Tumor and microenvironment gene expression, compositions of matter and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2018100201-A1
Application number	US-201715844601-A
Country	US
Kind code	A1
Filing date	Dec 17, 2017
Priority date	Jun 29, 2015
Publication date	Apr 12, 2018
Grant date	—

Abstract

This invention relates generally to compositions and methods for identifying genes and gene networks that respond to, modulate, control or otherwise influence tumors and tissues, including cells and cell types of the tumors and tissues, and malignant, microenvironmental, or immunologic states of the tumor cells and tissues. The invention also relates to methods of diagnosing, prognosing and/or staging of tumors, tissues and cells, and provides compositions and methods of modulating expression of genes and gene networks of tumors, tissues and cells, as well as methods of identifying, designing and selecting appropriate treatment regimens. The invention also relates to the modulation of complement activity to shift cellular immunity and obtain an effective therapeutic response.

First claim

What is claimed is:

1 . A method of diagnosing, prognosing and/or staging a condition or disorder having an immunological state, comprising detecting a first level of expression, activity and/or function of one or more signature genes or one or more products of one or more signature genes in one or more cell(s) of the disorder and comparing the detected level to a control level of signature gene or gene product expression, activity and/or function, wherein the one or more signature genes comprise a component of the complement system, and wherein a difference in the detected level and the control level indicates an immunologic state of the condition or disorder.

2 . The method of claim 1 , wherein the one or more signature genes comprise C1S, C1R, C3, C4A, CFB, C1QA, C1QB, C1QC, CD46, CD55, CD59 or SERPING1.

3 . The method of claim 1 , wherein the immunologic state of the condition or disorder is characterized by the presence or absence of immune cells comprising myeloid-derived suppressor cells (MDSC), macrophages, dendritic cells (DC), natural killer cells (NK), T cells and/or B cells, wherein expression of the one or more signature genes correlates to the abundance of the immune cells.

4 . The method of claim 1 , wherein the condition or disorder comprises autoimmune diseases, inflammatory diseases, infections or cancer.

5 . The method of claim 1 , wherein the inflammatory disease comprises a pathogenic or non-pathogenic Th17 response.

6 . The method of claim 1 , wherein the cancer comprises Non-Hodgkin's Lymphoma (NHL), clear cell Renal Cell Carcinoma (ccRCC), melanoma, sarcoma, leukemia or a cancer of the bladder, colon, brain, breast, head and neck, endometrium, lung, ovary, pancreas or prostate.

7 . The method of claim 6 , wherein the cancer is a recurrent cancer.

8 . The method of claim 6 , wherein the cancer is from a patient who progressed through chemotherapy.

9 . The method of claim 1 , wherein the one or more signature genes comprises a gene that indicates the abundance of T cells.

10 . The method of claim 9 , wherein the one or more signature genes is detected in CAFs.

11 . The method of claim 10 , wherein the one or more signature genes comprises C1S, C1R, C3, C4A, CFB, or SERPING1.

12 . The method of claim 9 , wherein the one or more signature genes is detected in macrophages.

13 . The method of claim 12 , wherein the one or more signature genes comprises C1QA, C1QB or C1QC.

14 . The method of claim 1 , wherein the one or more signature genes comprises a gene that indicates the abundance of B cells.

15 . The method of claim 14 , wherein the one or more signature genes is detected in CAFs.

16 . The method of claim 15 , wherein the one or more signature genes comprises C7 or C3.

17 . The method of claim 1 , wherein the one or more signature genes comprises a gene that indicates the abundance of macrophages.

18 . The method of claim 17 , wherein the one or more signature genes is detected in CAFs.

19 . The method of claim 18 , wherein the one or more signature genes comprises C1S, C1R or CFB.

20 . The method of claim 1 , wherein the level or expression of the one or more signature genes is determined by single-cell RNA sequencing.

21 . The method of claim 20 , wherein the single-cell RNA sequencing comprises single nucleus RNA-Seq.

