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Tumor infiltrating lymphocytes for treatment of cancer

A cell, cancer technology, applied in the field of compositions for treating cancer

Inactive Publication Date: 2018-12-21
DUKE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, current therapies focused on activating TILs are only effective in a minority of patients, highlighting the need for improved cancer treatments

Method used

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  • Tumor infiltrating lymphocytes for treatment of cancer
  • Tumor infiltrating lymphocytes for treatment of cancer
  • Tumor infiltrating lymphocytes for treatment of cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] method

[0094] Mouse and murine cell lines: C57BL / 6J (wild type) mice (stock #000664), C3- / - mice (N7, stock #003641), TCRα- / - mice (N13, stock #002116) , IL10- / - mice (N13, stock number: 002251) and IL10GFP reporter (Tiger) mice (N10, stock number: 008379) were purchased from The Jackson Laboratory. C3- / - mice were further backcrossed with C57BL / 6J for 5 generations (N12). N represents the number of backcross generations. Six to eight week old mice were used for all experiments. All mouse strains are of C57BL / 6 genetic background. Mice were housed in a designated pathogen-free facility at Duke University Medical Center and used according to protocols approved by the Duke University Institutional Animal Care and Use Committee. The B16-F10 murine melanoma cell line was purchased from ATCC in 2011. E0771 is a mouse breast carcinoma, a gift from Dr. Scott A. Gerber (University of Rochester) in 2013.

[0095] Tumor model: Dissolve a total of 5 x 10 in 100 μL PBS 4 t...

Embodiment 2

[0119] Regulation of IL-10 Expression in CD8+ T Cells by Complement

[0120] To investigate the molecular regulation of IL-10 production in effector CD8+ T cells, the gene expression profiles of IL-10+CD8+ T cells were analyzed based on data collected by Trandem and colleagues (Journal of Immunology, 186:3642-52). Figure 1A Heatmaps of genes differentially expressed in IL-10+CD8+ T and IL-10-CD8+ T cells are shown. IL10 mRNA levels were higher in GFP+CD8+ T cells than in GFP-CD8+ T cells, indicating that GFP expression faithfully mirrored IL-10 expression in this dataset ( Figure 8A ). Pathway analysis revealed that genes involved in the complement pathway were highly enriched among genes differentially expressed between IL-10+ and IL-10-CD8+ T cells ( Figure 1B ). The mRNA expression levels of several complement components and their receptors were upregulated in IL-10+CD8+ T cells ( Figure 1C and D). These data suggest that the complement signaling pathway may be inv...

Embodiment 3

[0123] Inhibition of T cell-mediated antitumor immunity by complement

[0124] Development of melanoma in C3-deficient mice: B16F10 melanoma cells (2 × 10 5 / mouse) were inoculated subcutaneously into 6-8 week old wild-type (WT) and C3 knockout (C3- / -) mice. Tumor growth was monitored daily starting on day 7. The growth rate of B16 melanoma in C3-deficient mice was significantly lower than that in wild-type mice ( Figure 2A –C). Specifically, C3-deficient mice exhibited significantly smaller tumor volumes compared to WT controls ( Figure 2A ), tumor size ( Figure 2B ) and tumor weight ( Figure 2C ).

[0125] Development of breast cancer in C3-deficient mice: E0771 breast cancer cells (1×10 6 / mouse) were inoculated subcutaneously into 6-8 week old wild-type (WT) and C3 knockout (C3- / -) mice. Tumor growth was monitored every other day starting on day 7. The development speed of E0771 breast cancer cells in C3-deficient mice was significantly lower than that in wild...

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Abstract

Tumor infiltrating lymphocytes (TILs) are white blood cells that are actively recruited to the tumor site to mount an immune response against tumor growth and metastasis. The disclosure provides methods for treating cancer that comprise steps of isolating CD8+ T cells from a sample derived from a subject, expanding the CD8+ T cells in the presence of interleukin-10, and administering the expandedCD8+ T cells to the subject. Methods of treating cancer may be used in combination with inhibitors of the complement signaling pathway.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application Nos. 62 / 257,143, filed November 18, 2015, and U.S. Provisional Application Nos. 62 / 265,508, 62 / 265,511, and 62 / 265,513, filed December 10, 2015, the contents of which Incorporated herein in its entirety by reference. [0003] Statement of Government Interests [0004] This invention was made with support under Grant No. R01AI074944-01 awarded by the National Institutes of Health. The US Government has certain rights in this invention. technical field [0005] The present disclosure relates to tumor infiltrating lymphocytes and compositions and methods for treating cancer. Background technique [0006] Tumor-infiltrating lymphocytes (TILs) are white blood cells that are actively recruited to tumor sites to generate an immune response against tumor growth and metastasis. Multiple signaling pathways control the activation of TILs, and many have been i...

Claims

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Application Information

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IPC IPC(8): A01N63/00A61K38/20A61K38/21A61K39/00A61P35/00C07H21/02A61K33/243
CPCA61K38/00A61K45/06A61K31/555C07K14/5428C07K16/2818C07K2319/33C07K2319/75A61P35/00A61K33/243A61K39/464492A61K2239/31A61K2239/57A61K39/4611A61K2239/38A61K2300/00A61K33/24C07K14/705C07K14/54A61K35/17
Inventor 何有文王宇
Owner DUKE UNIV
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