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Cells, compositions and methods for enhancing immune function

A cell and motif-binding technology, applied in the treatment of cancer or infection, the immune function of T cells, the field of T cells in immune function, can solve problems that do not benefit from cancer immunotherapy

Pending Publication Date: 2022-01-07
COUNCIL OF THE QUEENSLAND INST OF MEDICAL RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, although cancer immunotherapy has provided an expanded toolbox for cancer treatment and is highly effective for some patients, many patients do not benefit from currently approved cancer immunotherapies
In addition to primary unresponsiveness, many patients develop resistance to current immune checkpoint blocking antibodies

Method used

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  • Cells, compositions and methods for enhancing immune function
  • Cells, compositions and methods for enhancing immune function
  • Cells, compositions and methods for enhancing immune function

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0252] Materials and methods

[0253] mouse

[0254]Wild-type (WT) C57BL / 6 was purchased from Walter and Eliza Hall Institute for Medical Research or bred in-house. C57BL6 Pmel-1 TCRtg GFP mice (Glodde et al., 2017), C57BL / 6CD226-deficient (CD226KO) mice (Gilfillan et al., 2008), C57BL / 6CD226KO Pmel-1 TCRtg GFP mice, C57BL / 6CD226Y319F (CD226Y ) mice (Zhang et al., 2015), C57BL / 6CD226Y Pmel-1 TCRtg GFP mice, and C57BL / 6CD155-deficient (CD155KO) (Li et al., 2018) mice were housed in-house and maintained at the QIMR Berghofer Institute for Medical Research. Mice older than 6 weeks were sex-matched to the appropriate model. The number of mice in each treatment or mouse strain for each experiment is indicated in the legend. In all studies, no mice were excluded according to pre-established criteria and randomization was applied immediately before treatment in the treatment experiments. Experiments were performed with the approval of the Animal Ethics Committee of the QIMR Bergh...

Embodiment 2

[0320] CD8 T cell-mediated responses in DNAM-1-deficient mice

[0321] In contrast to most other activating receptors, DNAM-1 (or CD226) was activated in mouse naive ( T,TN) and central memory (TCM) CD8+ T cells were similarly expressed, whereas only a small fraction of effector memory (TEM) CD8+ T cells were found to be DNAM-1 negative (data not shown). However, CD226 was uniformly upregulated following T cell receptor (TCR) stimulation of splenic CD8+ T cells (data not shown).

[0322] In wild-type (C57BL / 6J) and DNAM-1-deficient (also known as DNAM-1 KO or CD226 KO ) mice to assess CD8+ T cell-mediated responses. As described in Example 1, B16F10, MC38, MC38OVA bright or MC38OVA bright Cells were injected subcutaneously into the loin of mice, and tumor size was assessed at 15-25 days. Mice were subsequently euthanized and flow cytometry was performed to detect tumor-infiltrating total CD8+ and OVA-specific CD8+ T cells.

[0323] Such as figure 1 As shown in, CD226 ...

Embodiment 3

[0325] Assessing DNAM-1 in the tumor microenvironment - T cell function

[0326] To further assess CD226 in the tumor microenvironment - (i.e. DNAM - ) T cell function, MC38-OVA was examined hi CD226 positive in C57BL / 6J (WT) mice (CD226 + ) and CD226 negative (CD226 - ) CD8+ T cells. Infiltration of MC38-OVA in WT mice hi Flow cytometric analysis of CD226 expression on CD8+ T cells of tumors indicated that CD226 - CD8+ T cells accumulated in tumors (data not shown). However, in this population, with CD2261 + The frequency of IFN-γ producing cells was significantly lower compared to CD8+ T cells (data not shown). In addition, with CD226 + CD8 + T cells compared to CD226 - Ki67 in CD8+ T cells + Cell frequency was also reduced, indicating that CD226 - CD8+ T cells as a population are less proliferative than CD226 + CD8+ T cells. These data suggest that dysfunctional CD226 - CD8+ T cells accumulate in the tumor microenvironment.

[0327] In a further study, the...

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Abstract

The present disclosure relates generally to polypeptides, cells, compositions and methods for enhancing immune function, and in particular the immune function of T cells, such as CD8+ T cells. More particularly, the present invention relates to modified DNAM-1 polypeptides, T cells expressing recombinant and / or modified DNAM-1, and methods of using these cells in adoptive T cell transfer, such as for the treatment of cancer or infection. The disclosure also relates to methods for preparing T cells with enhanced immune function; methods for preparing T cells for adoptive cell therapy; methods for assessing the immune function of T cells in a subject or cell population; methods for predicting the responsiveness of a subject with cancer to cancer therapy; and methods for predicting the survival or survival time of a subject with cancer.

Description

[0001] related application [0002] This application claims priority to Australian Provisional Application No. 2019900621, filed 27 February 2019, entitled "Cells, Compositions and Methods for Enhancing Immune Function", the contents of which are incorporated herein by reference in their entirety. [0003] field of invention [0004] The present disclosure relates generally to polypeptides, cells, compositions and methods for enhancing immune function, and in particular the immune function of T cells such as CD8+ T cells. More particularly, the invention relates to modified DNAM-1 polypeptides, T cells expressing recombinant and / or modified DNAM-1, and methods of using these cells in adoptive T cell transfer, such as for the treatment of cancer or infection. The present disclosure also relates to methods of producing T cells with enhanced immune function; methods for producing T cells for adoptive cell therapy; methods for assessing the immune function of T cells in a subject o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K35/17A61K38/16C07K14/705A61P31/00A61P35/00G01N33/566
CPCA61K35/17A61P35/00A61P31/00G01N33/566C07K14/70596C12N5/0636C12N15/67G01N33/574G01N33/56972A61K38/00C12N2501/505C12N2501/599C12N2510/00G01N2333/70596G01N2800/52G01N33/57492A61K45/06C07K14/70503C07K14/7051G01N33/5091G01N2333/70503
Inventor T·巴尔德M·布洛恩M·斯迈思
Owner COUNCIL OF THE QUEENSLAND INST OF MEDICAL RES
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