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Link:  Pharm/Biotech Resources


Title:  Method of modulating tumor immunity

United States Patent:  6,953,576

Issued:  October 11, 2005

Inventors:  Zhang; Li (Toronto, CA); Young; Kevin (Toronto, CA)

Assignee:  University Health Network (Toronto, CA)

Appl. No.:  933131

Filed:  August 21, 2001

Abstract

Novel cells and molecules involved in tumor immunity are disclosed. The novel cells are regulatory T-cells having the phenotype CD3+αβ-TcR+CD4-CD8-CD44-CD28-NK1.1-. The regulatory cells express Ly6A and osteopontin while non-regulatory cells do not.

SUMMARY OF THE INVENTION

The inventors have demonstrated that anti-lymphoma effects can be achieved in the absence of GVHD by a single injection of either viable allogeneic splenocytes or double negative regulatory T cells (DN Tr cells), which differ in one MHC class I locus with recipients. Tolerance of the host is permanent and does not need any non-specific toxic immunosuppressive drugs. Furthermore, the inventors demonstrated that DN Tr cells are able to function as a double-edged sword to kill both syngeneic anti-host CD8+ T cells and allogeneic lymphoma cells. These findings reveal for the first time the dual role of Tr cells both in inhibiting GVHD and blocking the development of leukemia. They also provide a novel concept for the treatment of lymphoma/leukemia by allogeneic lymphocytes.

The novel double negative regulatory T-cells isolated by the inventors are CD3+αβ-TcR+CD4-CD8-CD44-CD28-NK1.1-. The cells do not express IL-2, IL-4, IL-10 and IL-13 but do express IFN-γ, TNF-α and TGF-β mRNA after activation. Treatment of the regulatory T-cells with IL-10, cyclosporin A or anti-IFN-γ antibodies abrogates suppression by the cells.

Accordingly, the present invention provides the use of the novel regulatory cells to modulate tumor immunity or graft versus host disease (GVHD). Accordingly, the present invention provides a method of inhibiting tumor cell growth or proliferation comprising administering an effective amount of (i) a regulatory T-cell having the phenotype CD3+αβ-TcR+CD4-CD8-CD44-CD28-NK1.1-, or (ii) an agent that can induce or activate the regulatory T-cell to an animal in need of such treatment.

In one embodiment, the present invention provides a method of preventing or treating cancer comprising administering an effective amount of a regulatory T cell having the phenotype CD3+αβ-TcR+CD4-CD8-CD44-CD28-NK1.1-to an animal in need of such treatment.

The present inventors have also found that the proteins Ly6A and osteopontin are expressed on the above described regulatory T-cells but not on non-regulatory cells. Further, they have also shown that blocking Ly6A or osteopontin abolishes the effect of these cells.

Accordingly, the present invention provides a method of inhibiting tumor cell growth comprising administering an effective amount of an Ly6A protein, a nucleic acid sequence encoding an Ly6A protein, osteopontin or a nucleic acid sequence encoding osteopontin to an animal in need of such treatment.

The invention also includes pharmaceutical compositions containing the DN regulatory cells, agents that induce or activate the regulatory cells, antibodies to the novel cells, Ly6A proteins, nucleic acids encoding Ly6A protein, osteopontin or a nucleic acid sequence encoding osteopontin for use in modulating tumor immunity or graft versus host disease.

Other features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION OF THE INVENTION

