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Methods for treating tumours

A tumor and immunotherapy technology, applied in anti-tumor drugs, biochemical equipment and methods, pharmaceutical formulations, etc., can solve problems such as difficulty in effective delivery, unsustainable normalization of blood vessels, and damage to tumor blood vessels.

Inactive Publication Date: 2018-07-31
CENTENARY INST CANCER MEDICINE & CELL BIOLOGY +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, antiangiogenic agents can cause extensive damage (including destruction) to tumor vessels, and vascular normalization is not sustained
Thus, current tumor treatments pose difficulties in their effective delivery, and the high doses of therapeutic agents required in treatment regimens may produce undesired side effects

Method used

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  • Methods for treating tumours
  • Methods for treating tumours
  • Methods for treating tumours

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0148] Example 1-CD5-2 promotes the infiltration of CD8+ T cells into tumors and induces tumor cell apoptosis

[0149] At 27 weeks of age, RIP1-TAG5 mice were injected with control Blockmir or Blockmir CD5-2. Then 2 days later, the mice were injected with Tag-specific activated CD8+ T cells and sacrificed an additional 12 days later. Infiltration of CD8+ T cells was determined by immunofluorescence staining for CD8. Compared with the control Blockmir ( figure 1 ) injection, mice injected with CD5-2 displayed an increased ratio of infiltrating T cells (relative to cells in the field of view), suggesting that Blockmir CD5-2 promotes tumor infiltration through adoptively transferred T cells. Therefore CD5-2 can modulate the tumor microenvironment to increase the sensitivity of solid tumors to immune responses.

[0150] In another model, the B16F10 melanoma model, endogenous T cell infiltration into the middle of the tumor parenchyma was increased in Blockmir CD5-2-treated mice...

example 2

[0153] Example 2 - Blockmir CD5-2 regulates tumor vasculature and tumor vascular cell morphology

[0154] Tumor vasculature in mice bearing B16F10 melanoma was visualized using immunohistochemistry for CD31. Compared to control Blockmir-treated mice, mice treated with Blockmir CD5-2 6 to 8 days before sacrifice showed smaller blood vessels within tumors. Although the number of blood vessels per field of view was higher in Blockmir CD5-2-treated mice than in control Blockmir-treated mice, receiving Blockmir CD5-2 ( image 3 ) mice showed a significant reduction in mean vessel volume, suggesting that Blockmir CD5-2 can alter the morphology of tumor vasculature without vascular pruning. Consistent with this, CD5-2-treated EC in vitro showed no changes in angiogenesis-related features, including proliferation (data not shown), senescence (data not shown), and migration (data not shown).

[0155] Figure 4 Scanning electron microscopy approach demonstrating blood vessels within ...

example 3

[0158] Example 3 - Tumor Vasculature Function Altered by Blockmir CD5-2

[0159] In addition to altering the structure of tumor vasculature, Blockmir CD5-2 modulates the permeability and perfusion of tumor vasculature in the Bl 6F10 mouse melanoma model. Figure 8 Demonstrates extravasation of R50 fluorescent microspheres injected into control Blockmir or Blockmir CD5-2 treated mice. CD5-2 reduces vascular permeability as measured by the number of R50 fluorescent microspheres within the tumor parenchyma ( Figure 8 A). as shown in Figure 8 In B, the ratio of microspheres to endothelial markers (CD31 ) was significantly reduced in Blockmir CD5-2-treated animals relative to controls, indicating reduced leakage of Blockmir CD5-2-treated blood vessels. Consistent with this reduced vascular permeability, there was reduced deposition of fibrinogen into the stroma ( Figure 8 C and 8D).

[0160] In addition, compared to the control Blockmir treatment ( Figure 9 ), as demonstr...

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Abstract

The present invention provides methods for increasing the sensitivity of a tumour to immunotherapy, chemotherapy or radiotherapy by administering an effective amount of an oligonucleotide that inhibits the binding of miR-27a, or a variant thereof, to its target mRNA. Oligonucleotides used in the invention are typically in the form of a blockmirs used as an adjunctive therapy to inhibit tumour growth, normalise and / or improve functions of tumour vasculature, and / or promote immune cell infiltration of tumours.

Description

technical field [0001] The present invention generally relates to the use of oligonucleotides as adjuvant therapy in inhibiting tumor growth, for normalizing and / or improving the function of tumor vasculature, and / or increasing immune cell infiltration of tumors. Background technique [0002] As a tumor grows, its need for nutrients becomes greater, and angiogenesis is induced to provide the tumor with new vasculature. This tumor vasculature differs from normal vasculature in that it is poorly organized and has abnormal vessel walls. Fewer tight junctions, spaces between endothelial cells, loosely attached pericytes, and abnormal basement membrane and extracellular matrix result in a hyperpermeable endothelial barrier. This poor vascularization contributes to a hypoxic microenvironment in tumors, which induces biochemical pathways that promote further tumor progression, for example via vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF). Thus, hypo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/7088A61K31/7115A61P35/00A61P35/04
CPCA61K31/7105A01K2227/105A01K2267/0331A61P35/00A61K45/06C12N15/113C12N2310/113C12N2310/321C12N2310/323C12N2310/3231C12N2320/31
Inventor 詹妮弗·甘布勒索尔莱夫·默勒马修·沃道什
Owner CENTENARY INST CANCER MEDICINE & CELL BIOLOGY
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