22 . The method of claim 1 , wherein level of expression, activity and/or function of one or more signature genes is determined by the level of expression of one or more products encoded by one or more signature genes in one or more cell(s).

23 . The method of claim 22 , wherein the level of expression of one or more products encoded by one or more signature genes is determined by a colorimetric assay or absorbance assay.

24 . The method of claim 1 , wherein level of expression, activity and/or function of one or more signature genes or one or more products of one or more signature genes in one or more cell(s) is determined by deconvolution of bulk expression data.

25 . A method of treating or enhancing treatment of condition or disorder having an immunological state, which comprises administering an agent that increases or decreases the function, activity and/or expression of one or more signature genes or one or more products of one or more signature genes in one or more cell(s) of the condition or disorder, wherein the one or more signature genes comprise a component of the complement system, and wherein administering of the agent increases or decreases an immune response.

26 . The method of claim 25 , wherein administering of the agent increases or decreases the abundance of an immune cell.

27 . The method of claim 26 , wherein the agent increases or decreases the function, activity and/or expression of C1S, C1R, C3, C4A, CFB, C1QA, C1QB, C1QC, CD46, CD55, CD59, C5 or SERPING1(CFI).

28 . The method of claim 27 , wherein the condition or disorder is cancer and the agent decreases the function, activity and/or expression CD46, CD55 or CD59, whereby malignant cells are susceptible to killing by complement activation.

29 . The method of claim 25 , wherein the agent comprises a CRISPR-Cas system that activates expression of the component of the complement system.

30 . The method of claim 25 , wherein the agent comprises a CRISPR-Cas system that targets the component of the complement system, whereby the component gene is knocked out or expression is decreased.

31 . The method of claim 25 , wherein the agent is an isolated natural product, whereby the component of the complement system is activated.

32 . The method of claim 31 , wherein the agent comprises a metalloproteinase, whereby a component of the complement system is directly cleaved.

33 . The method of claim 31 , wherein the agent comprises a serine protease, whereby a component of the complement system is directly cleaved.

34 . The method of claim 25 , wherein the agent comprises a therapeutic antibody or fragment thereof.

35 . A method of treating cancer in a patient in need thereof comprising administering a therapeutically effective amount of an agent capable of targeting or binding to a component of the complement system presented on the surface of a cancer cell.

36 . The method of claim 35 , wherein the component of the complement system is CD46, CD55 or CD59.

37 . The method of claim 36 , wherein the agent is a therapeutic antibody or fragment thereof, antibody drug conjugate or fragment thereof, or a CAR T cell.

38 . The method of claim 35 , wherein the cancer comprises Non-Hodgkin's Lymphoma (NHL), clear cell Renal Cell Carcinoma (ccRCC), melanoma, sarcoma, leukemia or a cancer of the bladder, colon, brain, breast, head and neck, endometrium, lung, ovary, pancreas or prostate.

39 . A method of treating glioma, comprising administering to a subject in need thereof having glioma a therapeutically effective amount of an agent:
capable of reducing the expression or inhibiting the activity of one or more stem cell or progenitor cell signature genes or polypeptides; or capable of targeting or binding to one or more cell surface exposed stem cell or progenitor cell signature pol

Assignees

• Broad Inst Inc
• Massachusetts Inst Technology
• Dana Farber Cancer Inst Inc
• Massachusetts Gen Hospital

Inventors

• Garraway Levi A
• Izar Benjamin
• Prakadan Sanjay
• Regev Aviv
• Rozenblatt-Rosen Orit
• Shalek Alexander K
• Suva Mario
• Tirosh Itay
• Venteicher Andrew
• Wadsworth Ii Marc H
• Bernstein Bradley
• Parikh Anuraag
• Puram Sidharth

Classifications

• C12Q1/6886 Primary

  for cancer (immunoassay for cancer G01N33/575) · CPC title

• C12Q2600/112

  Disease subtyping, staging or classification · CPC title

• C12Q2600/106

  Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism · CPC title

• C12Q2600/158

  Expression markers · CPC title