The inventors have show that reconstitution of immunodeficient mice with spleen cells from one MHC class I Ld mismatched donors leads to an indefinite survival of all the recipients free of GVHD and tumour after being challenged with a lethal dose of lymphoma. To study the mechanisms involved in this phenomenon, the fate of infused donor cells in vivo was monitored. The number of anti-host CD8+ cells was initially augmented, but quickly diminished and remained very low throughout the rest of the experimental period. Interestingly, a marked (>30 fold) increase of DN Tr cells in the periphery of recipient mice was observed, which remained elevated throughout the experimental period. Moreover, the DN Tr cells isolated from reconstituted mice could suppress the proliferation of anti-host T cells, and the DN Tr cell lines generated in vitro could specifically kill activated anti-host CD8+ T cells. These findings suggest that DN Tr cells may prevent GVHD by directly killing anti-host CD8+ T cells in vivo. Furthermore, the inventors demonstrated that DN Tr were cytotoxic to lymphoma cells in vitro. When co-injected with a lethal dose of lymphoma into naive mice, the DN Tr cells were capable of preventing leukemia onset in all recipients. In conclusion, the infusion of one class I MHC locus mismatched splenocytes together with a lethal dose of lymphoma cells does not cause GVHD or leukemia, but results in an expansion of DN Tr cells in the periphery of the recipients. These DN Tr cells are cytotoxic to both anti-host CD8+ T cells and leukemia cells, indicating a dual role for DN Tr cells in the prevention of both GVHD and leukemia.

The DN regulatory T-cells of the invention are distinguished from previously described regulatory cells as they possess a unique phenotype and express a unique array of cytokines. In particular, the novel cells are CD3+αβ-TCR+CD4-CD8-CD25+CD28-CD30+CD44-NK1.1-. These cell surface markers distinguish the cells from any previously described T-cell subset such as activated helper, cytotoxic or memory T-cells. The novel regulatory cells are also distinguished from bone marrow derived CD4-CD8-T-cells which express NK1.1 and from CD4-CD8- T-cells described by others. The novel regulatory cells do not express IL-2, IL-4, IL-10 and IL-13 but do express IFN-γ and TGF-β mRNA after activation which distinguish them from Th1, Th2 or Th3/Tr1 cells.

The regulatory cells having the phenotype CD3+αβ-TcR+CD4-CD8-CD44-CD28-NK1.1- are sometimes referred to herein as "the regulatory cells of the invention", "the DN regulatory T cells" or "the DN Tr cells".

I. Methods of Inhibiting Tumor Cell Growth/Treating Cancer

Accordingly, the present invention provides a method of inhibiting tumor cell growth or proliferation comprising administering an effective amount of (i) a regulatory T-cell having the phenotype CD3+αβ-TcR+CD4-CD8-CD44-CD28-NK1.1-, or (ii) an agent that can induce or activate the regulatory T-cell to an animal in need of such treatment. The present invention also includes a use of (i) a regulatory T-cell having the phenotype CD3+αβ-TcR+CD4-CD8-CD44-CD28-NK1.1-, or (ii) an agent that can induce or activate the regulatory T-cell to prepare a medicament to inhibit tumor cell growth or proliferation. The invention further includes a use of (i) a regulatory T-cell having the phenotype CD3+αβ-TcR+CD4-CD8-CD44-CD28-NK1.1-, or (ii) an agent that can induce or activate the regulatory T-cell to inhibit tumor cell growth or proliferation.

(i) Administering DN Tr Cells

In one embodiment, the method involves administering DN Tr cells that are generated in vitro. The cells may be isolated from normal animals, for example by labelling T-cells and sorting for cells containing the desired phenotype using a FACS sorter. The inventors have demonstrated that the novel regulatory cells require IL-2, IL-4 to proliferate and to suppress. The inventors have further developed methods to activate and expand antigen-specific regulatory T cells in vitro by stimulating the novel regulatory T cells with one class I mismatched allogeneic lymphocytes in the presence of IL-2 and IL-4. Accordingly, IL-2 and IL-4 can be used to increase the number and improve the function of the novel regulatory cells. The regulatory cells of the invention can be activated and expanded in vitro by stimulating the cells with antigens in forms such as purified peptides, soluble proteins, plasmid expressing cDNA encoding specific antigens, cell lines expressing specific antigens (EBV transformed cell lines, dendritic cells, fibroblasts transfected with specific antigens such as foreign MHC molecules), tumor antigens and molecules that cause autoimmune diseases and allergy.

The inventors have also shown that injection of the regulatory T cells that are generated in vitro into animals can prevent death caused by injection of lethal dose of tumor cells in the absence of GVHD. Accordingly, in vitro cultured regulatory T cells can be used in the treatment of leukemia, lymphomas and other malignant diseases.

