WO2002072032A2 - Composes et procedes d'identification, de stadification et de traitement de lymphome cutane a cellules t - Google Patents

Composes et procedes d'identification, de stadification et de traitement de lymphome cutane a cellules t Download PDF

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Publication number
WO2002072032A2
WO2002072032A2 PCT/US2002/007847 US0207847W WO02072032A2 WO 2002072032 A2 WO2002072032 A2 WO 2002072032A2 US 0207847 W US0207847 W US 0207847W WO 02072032 A2 WO02072032 A2 WO 02072032A2
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WO
WIPO (PCT)
Prior art keywords
cd40l
patients
ctcl
patient
sezary syndrome
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Application number
PCT/US2002/007847
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English (en)
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WO2002072032A3 (fr
Inventor
Alain H. Rook
Lars E. 7 Leon-Gaud 1206 Geneva French
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The Trustees Of The University Of Pennsylvania
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Application filed by The Trustees Of The University Of Pennsylvania filed Critical The Trustees Of The University Of Pennsylvania
Priority to AU2002258519A priority Critical patent/AU2002258519A1/en
Publication of WO2002072032A2 publication Critical patent/WO2002072032A2/fr
Publication of WO2002072032A3 publication Critical patent/WO2002072032A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to treating cutaneous T-cell lymphoma (CTCL) and cancers with recombinant human CD40 ligand (CD40L) .
  • CTCL cutaneous T-cell lymphoma
  • CD40L recombinant human CD40 ligand
  • This invention also relates to identifying and staging CTCL.
  • Cutaneous T-cell lymphoma is a disease in which T-lymphocyte cells of the lymphatic system become malignant and affect the skin.
  • CTCL localizes to the skin more often than other forms of non-Hodgkin' s lymphomas .
  • the etiology of CTCL is unknown.
  • Various theories implicate infectious agents, oncogenes, cytokines or occupational or environmental exposures. While clusters of cases are reported within families, CTCL is considered to be a sporadic disease without any real evidence of transmissibility.
  • CTCL is a lymphoproliterative disorder typically characterized by infiltration of the skin with clonally derived malignant CD4+ T lymphocytes that phenotypically resemble mature T cells (Diamandidou, E. et al. 1996. Blood 88:2385-2409). Early presentation of the disease may be confused with eczema, tinea corpus, or psoriasis. Therapeutic efforts are based on the extent of disease, the integrity of the immune system, and the likelihood for progression of disease.
  • the malignant cells in CTCL appear to arise from the expansion of a single clone of T-lymphocytes which bears the phenotype of mature helper T-cells expressing CD4+/CD45RO+ .
  • a decline in cell-mediated immunity is typically observed, characterized by depressed cell-mediated cytotoxicity and deficient responsiveness of T- cells to antigens and mitogens.
  • Studies of the nature of the malignant T-cells have provided evidence that these cells are at least partially responsible for the generation of the immune defects by way of production of T-immunosuppressive T- helper type 2 (Th2) cytokines and by the depressed production of T-helper type 1 (Thl) cytokines.
  • Th2 T-immunosuppressive T- helper type 2
  • Thl T-helper type 1
  • IL-12 interleukin-12
  • PUVA ultraviolet A light
  • Advanced forms of CTCL are not as easily cured, and are often fatal.
  • the patient with advanced forms of CTCL may present with malignancies that progress from plaques to tumors.
  • a more common form of advanced CTCL, Sezary Syndrome involves erythroderma occurring throughout the course of disease.
  • Sezary Syndrome the malignant cell population, which has an early propensity to localize within the upper dermis, and particularly, within the epidermis (epidermotropism) , also becomes nonepidermotropic and is associated with deeper dermal extension and involvement of the peripheral blood. Concurrent with this leukemic, progressive phase of the disease, is the onset of progressive immunologic dysfunction.
  • PBMC peripheral blood mononuclear cells
  • PBMC from patients with Sezary Syndrome produce increased concentrations of interleukin-4 , the levels of which correlate with numbers of circulating malignant T cells (Vowels, B.R. et al . 1992. J. Invest . Dermatol . 99:90).
  • Interleukin-12 is a cytokine that is a powerful inducer of interferon- ⁇ production and that exerts potent Thl- inducing effects during the evolution of immunologic responses against certain microbial antigens (Chan, S.H. et al . 1991. J. Exp . Med. 173:869-879; Hsieh, C.S. et al . 1993. Science 260:547-549).
  • IL-12 augments Natural Killer (NK) cell cytotoxicity and cytotoxic T cell proliferation and function (Hiramatsu, K. et al . 1998. Cancer Immunol . Immunother. 46:1- 6; Haku, T. et al . 1997.
  • IL-12 has been shown to have potent antitumor activity in mice with transplantable and primary tumors (Nishimura et al . 1995. Immunol . Lett . 48:149-152) and in mice with metastatic residual lymphoma (Verbik et al . 1996. Clin . Exp . Metastasis 14:219-229). Brunda and colleagues (1993. J " . Exp. Med. 178:1223) have demonstrated antitumor activity of IL-12 in mice following both systemic and intralesional administration. Recent in vi tro experiments have also shown that the depressed interferon- ⁇ production observed in peripheral blood mononuclear cells isolated from patients with advanced CTCL is normalized by the addition of recombinant IL-12.
  • the present invention provides methods of identifying, staging and treating CTCL. SUMMARY OF THE INVENTION
  • An object of the present invention is to provide a method of treating CTCL in humans comprising administering to a human an effective amount of recombinant human CD40L in an amount which effectively enhances the TH1-mediated immune responses of a patient.
  • Another object of the present invention is to provide a method of staging cancer comprising identifying a human patient as having cancer, determining the level of expression of CD40L in the patient and comparing said level with the expression level of CD40L previously expressed by the patient or with an expression level of CD40L found in a healthy control .
  • CD40L This defect in CD40L expression results in defective production of TH1 cytokines, Interferon gamma (IFN ⁇ ) , IL-12 and tumor necrosis factor alpha (TNF ⁇ ) by lymphocytes and/or antigen presenting cells.
  • IFN ⁇ Interferon gamma
