COMPOSITIONS AND METHODS REGARDING ENGINEERED AND NON-ENGINEERED [Gamma][Delta]-T CELLS FOR TREATMENT OF SOLID TUMORS

A technology of tumor cells and cells, which is applied on the surface of cells, including domains, can solve problems such as uncertainty

Pending Publication Date: 2021-08-17
APPLIED IMMUNE TECH LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Notably, given the current lack of understanding of the costimulatory requirements of γδ T cells compared with αβ T cells, practical translation of any of these various approaches to γδ T cells is uncertain at best

Method used

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  • COMPOSITIONS AND METHODS REGARDING ENGINEERED AND NON-ENGINEERED [Gamma][Delta]-T CELLS FOR TREATMENT OF SOLID TUMORS
  • COMPOSITIONS AND METHODS REGARDING ENGINEERED AND NON-ENGINEERED [Gamma][Delta]-T CELLS FOR TREATMENT OF SOLID TUMORS
  • COMPOSITIONS AND METHODS REGARDING ENGINEERED AND NON-ENGINEERED [Gamma][Delta]-T CELLS FOR TREATMENT OF SOLID TUMORS

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0154] In the presence of IL-2 (100 U / mL), 1×10 6 / mL human PBMC were activated for 5 days in modified medium with anti-Vδ1 antibody D1-08 or D1-35 precoating. On day 5, cell cultures were transduced with a gamma-retroviral construct encoding an anti-TyrD chimeric antigen receptor (SEQ ID NO:8) in the presence of retronectin. On day 6, cells were returned to the modified medium and further expanded with feed and IL-2 replacement as needed. On day 17, 18 or 19, cells were harvested and used A kit (Miltenyi Biotec) was used to deplete remaining αβ T cells. Purity and transduction efficiency of γδ cell populations were assessed by FACS. In parallel, non-transduced cell cultures were expanded in the same manner without addition of retroviral supernatant. Such as figure 2 As shown, untransduced, expanded Vδ1 cells primed against cells known to express tyrosinase and present Tyr 369-377 Some degree of cytotoxicity of peptide 526 and WM266.1-Luc melanoma cell lines. This cyt...

Embodiment 2

[0156] WM266.4-Luc cells (4x10 6 individuals / animal) were subcutaneously implanted into NSG mice (Jackson Labs). When the tumor reaches 100-200mm 3 size, place the animal in a 6x10 6 An anti-TyrD CAR+Vδ1 cell therapy. Animals were concomitantly administered IL-2 (60,000 U / dose) 3 times a week throughout the study. result in image 3 described in . Such as image 3 As shown, animals administered anti-TyrD CAR+Vδ1 cells exhibited robust control of tumor burden.

Embodiment 3

[0158] The Tyr CAR construct was introduced into Vδ1 T cells as described above and the cells were expanded and tested in a cytotoxicity assay against WM266.4-Luc cells. A control, non-TyrD targeting CAR construct was used as a control. result in Figure 5 described and showed the increased cytotoxicity provided by anti-TyrD CAR constructs.

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Abstract

Aspects of the invention include compositions and methods for treatment of solid tumors with engineered or non-engineered [Gamma][Delta]-T cells. In some embodiments, the [Gamma][Delta]-T cells comprise a chimeric antigen receptor (CAR) construct. The CAR construct can contain an anti-TryD binding domain, a CD8alpha hinge and transmembrane domain, a costimulatory domain, a 003zeta signalling domain, a combination thereof, or all thereof. The CAR construct can contain an anti-GPC3 binding domain, a CD8alpha hinge and transmembrane domain, a costimulatory domain, a CD3zeta signalling domain, a combination thereof, or all thereof. The CAR construct can contain a domain encoding for a secreted common gamma chain cytokine such as a sIL 15 domain.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 739,826, filed October 1, 2018, the contents of which are hereby incorporated for any and all purposes. [0003] sequence listing [0004] This application contains a Sequence Listing, which was filed electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on January 8, 2020, is named ADC-0006-PCT_SL.txt and is 48,406 bytes in size. Background technique [0005] Adoptive cell therapy has undergone more than thirty (30 ) years of continuous iteration. While there have been hints and indications along the way of the healing potential of these approaches, much work remains to be done. In particular, whether CAR-T lymphocytes can successfully eradicate tumors depends on the persistence and effector functions of CAR-T cells, but an excess of either of these can trigger graf...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P35/00C07K16/28C07K16/30C07K19/00
CPCC07K16/2833C07K16/303C07K16/30C07K2317/622C07K2317/32C07K2317/73C07K2319/03C07K2319/33C07K2317/34A61P35/00C12N5/0636A61K35/17C12N2510/00A61K2039/5156A61K39/0011A61K39/001156C07K14/705C07K14/70517C07K14/70521C07K14/70578C07K14/5443C12N15/62C07K2319/02C07K2317/565A61K2039/585A61K38/177A61K38/1774A61K38/2013A61K38/2086A61K39/39558A61K2039/505A61K2039/5158C07K14/7051C07K2317/74C07K2319/30
Inventor D.K.萨特帕耶夫M.A.赫尔曼J.M.罗梅罗Y.F.靖Z.安A.贾克博维茨
Owner APPLIED IMMUNE TECH LTD
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