Methods and compositions for use of therapeutic t cells in combination with kinase inhibitors

A treatment method and inhibitor technology, applied in the field of preparing such engineered cells, can solve the problems of incompletely satisfactory methods and the like

Pending Publication Date: 2019-12-06
JUNO THERAPEUTICS +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In some respects, the available meth

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  • Methods and compositions for use of therapeutic t cells in combination with kinase inhibitors
  • Methods and compositions for use of therapeutic t cells in combination with kinase inhibitors
  • Methods and compositions for use of therapeutic t cells in combination with kinase inhibitors

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preparation example Construction

[0455] B. Cells and Cell Preparation for Genetic Engineering

[0456] Cells expressing receptors and administered by the provided methods include engineered cells. Genetic engineering generally involves introducing nucleic acids encoding recombinant or engineered components into cell-containing compositions, such as by retroviral transduction, transfection or transformation.

[0457] In some embodiments, the nucleic acid is heterologous, i.e., not normally present in the cell or a sample obtained from the cell, such as a nucleic acid obtained from another organism or cell, e.g., the nucleic acid is not normally present in the engineered cell and / or the organism from which such cells are derived. In some embodiments, the nucleic acid is not a naturally occurring nucleic acid such as one not found in nature, including nucleic acids comprising chimeric combinations of nucleic acids encoding various domains from multiple different cell types.

[0458] Cells are typically eukaryo...

Embodiment 1

[0802] Example 1: Evaluation of the Phenotype and Function of CAR-Expressing T Cells in the Presence of Inhibitors of the TEC Family

[0803] The properties of CAR-expressing T cells in the presence of inhibitors of TEC family kinases, ibrutinib or a compound of formula (II) were evaluated in in vitro studies.

[0804]To generate CAR-expressing T cells, T cells were isolated from three healthy human donor subjects by immunoaffinity-based enrichment, and cells from each donor were activated and transduced with a viral vector encoding an anti-CD19 CAR. The CAR contains an anti-CD19 scFv, an Ig-derived spacer, a human CD28-derived transmembrane domain, a human 4-1BB-derived intracellular signaling domain, and a human CD3ζ-derived signaling domain. The CAR-encoding nucleic acid construct also includes a truncated EGFR (tEGFR) sequence used as a transduction marker, which is separated from the CAR sequence by a self-cleaving T2A sequence.

[0805] CAR-expressing CD4+ and CD8+ ce...

Embodiment 2

[0823] Example 2: Improving the anti-tumor activity of CAR-expressing T cells in the presence of inhibitors of TEC family kinases sex

[0824] A disseminated tumor xenograft mouse model was generated by injecting NOD / Scid / gc- / - (NSG) mice with a CD19+Nalm-6 disseminated tumor cell line identified as resistant to BTK inhibition.

[0825] On day zero (0), NSG mice were injected intravenously with 5x 10 5 Nalm-6 cells expressing firefly luciferase. Beginning on day 4 and for the duration of the study mice were treated daily with vehicle control or ibrutinib, in each case by daily oral gavage (po) at 25 m / kg four times per day. To allow assessment of the effect of combination therapy with inhibitors, suboptimal doses of anti-CD19 CAR T cells from two different donors were administered at 5x10 on day 5. 5 / mouse Intravenous injection into mice. As a control, mice were given vehicle control or ibrutinib, but no CAR-T cells. Eight (N=8) mice were monitored per group.

[0826...

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Abstract

The present disclosure relates to methods, compositions and uses involving immunotherapies and inhibitors of a target protein tyrosine kinase in which the kinase is not IL-2-inducible T cell kinase (ITK) and/or is selected from Bruton's tyrosine kinase (BTK), tec protein tyrosine kinase (TEC), BMX non-receptor tyrosine kinase (Etk), TXK tyrosine kinase (TXK) and/or receptor tyrosine-protein kinaseErbB4 (ErbB4). The provided methods, compositions and uses include administration of one or more such inhibitor with another agent, such as an immunotherapeutic agent targeting T cells and/or genetically engineered T cells, such as CAR-expressing T cells. Also provided are methods of manufacturing engineered cells, cells, compositions, methods of administration, nucleic acids, articles of manufacture and kits. In some aspects, features of the methods and cells provide for improved activity, efficacy, persistence, expansion and/or proliferation of T cells for adoptive cell therapy or endogenous T cells recruited by immunotherapeutic agents.

Description

[0001] Cross References to Related Applications [0002] This application claims the U.S. provisional application titled "Methods and Compositions for Use of Therapeutic T cells in Combination with Kinase Inhibitors," filed December 3, 2016. Application No. 62 / 429,732 and filed on November 3, 2017, entitled "Methods and Compositions for Use of Therapeutic T cells in Combination with Kinase Inhibitors" Priority of US Provisional Application No. 62 / 581,644, the contents of which are incorporated by reference in their entirety. [0003] Incorporated by reference into the sequence listing [0004] This application is filed together with a Sequence Listing in electronic format. The sequence listing is provided as a file named 735042008940seqlist.txt created on November 29, 2017, which is 24,225 bytes in size. The information in electronic format of the Sequence Listing is incorporated by reference in its entirety. technical field [0005] The present disclosure relates in so...

Claims

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Application Information

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IPC IPC(8): A61K35/00C07K14/00C07K16/28A61K45/06A61K31/505A61K31/506A61K39/395A61K35/17
CPCA61K39/395A61K45/06A61K31/505A61K31/506A61K35/17C07K16/2803C07K2317/622C07K2319/03C07K2319/033A61K2300/00A61K9/0053C07K16/2809C12N5/0638C12N15/85A61K31/05
Inventor M·波斯J·秦R·萨蒙O·巴特罗维奇
Owner JUNO THERAPEUTICS
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