Treatment for CD5+ B cell lymphoma

a lymphoma and cd5 technology, applied in the field of treatment of cd5 + b cell lymphoma, can solve the problems of insufficient antibody production, direct tissue infiltration of cll, and inability to produce antibodies, and achieve the effect of increasing the expression of at least one cell surface molecul

Inactive Publication Date: 2005-03-10
COLEY PHARMA GRP INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

Accordingly, the invention provides a method of treating a CD5+ B cell lymphoma. Generally, the method includes administering to a subject an IRM compound in an amount effective to ameliorate at least one symptom or clinical sign of the CD5+ B cell lymphoma. In some embodiments, administering the IRM compound may result in at least a 50% decrease in peripheral blood lymphocytes, lymphadenopathy, or splenomegaly for at least two months. In other embodiments, administering the IRM compound can inhibit or even prevent the development of progressive disease, wherein progressive disease is at least a 50% increase in circulating lymphocytes or a progression to a more aggressive histology. In still other embodiments, administering the IRM compound can resolve nodular, erythematous lesions associated with CD5+ B cell lymphoma.
In another aspect, the invention provides a method of increasing proliferation of CD5+ B cell lymphoma-specific cytotoxic T cells. Generally, the method includes contacting CD5+ B cell lymphoma cells with an IRM effective to increase the expression of at least one costimulatory molecule on the surface of CD5+ B cell lymphoma cells, and then contacting CD8+ T cells with the CD5+ B cell lymphoma cells, thereby activating the CD8+ T cells; wherein the activated T cells are CD5+ B cell lymphoma-specific cytotoxic T cells and demonstrate increased proliferation compared to T cells contacted with CD5+ B cell lymphoma cells that have not been contacted with an IRM.
In another aspect, the present invention also provides a method of increasing the killing of CD5+ B cell lymphoma cells by cytotoxic T cells. Generally, the method includes contacting CD5+ B cell lymphoma cells with an IRM effective to increase the expression of at least one costimulatory molecule on the cell surface of the CD5+ lymphoma cells, and then contacting CD8+ T cells with the CD5+ B cell lymphoma cells, thereby activating the CD8+ T cells; wherein the activated CD8+ T cells are CD5+ B cell lymphoma-specific cytotoxic T cells and demonstrate increased killing of CD5+ B cell lymphoma cells compared to T cells contacted with CD5+ B cell lymphoma cells that have not been contacted with an IRM.
In another aspect, the present invention also provides a method of treating a subject suffering from a CD5+ B cell lymphoma including administering to the subject an IRM effective to increase the expression of at least one cell surface molecule of the CD5+ B cell lymphoma cells.

Problems solved by technology

Immunodeficiency is also related to inadequate antibody production by the abnormal B cells.
With advanced disease, CLL may cause damage by direct tissue infiltration.

Method used

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  • Treatment for CD5+ B cell lymphoma
  • Treatment for CD5+ B cell lymphoma
  • Treatment for CD5+ B cell lymphoma

Examples

Experimental program
Comparison scheme
Effect test

example 1

Effect of IRM1 on Costimulatory Molecule Expression by CLL Cells

CLL cells from the indicated number of patients were cultured in IRM1 (1 μg / mL) for 3-4 days, and then assayed for expression of the costimulatory molecules indicated on the x-axis (at an intensity greater than the first decade of log fluorescence) of FIG. 1A. The percentage of cells that expressed each costimulatory molecule and the mean fluorescence intensity (MFI) of expression were measured by flow cytometry. The “fold-increase” was then calculated from the ratio of these measurements to the percentage and MFI of control cells cultured without activating agents. The average and standard error of these relative increases in costimulatory molecule expression are shown in the FIG. 1A.

IRM1 has especially strong effects on CD80, CD86, and CD54 expression, with IRM1 increasing the expression of CD54, CD80, and CD86 on CLL cells from all patients studied (n=31). The effect on CD80 was greater than on CD86 (compare FIGS...

example 2

Effects of IL-2 and IRM1 on Costimulatory Molecule Expression by CLL Cells

CLL cells were isolated and cultured alone or with IL-2 (5000 U / mL), IRM1 (1 μg / mL), or both IL-2 and IRM1 for 3-4 days. The expression of CD80, CD86, CD54, and CD83 was then determined by flow cytometry. FIG. 2A shows a characteristic example. The numbers in the dot plots in the upper and lower rows are the percentages of CD80+ and CD86+ CLL cells, respectively. FIG. 2B is a graphical representation of the percentage of CLL cells expressing the different costimulatory molecules (determined by the percentage of cells with staining intensity above the first decade of log fluorescence) from the number of patients indicated in the graph legend. The average and standard error for each of these measurements are shown in the graphs. The numbers over the double-headed arrows represent the p-values for the differences between sample means. FIG. 2C is a graphical representation of the mean fluorescence index (MFI) of...

example 3

Effect of PKC Activation on Costimulatory Phenotype and T Cell Stimulatory Ability of IL-2- and IRM1-Activated CLL Cells

CLL cells were purified from individual patients and cultured alone or with IL-2, IRM1, IL-2 and IRM1, PDB, PDB and IL-2, PDB and IRM1, or PDB, IL-2, and IRM1. After 3-4 days, these cells were harvested, washed extensively, irradiated (2500 cGy) and used to stimulate allogenic or autologous T cells from CLL patients (obtained at the same time as the CLL cells and rested in culture until added to the Mixed Lymphocytic Response (MLR) assay) after 5-6 days of culture, alamar blue was added and proliferation was measured in an optical density colorimetric microplate reader at wavelengths of 540 (reduced state) and 595 (oxidized state). The difference between these readings was used as a measure of the number of viable cells in the culture. Results are shown in FIG. 3A. The results from the T cell source that exhibited the greatest stimulation (after subtraction of th...

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Abstract

The present invention provides methods for increasing expression of cell surface molecules of CD5+ B cell lymphoma cells by contacting cells with immune response modifiers. The invention also provides methods for the treatment of CD5+ B cell lymphomas, including chronic lymphocytic leukemia and small lymphocytic lymphoma, by administering immune response modifier compounds to a subject in need of such treatment. Suitable immune response modifier compounds include agonists of TLR7 and / or TLR8.

Description

BACKGROUND The peripheral B cell neoplasm chronic lymphoid leukemia / small lymphocytic lymphoma represents the most common lymphoid leukemia. As the name implies, presentation can be as either leukemia or lymphoma. However, the two presentations of this neoplasm, chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), are morphologically, phenotypically, and genotypically indistinguishable, differing only in the degree of peripheral blood lymphocytosis. CLL is the most common leukemia of adults in the Western world. In CLL, the peripheral blood contains small, round lymphocytes with scant cytoplasm. Involvement of the bone marrow is observed in all cases of CLL and most cases of SLL, taking the form of interstitial infiltrates or nonparatubular aggregates of small lymphocytes. The tumor cells in CLL and SLL express the pan B cell markers CD29 and CD20. In addition, CD5-a T cell marker that is expressed only on a small subset of normal B cells—is present on the tumo...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4745A61K38/20A61K45/06
CPCA61K31/4745A61K38/2013A61K45/06A61K2300/00A61P7/00A61P35/00A61P35/02A61P37/04
Inventor MILLER, RICHARD L.SPANER, DAVID E.
Owner COLEY PHARMA GRP INC
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