  • IL-12 and TNF ⁇ production was restored by antigen presenting cells of CTCL patients. Therefore, recombinant human CD40L is useful for the immunotherapy of CTCL and other types of cancers, including but not limited to melanoma, lymphoma, leukemia, breast, colon cancer, lung cancer and such other cancers that benefit from enhanced TH1-mediated immune responses.
  • the present invention provides a useful method for alleviating symptoms and treating CTCL in patients which comprises administering a recombinant soluble human form of CD40L to the patient.
  • the method of the present invention is particularly useful in treating advanced Cutaneous T-cell Lymphoma, which includes patients presenting with plaques, Sezary Syndrome, or tumors with large cell transformation.
  • Recombinant soluble human form of CD40L can be administered either systemically [ e . g. , subcutaneously, intravenously) or intralesionally and can be formulated in any pharmaceutically acceptable carrier which is known to those of skill in the art.
  • An effective dose of a recombinant soluble human form of CD40L is administered repeatedly, for a period of time.
  • treatment would be extended for a period of months or until symptoms of CTCL (such as plaques, tumors or erythroder a) regress or are reduced.
  • An effective dose is one in which there is at least a partial response in the patient.
  • a partial response is considered to be a decrease in physical symptoms, a reverse in defective TNF alpha production, or a reverse in defective IL-12 production in patients with CTCL.
  • a reduction of symptoms of advanced CTCL represents a total absence of lesions after treatment.
  • Dosage schedules and regimens are routinely designed by those of skill based upon results described below.
  • the recombinant soluble human form of CD40L may be administered either alone or in combination with therapeutic agents or adjunct therapies that are targeted to CTCL treatment.
  • adjunct therapeutic agents and adjunct therapies include, but are not limited to, interferon alpha, interferon gamma, vitamin A derivatives (Acitretin, Bexarotene) , photopheresis and UVA phototherapy.
  • Also provided by this invention is a method of staging cancer in a human by identifying the human patient as having cancer and then evaluating the immune responsiveness of the patient by comparing the level of expression of CD40L.
  • CD40L expression is decreased in Sezary Syndrome patients as compared to healthy controls and also decreases as the severity of the disease increases (i.e. as the tumor burden is increased) .
  • the expression of CD40L in a patient directly correlates with the overall immune responsiveness of the patient. As described in Example 1, Sezary Syndrome patients with high circulating tumor burden have a more pronounced defect in CD40L expression than those patients with a low tumor burden.
  • the present invention provides a method of staging cancer comprising identifying a human patient as having cancer, determining the level of expression of CD40L in the patient and comparing said level with the expression level of CD40L previously expressed by the patient or with an expression level of CD40L found in a healthy control .
  • CD40L expression on CD4+ T-lymphocytes in response to T-cell activation by anti-CD3 showed that CD40L surface expression is decreased in these patients as compared to healthy controls. Further, patients with high circulating tumor burden were found to have a more pronounced defect in CD40L expression than those patients with low tumor burden.
  • FACS analysis of CD40L expression on activated (anti-CD3) or non-activated (vehicle) CD4+T cells of 5 normal donors and 7 Sezary Syndrome patients showed decreased induction of CD40L upon activation in Sezary Syndrome patients.
  • the CD40L induction rate for normal donors was found to be approximately twice as great as the induction rate for Sezary Syndrome patients (not inclusive of Sezary Syndrome patients with low tumor burden) .
  • FACS analysis of CD40 expression on CD14+/CD64- antigen presenting cells (APC) of a healthy control and high tumor burden Sezary patient showed conserved expression of CD40 in both cases.
  • PBMC peripheral blood mononuclear cells
  • IL-12 measured by ELISA in the culture media of PBMC from a normal donor and 3 Sezary Syndrome patients in response to LPS and interferon gamma (IFN ⁇ ) , illustrated that direct stimulation of Sezary Syndrome patients APC's are able to produce IL-12 in response to direct (LPS/IFN ⁇ ) as opposed to indirect T-cell mediated (anti-CD3) stimulation.
  • TNF alpha production by PBMC of Sezary patients in response to T-cell activation by anti-CD3 was measured.
  • the levels of TNF measured by ELISA in the culture media of PBMC from five normal donors and five Sezary Syndrome patients following anti-CD3 stimulation for 48 hours were measured, with the TNF production being at least twice as great in Sezary Syndrome patients not exhibiting a low tumor burden.
  • the levels of TNF measured by ELISA in the culture media of PBMC from a normal donor and 3 Sezary Syndrome patients in response to LPS and IFN ⁇ were measured.
  • CD40L (5 ⁇ g/ml) for 24 hours and CD83 and CD86 expression was assessed by FACS. Further, when dendritic cells were exposed to media alone, LPS (20ng(ml: positive control) , CD40L (5 ⁇ g/ml) or another TNF family member LIGHT (5 ⁇ g/ml)for 24 hours and measured for IL-12 expression assessed by ELISA, the recombinant human CD40L was also found to induce IL-12 production by dendritic cells.
  • Levels of IL-12 were also measured by ELISA in a culture media of PBMC from a normal donor (ND) when exposed to IFN ⁇ (1000U/ml) + mouse recombinant CD40L (muCD40L 10 ⁇ g/ml plated in wells) ,- IFN ⁇ (1000U/ml) + human recombinant CD40L (huCD40L 10 ⁇ g/ml plated in wells) or IFN ⁇ alone (lOOOU/ml: negative control) .
  • the level of IL-12 in the IFN/ human recombinant CD40L sample was found to be approximately at least 2.5 times as great as the IFN/mouse recombinant CD40L sample; and 5 times as great as the IFN only sample.
  • PBMC of Sezary patients by exposure to soluble recombinant human CD40L was evaluated.
  • Levels of IL-12 were measured by ELISA in the culture media of PBMC from a normal donor
  • the recombinant human CD40L corrected the ability of the Sezary Syndrome patients to generate an anti-tumor response.
  • the Sezary Syndrome patient with the lowest tumor burden exhibited elevated IFN-LPS; CD40L; and IFN-CD40L levels as compared to the Sezary Syndrome patient with moderate tumor burden.
  • Both the Sezary Syndrome patient with low tumor burden and the Sezary Syndrome patient with moderate tumor burden exhibited elevated CD40L and IFN-CD40L levels as compared to the Sezary Syndrome patient with high tumor burden.
  • PBMC of Sezary patients by exposure to soluble recombinant human CD40L was studied.
  • Levels of TNF alpha were measured by ELISA in the culture media of PBMC from a normal donor