(ii) Administering Agents That Stimulate DN Tr Cells

In another embodiment, the method of inhibiting tumor cell growth involves administering an agent that can induce or activate the DN regulatory T cells in vivo. Such agents include but are not limited to, cytokines, antigens, antibodies to the DN Tr cells that can activate the cells and one MHC Class I mismatched allogeneic lymphocytes as herein described.

The cytokine can be any cytokine that can stimulate or activate the DN Tr cells such as IL-2 and IL-4 and IFN-γ.

The antigens used to stimulate the DN Tr cells can be any antigen including, but not limited to, tumor antigens or allogeneic lymphocytes with one MHC Class I mismatch with the recipient. In particular, the inventors have identified the methods to increase the number of the novel regulatory T cells in immunodeficient recipients by infusion of one MHC class I locus mismatched lymphocytes, which lead to elimination of tumor cells in the absence of GVHD. Accordingly, the present invention also provides a method of inhibiting tumor cell growth comprising administering to an animal in need thereof allogeneic lymphocytes containing a mismatch at one MHC Class I locus with the animal.

The antibodies can be any antibody that can stimulate or activate the DN Tr cells. The inventors have prepared monoclonal antibodies (mAbs) generated by immunization of animals with regulatory T cells of the invention. The inventors have so far generated 25 mAbs that can specifically bind to the surface of regulatory T cells some of which enhance growth of the regulatory T cells.

Antibodies to the DN Tr cells may also be prepared using techniques known in the art such as those described by Kohler and Milstein, Nature 256, 495 (1975) and in U.S. Pat. Nos. RE 32,011; 4,902,614; 4,543,439; and 4,411,993, which are incorporated herein by reference. (See also Monoclonal Antibodies, Hybridomas: A New Dimension in Biological Analyses, Plenum Press, Kennett, McKeam, and Bechtol (eds.), 1980, and Antibodies: A Laboratory Manual, Harlow and Lane (eds.), Cold Spring Harbor Laboratory Press, 1988, which are also incorporated herein by reference). Within the context of the present invention, antibodies are understood to include monoclonal antibodies, polyclonal antibodies, antibody fragments (e.g., Fab, and F(ab′)2) and recombinantly produced binding partners.

Accordingly, the invention also includes the use of mAbs to the DN Tr cells and their therapeutic modifications in prevention and treatment of cancer. Modifications of mAbs include generation of recombinant mAbs fused with human immunoglobulin Fc portion, conjugate mAbs with enzymes, isotopes etc.

The inventors have postulated novel mechanisms by which the regulatory T cells prevent GVHD and promote anti-tumor response. After bone marrow transplantation mature donor T cells (CD4+ and CD8+) will recognize allo MHC expressed on the host, be activated and express high level of Fas. These activated donor T cells will destroy target cells and tissues that express the host alloantigens and cause GVHD. The inventors have demonstrated that the novel regulatory T cells constitutively express a high level of Fas ligand. Upon encountering antigen-presenting cells (APC), the regulatory T cells can "steal" host alloantigens from the surface of APC through the anti-host TCR, and turn themselves into killer cells. Because the regulatory T cells express the "stolen" host alloantigens on their surface, they can attract the activated anti-host cytotoxic T cells. Once the anti-host cytotoxic T cells recognised the alloantigens on the regulatory T cells, the latter will send death signals through Fas ligand to the former. Unlike the anti-host cytotoxic T cells, which kill target cells through perforin-mediated pathway, the killing mediated by the regulatory T cells requires direct cell-cell contact and depends on Fas-FasL interaction. Most host tissues, although they express MHC class I molecules, do not express Fas, and will not be destroyed directly by the regulatory T cells. Therefore the regulatory T cell themselves do not cause GVHD. On the other hand, the tumor cells, such as B cell lymphoma, express both recipients MHC class I and Fas. The regulatory T cells can recognize the MHC class I expressed on tumor cells through their specific TCR, and send death signals to tumor cells through Fas ligand to cause death of tumor cells and prevent death caused by lymphoma.

