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Combination cancer therapy using chimeric antigen receptor engineered natural killer cells as chemotherapeutic drug carriers

A chimeric antigen receptor, chemotherapy technology for targeting specific cell fusions, drug combinations, receptors/cell surface antigens/cell surface determinants, etc.

Inactive Publication Date: 2020-02-07
UNIV OF SOUTHERN CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, effective delivery of these systems to tumor sites while sparing healthy tissue remains elusive.

Method used

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  • Combination cancer therapy using chimeric antigen receptor engineered natural killer cells as chemotherapeutic drug carriers
  • Combination cancer therapy using chimeric antigen receptor engineered natural killer cells as chemotherapeutic drug carriers
  • Combination cancer therapy using chimeric antigen receptor engineered natural killer cells as chemotherapeutic drug carriers

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0161] experimental method

[0162] Cell lines and reagents: in 5% CO 2 MDA.MB.468 (ATCC HTB-132) and SKOV3 (ATCCHTB-77) tumor cell lines were maintained in RPMI 1640 (Gibco) supplemented with 10% FBS, 1% pen-strep and 2mM L-glutamine in the environment medium. NK92 cells (Dr. Jihane Khalife, Children's Hospital Los Angeles, ATCC CRL-2407) were maintained in supplemented with 10% FBS, 10% horse serum, 1% NEAA, 1% pen-strep, 1% sodium pyruvate, 0.1 mM 2- β-mercaptoethanol, 0.2 mM inositol and 2.5 μM folic acid in MEM-α (Gibco). SKOV3 cells were transduced with lentivirus containing CD19 cDNA and CD19 was sorted by fluorescence activated cell sorting (FACS) + cells, producing CD19 + SKOV3 (SKOV.CD19) cells.

[0163] PTX was purchased from Sigma-Aldrich (St. Louis, MO). All lipids were purchased from NOF Corporation (Japan): 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dioleoyl-sn-glycero-3-phosphate -(10-rac-glycerol)(DOPG) and 1,2-dioleoyl-sn-glyceryl-3-phospho...

Embodiment 2

[0180] Expression of anti-CD19 CAR and anti-Her2 CAR in NK92 cells

[0181] We confirmed the ability of NK92 cells to express an anti-CD19 CAR and an anti-Her2 CAR consisting of a scFv-derived antigen-binding domain, a CD8 hinge and transmembrane region, a CD28 and / or 4-1BB co-stimulatory domain, and CD3ζ signaling domain composition. Anti-CD19 CAR.NK cells were generated by retroviral transduction using the previously reported MP71 vector generously provided by Dr. Wolfgang Uckert. Generation of anti-Her2 CAR.NK cells with lentiviral transduction using previously described trastuzumab-derived CAR in pCCW vector, which is based on pCCL vector 43-45 And with the added WRE post-transcriptional regulatory region. Sorting transduced cells using fluorescence-activated cell sorting to further augment CAR + Percentage of cells ( Figure 1E ). CAR expression is stable for several months after initial transduction and sorting.

[0182] cMLV is stably conjugated to the surface of ...

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Abstract

Compositions are provided including NK cells that express chimeric antigen receptors (CARs) specific to CD19 and Her2 and a plurality of cell surface-bound multilamellar liposomal vesicles loaded withone or more anti-cancer therapeutics at an effective amount for inhibiting or killing tumor cells without causing toxicity to the NK cells. Methods of using these compositions to treat a subject withtumor are also provided, including administering an effective amount of the CAR-engineered NK cells, where an effective amount of anti-tumor therapeutics are delivered in particles (e.g., crosslinkedmultilamellar liposomal vesicles) that are bound to the surface of these CAR-engineered NK cells, without causing toxicity to the carrier NK cells.

Description

[0001] Cross References to Related Applications [0002] This application claims priority and benefit to US Provisional Application no. 62 / 523,401, filed June 22, 2017, the disclosure of which is hereby incorporated by reference in its entirety. [0003] Statement Regarding Federally Sponsored Research or Development [0004] This invention was made with government support under Grant No. AI068978 awarded by the National Institutes of Health. The US Government has certain rights in this invention. technical field [0005] Compositions and methods for treating cancer are described herein. Background technique [0006] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the informati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P35/00C07K14/725C07K16/28A61K9/127A61K39/00C07K14/55
CPCA61P35/00C07K14/70503C07K16/00C07K16/2803C07K16/32A61K2039/5156C07K2317/622C07K2319/03C07K2319/33A61K47/6901A61K47/6911A61K2039/6018A61K39/001112A61K39/001106A61K35/17A61K31/337A61K31/7088C12N5/0006C12N5/0646A61K2300/00A61K9/0019A61K2039/505A61K2039/54A61K2039/545C07K14/7051C07K14/70517C07K14/70521C07K14/70578C07K2317/24C07K2317/31C07K2319/30C12N2510/00
Inventor 王品伊丽莎白·西格勒陈显慧金宇廷
Owner UNIV OF SOUTHERN CALIFORNIA
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