T cell regulation

a technology of t cell and regulation, applied in the field of therapeutic and drug screening methods, can solve the problems of destroying t-cell activity, unable to meet the needs of patients, and unable to achieve optimal immunotherapy, so as to overcome the suppression of an immune response, increase the response of cancer patients, and increase the magnitude of anti-cancer response.

Inactive Publication Date: 2006-10-26
ST JUDE CHILDRENS RES HOSPITAL INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0016] In a fourth embodiment of the invention an improved method is provided for treating a cancer patient with an anti-cancer vaccine. An antibody which specifically binds to CD223 is administered to the cancer patient. An anti-cancer vaccine is also administered. The antibody increases magnitude of anti-cancer response of the cancer patient to the anti-cancer vaccine.
[0017] A fifth embodiment of the invention provides a method to overcome suppression of an immune response to an anti-cancer vaccine. An antibody which specifically binds to CD223 is administered to a cancer patient with regulatory T-cells which suppress an immune response to an anti-cancer vaccine. An anti-cancer vaccine is also administered to the patient. The antibody increases the response of the cancer patient to the anti-cancer vaccine.

Problems solved by technology

Augmentation of the immune response in immune compromised animals via infusions of lymphokines, adoptive immunotherapy has met with variable and limited success.
A number of conditions can result in deleterious T-cell activity.
However, these therapies are not completely effective and are associated with significant adverse side effects such as nephrotoxicity, hepatotoxicity, hypertension, hirsutism, and neurotoxicity.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Negative Regulation of T Cell Homeostasis by LAG-3 (CD223)

[0079] The following example shows that LAG-3 (CD223) negatively regulates CD4+ and CD8+ T cell homeostasis, supporting its identification as a novel therapeutic target for accelerating T cell engraftment following bone marrow transplantation.

[0080] Wild type C57BL / 6 mice have a constant number of αβ+ cells from 4 to 52 weeks of age. As previously reported, young 4 week old LAG-3− / − mice have normal T cell numbers. Miyazaki, T. et al., Science 272: 405-408 (1996). In contrast, the number of αβ+ T cells in LAG-3− / − mice steadily increases from 3 months of age to numbers ˜2-fold higher than wild type mice. This difference is highly significant given the tight homeostatic regulation of αβ+ T cell number evidenced by the very low standard deviation. Both CD4+ and CD8+ cells were increased in LAG-3− / − mice but the CD4:CD8 ratio was unchanged. Similarly, LAG-3− / − mice transgenic for the OT-II TCR (ovalbumin 326-339-specific, H-2A...

example 2

Materials and Methods

[0088] This example provides the experimental methods and materials for example 1.

[0089] Mice: The following mice were used: LAG-3− / − [obtained from Yueh-Hsiu Chen, Stanford University, Palo Alto, Calif., with permission from Christophe Benoist and Diane Mathis, Joslin Diabetes Center, Boston, Mass.; Miyazaki, T. et al., Science 272: 405-408 (1996)]; C57BL / 6J [Jackson Labs, Bar Harbor, Me.]; B6.PL-Thy1a / Cy (Thy1.1 congenic) [Jackson Labs]; RAG-1− / − [Jackson Labs, Bar Harbor, Me.; Mombaerts, P. et al., Cell 68: 869-877 (1992)]; MHC class II− / − [provided by Peter Doherty, St. Jude Children's Research Hospital, Memphis, Term.; Grusby, M. J. et al., Science 253:1417-1420 (1991)]; MHC class I− / − / II− / − [Taconic, Germantown, N.Y.; Grusby, M. J. et al., Proc. Natl. Acad. Sci. U.S.A 90: 3913-3917 (1993)]; OT-II TCR transgenic mice [provided by Stephen Schoenberger, La Jolla Institute for Allergy and Immunology, La Jolla, Calif., with permission from William Heath, Walt...

example 3

Induced Treg Cells with Potent Regulatory Activity

[0095] In order to identify Treg specific molecules, we performed a differential gene expression analysis of antigen-specific T cells differentiating to either effector / memory cells in response to viral infection or Treg cells upon encounter of cognate antigen as a self-antigen. This analysis revealed that the LAG-3 gene was selectively upregulated in Treg cells. The physiologic role of LAG-3, an MHC class II binding CD4 homologue, has not been clearly elucidated. Several in vitro studies have suggested that LAG-3 may have a negative regulatory function (Hannier et al., 1998; Huard et al., 1994; Workman et al., 2002a; Workman et al., 2002b). Here we show that membrane expression of LAG-3 selectively marks Treg cells independently of CD25 and that LAG-3 modulates both the in vitro and in vivo suppressive activity of Treg cells.

[0096] In order to study differences between T cell effector / memory and tolerance induction, we have utiliz...

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Abstract

Regulatory T cells (Treg) limit autoimmunity but can also attenuate the magnitude of anti-pathogen and anti-tumor immunity. Understanding the mechanism of Treg function and therapeutic manipulation of Treg in vivo requires identification of Treg selective receptors. A comparative analysis of gene expression arrays from antigen specific CD4+ T cells differentiating to either an effector/memory or a regulatory phenotype revealed Treg selective expression of LAG-3 (CD223), a CD4-related molecule that binds MHC class II. LAG-3 expression on CD4+ T cells correlates with the cells' in vitro suppressor activity, and ectopic expression of LAG-3 on CD4 T cells confers suppressor activity on the T cells. Antibodies to LAG-3 inhibit suppression both in vitro and in vivo. LAG-3 marks regulatory T cell populations and contributes to their suppressor activity.

Description

[0001] This application claims priority to provisional U.S. Application Ser. No. 60 / 451,039, filed Feb. 28, 2003, U.S. Application Ser. No. 60 / 482,143, filed Jun. 24, 2003, and U.S. Application Ser. No. 60 / 531,704, filed Dec. 22, 2003.[0002] The United States government, National Institutes of Health, provided funding (AI39480) for work that underlies the invention. Under the terms of that funding agreement, the United States government retains certain rights in the invention.FIELD OF THE INVENTION [0003] The invention relates to therapeutic and drug screening methods. BACKGROUND OF THE INVENTION [0004] A variety of diseases are characterized by the development of progressive immunosuppression in a patient. The presence of an impaired immune response in patients with malignancies has been particularly well documented. Cancer patients and tumor-bearing mice have been shown to have a variety of altered immune functions such as a decrease in delayed type hypersensitivity, a decrease in...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395A01N43/04A61K31/70A61K35/12A61K39/00A61K39/38C07K16/00C07K16/28C12NC12N5/0783C12P21/08G01N33/53
CPCA01K67/0271C07K16/42A01K2267/0381A61K39/0011A61K2035/122A61K2039/505A61K2039/5156A61K2039/55516C07K14/70503C07K16/2803C12N5/0636C12N2501/599C12N2510/00C12N2799/027A61K39/3955A61K39/39558A01K67/0276A61P11/06A61P25/00A61P25/02A61P25/28A61P31/00A61P31/04A61P31/12A61P31/18A61P35/00A61P37/02A61P37/04A61P37/06A61P37/08A61P43/00A61K39/001129A61K2039/80Y02A50/30A61K39/001111A61K2039/585A61K2039/507C07K16/18
Inventor PARDOLL, DREWHUANG, CHING-TAIVIGNALI, DARIOWORKMAN, CREGPOWELL, JONATHANDRAKE, CHARLES
Owner ST JUDE CHILDRENS RES HOSPITAL INC
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