The present inventors have isolated several genes that are expressed in the novel regulatory cells of the invention but are not expressed in non-regulatory cells. In particular, the inventors have determined that Ly6A is expressed on the novel regulatory cells. Ly6A is a glycosyl phosphatidylinositol (GPI)-anchored cell surface molecule expressed on most peripheral lymphocytes, thymocytes and other cells. Incubating the novel regulatory cells with IL-10 (which converts the regulatory phenotype into a non-regulatory one reduces the expression of Ly6A. Further, blocking Ly6A expression with an antisense oligonucleotide abolishes suppression by the novel regulatory cells. These results suggest that Ly6A may act to down regulate lymphocyte responses. Consequently, administering Ly6A may be used to inhibit tumor cell growth. Accordingly, the present invention provides a method of inhibiting tumor cell growth comprising administering an effective amount of an Ly6A protein or a nucleic acid encoding an Ly6A protein to an animal in need thereof.

The term "Ly6A protein" as used herein includes the full length Ly6A protein as well as fragments or portions of the protein. Preferred fragments or portions of the protein are those that are sufficient to suppress an immune response. The Ly6A protein also includes fragments that can be used to prepare antibodies.

The Ly6A protein may be prepared as a soluble fusion protein. The fusion protein may contain the extracellular domain of Ly6A linked to an immunoglobulin (Ig) Fc Region. The Ly6A fusion may be prepared using techniques known in the art. Generally, a DNA sequence encoding the extracellular domain of Ly6A is linked to a DNA sequence encoding the Fc of the Ig and expressed in an appropriate expression system where the Ly6A-FcIg fusion protein is produced. The Ly6A protein may be obtained from known sources or prepared using recombinant DNA techniques. The protein may have any of the known published sequences for Ly6A. The protein may also be modified to contain amino acid substitutions, insertions and/or deletions that do not alter the immunosuppressive properties of the protein. Conserved amino acid substitutions involve replacing one or more amino acids of the Ly6A amino acid sequence with amino acids of similar charge, size, and/or hydrophobicity characteristics. When only conserved substitutions are made the resulting analog should be functionally equivalent to the Ly6A protein. Non-conserved substitutions involve replacing one or more amino acids of the Ly6A amino acid sequence with one or more amino acids which possess dissimilar charge, size, and/or hydrophobicity characteristics.

The Ly6A protein may be modified to make it more therapeutically effective or suitable. For example, the Ly6A protein may be cyclized as cyclization allows a peptide to assume a more favourable conformation. Cyclization of the Ly6A peptides may be achieved using techniques known in the art. In particular, disulphide bonds may be formed between two appropriately spaced components having free sulfhydryl groups. The bonds may be formed between side chains of amino acids, non-amino acid components or a combination of the two. In addition, the Ly6A protein or peptides of the present invention may be converted into pharmaceutical salts by reacting with inorganic acids including hydrochloric acid, sulphuric acid, hydrobromic acid, phosphoric acid, etc., or organic acids including formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, benzenesulphonic acid, and tolunesulphonic acids.

The inventors have also demonstrated that osteopontin is highly expressed on regulatory but not on non-regulatory T cells and incubation of anti-osteopontin antibody can reverse the suppressive function of the regulatory T cells. Consequently, administering osteopontin may be used to inhibit tumor cell growth. According, the present invention provides a method of inhibiting tumor cell growth comprising administering an effective amount of an osteopontin or a nucleic acid encoding an osteopontin to an animal in need thereof.

The term "osteopontin protein" as used herein includes the full length osteopontin protein as well as fragments or portions of the protein. Preferred fragments or portions of the protein are those that are sufficient to suppress an immune response. The osteopontin protein also includes fragments that can be used to prepare antibodies.

