Assays for detecting t cell immune subsets and methods of use thereof

Inactive Publication Date: 2016-06-09
GENENTECH INC
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  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0016]In certain aspects, the present disclosure provides a method for determining prognosis of a subject having cancer, comprising: (a) measuring the number of OX40+, CD4+ OX40+ Foxp3+, or CD4+ OX40+ Foxp3− lymphocytes in a sample comprising metastatic cancer cells and lymphocytes obtained from the subject; and (b) determining the prognosis of the subject based on the number of OX40+, CD4+ OX40+ Foxp3+, or

Problems solved by technology

In a subset of these indications, increased intratumoral T reg cell densities are associated with poor

Method used

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  • Assays for detecting t cell immune subsets and methods of use thereof
  • Assays for detecting t cell immune subsets and methods of use thereof
  • Assays for detecting t cell immune subsets and methods of use thereof

Examples

Experimental program
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example 1

Inverse Correlation Between T-Cell Subsets and Cancer Stage

[0416]Increased numbers of OX40+ T cells in the tumor microenvironment of colorectal cancer (CRC) patients have been associated with improved outcome (Petty, J. K., et al. (2002) Am. J. Surg. 183(5):512-8). However, the OX40+ T cell population is heterogeneous and includes, among others, CD4+Foxp3+ regulatory T cells (Tregs) as well as CD4+Foxp3− effector T cells (Teff).

[0417]To study the functional significance of these T cell subsets, a multiplex immunofluorescence assay was developed to evaluate the expression of OX40 in certain CD4+ T cell subsets. This assay was utilized to determine whether OX40+ cell subsets and clinical outcome are associated in colorectal cancer (CRC) patients.

[0418]Materials and Methods

Case Selection

[0419]Formalin-fixed paraffin-embedded (FFPE) CRC specimens including primary site (n=48) and matched metastases (n=19) were included from a collection annotated with treatment histories and survival ou...

example 2

Presence of Increased OX40+ Lymphocytes is Associated with Improved Survival

[0434]Because of the observed correlations between OX40+ T cell subsets and cancer stage described above, the presence of these T cell subsets was next analyzed with respect to prognosis.

[0435]The prevalence of T cell subsets in the tumor samples described above was analyzed to determine potential association with patient prognosis (e.g., overall survival). FIGS. 7A-8D show the results of these correlation analyses, with the T cell subsets selected for study provided as follows: CD4+ (FIG. 7A), Foxp3+ (FIG. 7B), OX40+ (FIG. 7C), OX40+ CD4+ (FIG. 8A), OX40+ CD4− (FIG. 8B), OX40+ CD4+ Foxp3+ (FIG. 8C), and OX40+ CD4+ Foxp3− (FIG. 8D). Overall survival was plotted for patients whose samples showed expression of the labeled marker(s) above or below the median of all samples, as indicated in each plot.

[0436]These analyses indicated that increased prevalence of CD4+ (p=0.019), total OX40+ (p=0.046), and OX40+ Treg...

example 3

Correlation Between OX40+ Status of Immune Infiltrates of Primary Tumors and Metastases

[0439]Given the correlations observed between OX40+ cells found in tumor samples and tumor stage and patient survival, OX40+ T cell subsets were next analyzed in paired primary and metastatic tumor samples.

[0440]FIGS. 9A-10D show the results of these correlation analyses, with the T cell subsets selected for study provided as follows: CD4+ (FIG. 9A), Foxp3+ (FIG. 9B), OX40+ (FIG. 9C), OX40+ CD4+ (FIG. 10A), OX40+ CD4− (FIG. 10B), OX40+ CD4+ Foxp3+ (FIG. 10C), and OX40+ CD4+ Foxp3− (FIG. 10D).

[0441]Analysis of paired primary and metastatic samples (n=19) showed strong correlations between positive cell counts for CD4 (r=0.75), total OX40+ (r=0.84), OX40+ Treg (0.52), and OX40+ Teff (r=0.85) subsets in primary and metastatic samples. These associations remained strong when counts were normalized to total cells. These results show that the OX40+ status of immune infiltrates of primary tumors and meta...

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Abstract

The present disclosure provides methods for measuring the number of CD4+ OX40+ Foxp3+ lymphocytes in a sample containing cancer cells and lymphocytes obtained from a subject by labeling lymphocytes that show CD4 expression in the sample, then labeling lymphocytes that show OX40 expression in the sample, then labeling lymphocytes that show Foxp3 expression in the sample, then measuring the number of CD4+ OX40+ Foxp3+ lymphocytes in the sample. Further provided are methods for determining the prognosis of a subject, predicting responsiveness of a subject having cancer to an OX40 agonist treatment, and methods for treating or delaying progression of cancer based on the number of CD4+ OX40+ Foxp3+ lymphocytes in a sample.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the priority benefit of U.S. Provisional Application Ser. No. 62 / 074,594, filed on Nov. 3, 2014, which is incorporated herein by reference in its entirety.SUBMISSION OF SEQUENCE LISTING ON ASCII TEXT FILE[0002]The content of the following submission on ASCII text file is incorporated herein by reference in its entirety: a computer readable form (CRF) of the Sequence Listing (file name: 146392029000SEQLIST.TXT, date recorded: Nov. 2, 2015 size: 185 KB).FIELD[0003]The present disclosure relates to assays for detecting T cell immune subsets, as well as methods for determining prognosis, predicting responsiveness to treatment, and methods of treatment related thereto.BACKGROUND[0004]OX40 (also known as CD134, TNFRSF4 and ACT35) is a member of the tumor necrosis factor receptor superfamily. OX40 is not constitutively expressed on naïve T cells, but is induced after engagement of the T cell receptor (TCR). The ligand for...

Claims

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Application Information

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IPC IPC(8): G01N33/569C07K16/28A61K38/17G01N33/58C12Q1/06
CPCG01N33/56972G01N33/582C12Q1/06A61K38/177C07K2317/24G01N2800/52G01N2800/7028C07K2317/75C07K16/2875G01N33/57419G01N2333/70514A61P35/00A61P35/04
Inventor CHU, FELIXFOREMAN, ODEDZIAI, JAMES
Owner GENENTECH INC
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