Compositions and methods for treatment of her2 positive metastatic breast cancer

A therapeutic composition and composition technology, applied in chemical instruments and methods, drug combinations, medical raw materials derived from mammals, etc., can solve problems such as low toxicity and adverse side effects

Inactive Publication Date: 2019-03-15
NANTCELL INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Although this treatment appears to have significantly lower toxicity and adverse side effects in patients, complete and permanent remission or eradication of cancer cells has not been consistently achieved

Method used

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  • Compositions and methods for treatment of her2 positive metastatic breast cancer
  • Compositions and methods for treatment of her2 positive metastatic breast cancer
  • Compositions and methods for treatment of her2 positive metastatic breast cancer

Examples

Experimental program
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Effect test

Embodiment 1

[0054] In an exemplary therapeutic approach to determine the efficacy of HER2.taNK in combination with metronomic Nant-paclitaxel (Abraxane) in a mouse model of HER2-positive breast cancer, the inventors used HER2.taNK cells as previously described (MolTher .2015;23(2):330-338). MDA-MB-453 cells (0.1 mL of 1 × 10 in 50% Matrigel 8 cells / mL) were injected subcutaneously into the left and right flank regions of female NOD / SCID mice (7 to 8 weeks old). When the tumor reaches about 100mm 3 At the same time, the mice were randomly divided into 4 groups, 4 mice in each group, given (intravenous injection) normal saline, nant-paclitaxel, γ-irradiated (10Gy) aNK cells / HER2.taNK cells, or nant-paclitaxel plus γ-irradiated (10 Gy) aNK cells / HER2.taNK cells (γ-irradiated cells to prevent cell replication). Tumor growth was measured with calipers twice a week prior to dosing and then twice a week; animals were weighed prior to dosing before cell injection and then twice a week. All da...

Embodiment 2

[0062]In a second exemplary treatment approach to determine the efficacy of haNK cells in combination with trastuzumab in a mouse model of HER2-positive breast cancer, the inventors used haNK cells as previously described. haNK cells were developed by transfecting the parental aNK cell line with a bicistronic plasmid vector containing a high-affinity V variant of CD16 (with a valine at position 158) and intracellularly retained IL-2, which renders haNK cells Able to grow in the absence of exogenous IL-2. This plasmid contains some human sequences of CD16 and IL-2, neither of which has any transforming properties.

[0063] MDA-MB-453 cells (0.1 mL of 1×10 8 / mL in 50% Matrigel) subcutaneously into female NOD-SCID IL2Rγ 空 (NSG, Jackson Laboratory) Left and right flank regions of mice (7 to 8 weeks old). Such as Figure 4A As shown, when the tumor reaches about 100mm 3 , mice were randomly assigned to one of 10 groups of 4 mice each, and physiological saline (PBS), IgG 1 (...

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Abstract

Contemplated immunotherapies include co-administration of an activated NK cell that is further genetically modified and a cancer therapeutic agent. In preferred embodiments, activated NK cells are further modified to taNK cells, which include a chimeric antigen receptor (CAR) with affinity for a cancer specific antigen, a cancer associated antigen, or a tumor specific antigen. Activated NK cells can also be further genetically modified to include high affinity Fc receptor CD16a (V158). Appropriate cancer therapeutic agents include chemotherapeutic drugs (e.g., nant-paclitaxel) or cancer targeted antibodies (e.g., trastuzumab).

Description

[0001] This application claims priority to U.S. Provisional Application Serial No. 62 / 265382 filed December 9, 2015. technical field [0002] The field of the present invention is pharmaceutically enhanced immunotherapy, in particular treatment with genetically modified natural killer cells expressing chimeric antigen receptors and microtubule inhibitors. Background technique [0003] The Background Description includes information useful in understanding the present invention. It is not an admission that any information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art. [0004] 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. If the definition or usage of a term in an incorporated reference is inconsistent or contrary...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K35/17A61K39/395A61K39/00A61K31/337
CPCA61K31/337A61K39/3955A61K45/06C07K16/32C07K2317/24C07K2317/76A61K35/17A61P35/00A61K2300/00A61K39/0011A61K39/395A61K39/001106A61K2039/5156
Inventor S·拉比扎德P·宋世宗H·克林格曼
Owner NANTCELL INC
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