The osteopontin protein may be prepared as a soluble fusion protein. The fusion protein may contain the extracellular domain of osteopontin linked to an immunoglobulin (Ig) Fc Region. The osteopontin fusion may be prepared using techniques known in the art. Generally, a DNA sequence encoding the extracellular domain of osteopontin is linked to a DNA sequence encoding the Fc of the Ig and expressed in an appropriate expression system where the osteopontin—FcIg fusion protein is produced. The osteopontin protein may be obtained from known sources or prepared using recombinant DNA techniques. The protein may have any of the known published sequences for osteopontin. The protein may also be modified to contain amino acid substitutions, insertions and/or deletions that do not alter the immunosuppressive properties of the protein. Conserved amino acid substitutions involve replacing one or more amino acids of the osteopontin amino acid sequence with amino acids of similar charge, size, and/or hydrophobicity characteristics. When only conserved substitutions are made the resulting analog should be functionally equivalent to the osteopontin protein. Non-conserved substitutions involve replacing one or more amino acids of the osteopontin amino acid sequence with one or more amino acids which possess dissimilar charge, size, and/or hydrophobicity characteristics.

The osteopontin protein may be modified to make it more therapeutically effective or suitable. For example, the osteopontin protein may be cyclized as cyclization allows a peptide to assume a more favourable conformation. Cyclization of the osteopontin peptides may be achieved using techniques known in the art. In particular, disulphide bonds may be formed between two appropriately spaced components having free sulfhydryl groups. The bonds may be formed between side chains of amino acids, non-amino acid components or a combination of the two. In addition, the osteopontin protein or peptides of the present invention may be converted into pharmaceutical salts by reacting with inorganic acids including hydrochloric acid, sulphuric acid, hydrobromic acid, phosphoric acid, etc., or organic acids including formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, benzenesulphonic acid, and tolunesulphonic acids.

Administration of an "effective amount" of the active agent (i.e., DN regulatory T cells, agents that induce or activate the DN regulatory cells, antibodies, osteopontin or Ly6A protein or a nucleic acid molecule encoding Ly6A or osteopontin) is defined as an amount effective, at dosages and for periods of time necessary to achieve the desired result (e.g. inhibition or reduction of tumor cell growth). The effective amount of the active agent may vary according to factors such as the disease state, age, sex, and weight of the animal. Dosage regima may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.

The term "animal" as used herein includes all members of the animal kingdom including humans. The animal is preferably an animal with cancer or predisposed to getting cancer.

The term "inhibiting tumor cell growth" means that there is an inhibition or reduction in the growth, proliferation or metastasis of a tumor as compared to the growth observed in the absence of administering a DN Tr cell, an agent that activates a DN Tr cell, or Ly6A or osteopontin.

The term "tumor" includes any cancer, neoplasm or malignant disease including both solid and non-solid cancers. The method may be used to treat any cancer or malignant disease including, but not limited to, leukemias, lymphomas (Hodgkins and non-Hodgkins), liver cancer, lung cancer, plasmacytomas, histiocytomas, melanomas, adenomas, sarcomas, carcinomas of solid tissues, hypoxic tumours, squamous cell carcinomas, genitourinary cancers such as cervical and bladder cancer, hematopoietic cancers, head and neck cancers, and nervous system cancers.

Because the regulatory T cells express high level of Fas ligand and are able to recognize the host HLA alloantigens expressed on tumor cells through their TCR, they should be able to kill tumor cells that express both host HLA class I molecules and Fas as the inventors have demonstrated. In case that tumor cells do not express HLA class I antigen or Fas, the regulatory T cells will be co-injected with mature donor CD8+ T cells. As the regulatory T cells can kill CD8+ T cells that are activated by the same alloantigen, activated donor CD8+ T cells that can specifically recognize host antigen and cause GVHD will be killed by the regulatory T cells though the mechanisms the inventors have demonstrated. However, the donor CD8+ T cells that are activated by tumor antigens will not be affected by regulatory T cells. Therefore tumor cells can be eliminated by co-injected tumor-specific CD8+ T cells through a perforin-dependant pathway. For hematopoietic malignancies, the regulatory T cells will be injected intravenously, for solid tumors, regulatory T cells will be injected both intravenously and at the side of tumor, preferably after surgical removal of the tumor.

