti-murine CD19CAR constructs, including am19mDEL, am19mDELp2A_IL-33, am19mZ, am19mZp2A_IL-33, am19m28Z and am19m28Zp2A_IL-33. Anti-mouse CD19 (am19) was derived from 1D3 scFv. All constructs utilize the CD28 proximal extracellular and transmembrane domains as hinges. In all constructs that secreted murine IL-33, the cytokine was dissociated from the CAR by a self-cleaving P2A element.

[0352] Increased secretion of cytokines

[0353] IL-33 secretion in T cells transduced with one of the above constructs was analyzed. These modified T cells were co-cultured with antigen-positive tumor cells + EL4h19Sm19 (EL4 cells were purchased from Sigma, knock-in mice) alone or at an effector:tumor ratio of 1:1. After 24 hours, super...

Embodiment 3

[0359] Example 3-CAR-T cells secreting interleukin 33 (IL-33) in a human model

[0360] A CAR construct that secretes human IL-33

[0361] The biological role of IL-33-secreting CAR-T cells was analyzed in a human model. Such as Figure 15 As shown, various anti-human CD19CARs with or without secretable human IL-33 polypeptide constructs were constructed in the SFG retroviral vector backbone, including ah19hDEL, ah19hZ, ah19hBBZ, ah19h28Z, ah19hDELp2A_IL-33, ahl9hZp2A_IL_33, ah19hBBZp2a_IL-33 and ah19h28Zp2A_IL-33. All constructs utilized the CD28 proximal extracellular and transmembrane domains as hinges (including 4-1BB-based constructs). In all constructs that secreted human IL-33, the cytokine was dissociated from the CAR by a self-cleaving P2A element.

[0362] T cells were transduced with one of the above constructs.

[0363] Cell surface CAR expression

[0364] CAR expression on the cell surface of the modified T cells was analyzed by flow cytometry, and the r...

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Abstract

The present disclosure provides methods and compositions for enhancing the immune response toward cancers and pathogens. It relates to an immunoresponsive cell comprising an antigen-recognizing receptor (e.g., a chimeric antigen receptor (CAR) or a T cell receptor (TCR)), and expressing increased level of IL-33. In certain embodiments, the engineered immunoresponsive cells are antigen-directed andhave enhanced immune-activating properties.

Description

[0001] Cross References to Related Applications [0002] This application claims priority from and claims priority to U.S. Provisional Application No. 62 / 585,833, filed November 14, 2017, which is incorporated herein by reference in its entirety. technical field [0003] The presently disclosed subject matter provides methods and compositions for enhancing immune responses against cancer and pathogens. The invention relates to immune response cells comprising an antigen recognition receptor (eg, a chimeric antigen receptor (CAR) or a T cell receptor (TCR)) engineered to express an IL-33 polypeptide. These engineered immune response cells are antigen-directed, promote the recruitment of other cytokines and display enhanced anti-target efficacy. Background technique [0004] Despite currently available therapies, most adult B-cell malignancies, including acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia, and non-Hodgkin's lymphoma, remain incurable. Adoptive t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/54C07K14/705C12N5/00
CPCC07K14/54C07K14/7051C12N2510/00C12N5/0636C12N2501/599C12N2501/2333A61K2239/48A61K39/464412A61K39/4637A61K39/4631A61K2239/38A61K39/4611A61K38/177A61K38/20C07K14/4748C07K14/535C07K14/55C07K2319/02C12N15/867C07K16/2803C07K2317/622C07K14/70521A61K2039/505
Inventor A·丹尼安R·J·布伦特延斯
Owner MEMORIAL SLOAN KETTERING CANCER CENT
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