Compositions and methods for immune-mediated cancer therapy

An immune response and immune checkpoint technology, applied in the field of immune response kits, solid tumor immune response, and enhanced immune response against solid tumors, can solve the problem of over-reliance on compounds that break the balance of the immune system and weaken immune suppression. general immunity

Active Publication Date: 2018-08-31
TECLISON LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Efforts have been made to manipulate immune signaling responses for cancer treatment, but response rates and impact on progression-free survival leave much room for improvement
In addition, excessive reliance on compounds that weaken immune suppression may tip the balance between the immune system and autoimmune disease
For example, observed side effects of nivolumab and pembrolizumab include various immune-related hepatitis, pneumonia, hypophysitis, colitis, etc., suggesting that further enhancement of general immunity may bring potential risks of

Method used

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  • Compositions and methods for immune-mediated cancer therapy
  • Compositions and methods for immune-mediated cancer therapy
  • Compositions and methods for immune-mediated cancer therapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1. Combination of tirapazamine and hepatic artery ligation in a hepatocellular carcinoma model.

[0066] Materials and Methods: All HBx transgenic mice were fed and followed in a specific pathogen-free facility; the tails of individual mice were subsequently collected for the genotyping process at weaning at 3 weeks of age. Hepatocellular carcinoma (HCC) arises spontaneously in >95% of male HBx transgenic mice aged 17-18 months. Transgenic mice with 0.5-2 cm diameter tumors were used for the study.

[0067] Treatment of tumor-bearing HBx mice with tirapazamine and hepatic artery ligation: HBx transgenic mice were subjected to ligation of the left hepatic artery for 40 min, followed by removal of the silk ligature. In the drug effect study, 0.9% saline, doxorubicin (10 mg / kg) or TPZ (3 mg / kg) were injected into the tail vein of each mouse for 7 min prior to hepatic artery ligation. After injection, a midline laparotomy was performed to expose the left hepatic...

Embodiment 2

[0069] Example 2: Combination of tirapazamine and combretastatin A4 and DMXAA in a lung cancer model.

[0070] Materials and methods: Human lung cancer NCI-H460 cells were purchased from ATCC and used in this study. Cells were subcultured within 5 passages prior to inoculation into mice. After the animal acclimation period, under anesthesia with 3-4% isoflurane, add approximately 1.5 x 10 in 200 μL of serum-free medium / matrigel (50:50 v / v)6 NCI-H460 cells were injected subcutaneously into each mouse. BALB / c nude mice (male, about 4-5 weeks old and weighing 18-20 g) were purchased from Shanghai SLAC Laboratory Animal Co. Ltd., China, and were given 3- 5 mice / cage were housed in the animal house. Mice had free access to food (irradiated, Shanghai Slack Laboratory Animal Co., Ltd., China) and water (municipal tap water filtered by Mol Ultrapure Water System).

[0071] On day 18 after the first dose, with CO 2 Mice from each group were euthanized by cervical dislocation afte...

Embodiment 3

[0072] Example 3: Induction of tumor necrosis and transformation of tumors into cancer vaccines in vivo.

[0073] To address the issues of tumor heterogeneity and genomic instability, the ideal cancer vaccine is each patient's autologous tumor. However, tumors themselves are often not extremely immunogenic, and even in the presence of immune checkpoint inhibitors alone, the extent of antitumor immunity is often insufficient. The immune response can be enhanced by inducing tumor necrosis, which is associated with a strong inflammatory response that results in the presentation of tumor-associated antigens to T cells and increases the population of tumor-specific T cells. One method of inducing tumor necrosis is applicable, for example, to cancers within the liver, an organ with a dual blood supply from the portal vein and hepatic artery, allowing embolization of the hepatic artery supplying the tumor without significant damage to the normal liver. The strategy to induce tumor...

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Abstract

Disclosed herein are methods and compositions for enhancing an immune response to a solid tumor in a subject. In some embodiments, a method comprises: (a) administering to the subject a hypoxia-activated bioreductive agent (HABA); (b) inducing hypoxia by (i) administering a hypoxia-inducing agent to the subject or (ii) embolizing one or more blood vessels supplying the solid tumor; and (c) administering an immune checkpoint inhibitor prior to, simultaneously with, or subsequent to step (b) in an amount effective to enhance an immune response to the solid tumor, as compared to an immune response in the absence of the immune checkpoint inhibitor. Kits for use in the disclosed methods are also provided.

Description

[0001] cross reference [0002] This PCT application claims priority to US Provisional Patent Application No. 62 / 244,457, filed October 21, 2015, which is incorporated herein by reference in its entirety for all purposes. Background technique [0003] Although some patients have been shown to exhibit immunity to cancer based on the detection of tumor-specific cytotoxic T cells, these T cells appear to be sidelined from acting on the tumor and thus provide little treatment or protection of any kind benefit. Some explain this at odds with the theory that tumors evolve various mechanisms to avoid immune attack. For normal immune responses, APCs ingest tumor-derived antigens and, after processing, present them to T cells to elicit cytotoxicity against tumor cells bearing the antigen. The interaction between APCs and T cells is regulated by various ligand-receptor interactions, including the T cell receptor (TCR), which recognizes tumor-associated antigens and forms complexes wi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61K31/135A61K31/53A61K35/17
CPCA61K45/06A61K31/53A61P35/00A61K2300/00A61K39/395A61K35/17A61K39/39541A61K31/09A61K31/485C07K16/2818A61K2039/505C07K2317/73A61K31/05A61K31/136A61K31/27A61K31/352
Inventor 李瑞民
Owner TECLISON LTD
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