The present invention also provides a method of preventing or treating cancer comprising administering an effective amount of (i) a regulatory T-cell having the phenotype CD3+αβ-TcR+CD4-CD8-CD44-CD28-NK1.1-, or (ii) an agent that can induce or activate the regulatory T-cell to an animal in need of such treatment. In one embodiment, the regulatory T cells may be induced with IL-2 and IL-4 or by an antibody that stimulates the regulatory cells.

The term "treating cancer" includes, but is not limited to, alleviation or amelioration of one or more symptoms or conditions of cancer, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, remission (whether partial or total), whether detectable or undetectable and/or prolonging survival as compared to expected survival if not receiving treatment.

II. Compositions

The invention also includes pharmaceutical compositions containing the DN regulatory T cells, agents that induce or activate the DN Tr cells, the antibodies to the T cells, Ly6A or osteopontin proteins or nucleic acids for use in treating cancer.

Such pharmaceutical compositions can be for intralesional, intravenous, topical, rectal, parenteral, local, inhalant or subcutaneous, intradermal, intramuscular, intrathecal, transperitoneal, oral, and intracerebral use. The composition can be in liquid, solid or semisolid form, for example pills, tablets, creams, gelatin capsules, capsules, suppositories, soft gelatin capsules, gels, membranes, tubelets, solutions or suspensions.

The pharmaceutical compositions of the invention can be intended for administration to humans or animals. Dosages to be administered depend on individual needs, on the desired effect and on the chosen route of administration.

The pharmaceutical compositions can be prepared by per se known methods for the preparation of pharmaceutically acceptable compositions which can be administered to patients, and such that an effective quantity of the active substance is combined in a mixture with a pharmaceutically acceptable vehicle. Suitable vehicles are described, for example, in Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., USA 1985).

On this basis, the pharmaceutical compositions include, albeit not exclusively, the active compound or substance in association with one or more pharmaceutically acceptable vehicles or diluents, and contained in buffered solutions with a suitable pH and iso-osmotic with the physiological fluids. The pharmaceutical compositions may additionally contain other agents such as chemotherapeutic agents, immunosuppressive drugs or antibodies to enhance immune tolerance or immunostimulatory agents to enhance the immune response.

In one embodiment, the pharmaceutical composition for use in treating cancer comprises an effective amount of an Ly6A protein or osteopontin in admixture with a pharmaceutically acceptable diluent or carrier. The Ly6A protein or osteopontin is preferably prepared as an immunoadhesion molecule in soluble form which can be administered to the patient. The composition preferably contains Ly6A proteins or osteopontin in soluble form which may be injected intravenously or perfused directly at the site of the tumor.

In another embodiment, the pharmaceutical composition for use in treating cancer comprises an effective amount of a nucleic acid molecule encoding an Ly6A protein or osteopontin in admixture with a pharmaceutically acceptable diluent or carrier.

The nucleic acid molecules of the invention encoding an Ly6A or osteopontin protein may be used in gene therapy to treat cancer. Recombinant molecules comprising a nucleic acid sequence encoding an Ly6A or osteopontin protein, or fragment thereof, may be directly introduced into cells or tissues in vivo using delivery vehicles such as retroviral vectors, adenoviral vectors and DNA virus vectors. They may also be introduced into cells in vivo using physical techniques such as microinjection and electroporation or chemical methods such as coprecipitation and incorporation of DNA into liposomes. Recombinant molecules may also be delivered in the form of an aerosol or by lavage. The nucleic acid molecules of the invention may also be applied extracellularly such as by direct injection into cells. The nucleic acid molecules encoding Ly6A or osteopontin are preferably prepared as a fusion with a nucleic acid molecule encoding an immunoglobulin (Ig) Fc region. As such, the Ly6A or osteopontin protein will be expressed in vivo as a soluble fusion protein.
 

Claim 1 of 5 Claims

1. A method of inhibiting lymphoma cell growth or proliferation comprising administering an effective amount of a regulatory T-celi having the phenotype CD3+αβ-TcR+CD4-CD8-CD44-CD28-NK1.1- to an animal in need of such treatment.

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