CD1D-restricted NKT cells as a platform for off-the-shelf cancer immunotherapy

A kind of NKT cell and cell technology, applied in the fields of immunology and medicine, cell biology, molecular biology, can solve the problem of donor cell killing and so on

Pending Publication Date: 2020-05-01
BAYLOR COLLEGE OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, HLA class I molecules also act as inhibitory ligands for NK cells, and loss of B2M expression is expected to render donor cells vulnerable to host NK cell killing (24)

Method used

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  • CD1D-restricted NKT cells as a platform for off-the-shelf cancer immunotherapy
  • CD1D-restricted NKT cells as a platform for off-the-shelf cancer immunotherapy
  • CD1D-restricted NKT cells as a platform for off-the-shelf cancer immunotherapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Generation of tumor-specific and generally tolerable NKT cells from healthy donors for off-the-shelf cancer immunotherapy

[0094] Screen healthy donors to select candidates with highly functional NKTs.

[0095] Since NKT cell frequencies in human PBMCs vary from less than 0.01% to greater than 1%, we first analyzed NKT cell frequencies in PBMCs isolated from prospective healthy donors according to our IRB-approved protocol. Next, we expanded NKT in culture for 12 days using a protocol developed in our laboratory and quantified their rate of expansion and the expression of key surface markers related to functional potential: CD62L, CD4, and PD1. We characterized 12 healthy donors. At least 3 donors (#6, 7, 8) had very high NKT cell expansion potential with good CD62L retention and low PD1 expression (Table 1).

[0096]

[0097]

[0098] Test for alloreactive NKT cells.

[0099] Since NKTs are restricted by monotype CD1d, they are not expected to respond to ...

Embodiment 2

[0138] Generation of tumor-specific and generally resistant cells other than NKT cells from healthy donors for off-the-shelf cancer immunotherapy

[0139] In certain embodiments, cells other than NKT cells are manipulated to have reduced expression of endogenous B2M and / or Ii. Such cells may be any immune cells other than NKT cells, such as T cells, gamma / delta T cells, mucosa-associated invariant T (MAIT) cells, NK cells, innate lymphoid cells (ILCs) or mixtures thereof. In some embodiments, a mixture of NKT cells and one or more immune cells other than NKT cells is used in the compositions and methods encompassed by the present disclosure.

[0140] Non-NKT cells can be manipulated to have reduced endogenous B2M and / or Ii expression by standard methods in the art, such as targeting the expression of B2M genes using one or more agents, including nucleic acids such as shRNA or CRISPR guide RNA. Other methods include at least morpholino, siRNA, S-DNA, TALENs, ZFNs, etc.

[014...

Embodiment 3

[0144] Generation of tumor-specific and tolerogenic NKT and other cells from healthy donors by targeting MHC class II-associated invariant chain (Ii) for off-the-shelf cancer immunotherapy

[0145] In some embodiments, cells used instead (or in addition) to reduce expression of B2M and methods of using same and / or cells have reduced expression of MHC class II-associated invariant chain (Ii). These cells can be used to replace cells with reduced endogenous B2M expression. In some cases, the same cell has reduced expression of B2M and Ii, and in some cases, a mixture of cells with reduced endogenous B2M expression or reduced endogenous Ii expression, respectively, is used. In cases where the same cell has reduced expression of endogenous B2M and endogenous Ii, the same type of reagents can be used to target their respective reduced expression. For example, in some cases, both B2M and Ii were targeted by shRNA to reduce their expression, or in other cases, both B2M and Ii were t...

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Abstract

Embodiments of the disclosure include methods and compositions for immunotherapy that comprise allogeneic cells that are able to be universally tolerated in host individuals. In specific embodiments the cells have reduced expression of endogenous beta2-microglobulin (B2M) and / or MHC class II-associated invariant chain (Ii), and in particular cases the cells are NKT cells that lack the ability to damage host tissues, have much reduced recognition by host immune cells, and surprisingly avoid destruction by host NK cells. In some embodiments, B2M- and / or Ii-targeting molecules are engineered to be expressed in combination (including within a single construct) with recombinantly engineered receptors, for example, for a one-hit generation of universally tolerated off-the-shelf immunotherapy.

Description

[0001] This application claims priority from EP Application No. 17185992.9 filed on 11 August 2017, which is hereby incorporated by reference in its entirety. technical field [0002] The present disclosure relates at least to the fields of cell biology, molecular biology, immunology and medicine. Background technique [0003] Cancer immunotherapy using autologous tumor-specific T cells. The strategy of isolating and expanding tumor-specific T cells followed by infusion (adoptive transfer) back into the patient is a promising modality in cancer therapy. This treatment has been successful in some melanoma patients, who can have complete and sustained tumor regression after infusion of autologous melanoma-specific T cells (1). However, as a treatment for other less immunogenic malignancies, T cell therapy is limited by the lack of molecularly defined tumor antigens capable of eliciting robust T cell responses and the difficulty of isolating these T cells from the tumor host. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N5/10A61K39/00A61P35/00A61P35/02
CPCC12N5/0646C12N2510/00A61K2039/5158A61K2039/5156C07K14/7051C07K2319/03A61K39/0011A61K35/17A61P35/00C12N15/113C07K14/705C07K14/54C07K14/70521C07K14/70596C12N15/11C12N15/86C12N2310/531C12N2740/10043
Inventor L·S·梅特利察金京玲刘斌
Owner BAYLOR COLLEGE OF MEDICINE
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