Abstract

L'invention concerne un procédé et une composition destinés au traitement de lymphome cutané à cellules T consistant à administrer un ligand CD40L humain recombinant. Elle concerne aussi des procédés d'identification et de stadification de ce lymphome (CTCL).
PCT/US2002/007847 2001-03-14 2002-03-14 Composes et procedes d'identification, de stadification et de traitement de lymphome cutane a cellules t WO2002072032A2 (fr)

Priority Applications (1)

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AU2002258519A AU2002258519A1 (en) 2001-03-14 2002-03-14 Compounds and methods for identifying, staging and treating cutaneous t-cell lymphoma

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US27556201P 2001-03-14 2001-03-14
US60/275,562 2001-03-14

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WO2002072032A2 true WO2002072032A2 (fr) 2002-09-19
WO2002072032A3 WO2002072032A3 (fr) 2003-02-13

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006025028A2 (fr) * 2004-09-01 2006-03-09 H.J.L, Inc. Nouvelle methode de classification des globules sanguins servant de base a des activites therapeutiques et preventives sur mesure
EP1977003A2 (fr) * 2005-12-22 2008-10-08 Dermagene Oy Méthodes et moyens relatifs à des maladies
WO2014107663A3 (fr) * 2013-01-07 2014-10-16 The Trustees Of The University Of Pennsylvania Compositions et procédé pour traiter un lymphome à cellules t cutané
US10105426B2 (en) 2002-12-30 2018-10-23 Trustees Of Dartmouth College Immunostimulatory combinations

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5747024A (en) * 1993-03-08 1998-05-05 Immunex Corporation Vaccine adjuvant comprising interleukin-15
US6087329A (en) * 1991-10-25 2000-07-11 Immunex Corporation CD40 ligand polypeptide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6087329A (en) * 1991-10-25 2000-07-11 Immunex Corporation CD40 ligand polypeptide
US5747024A (en) * 1993-03-08 1998-05-05 Immunex Corporation Vaccine adjuvant comprising interleukin-15

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
STORZ ET AL.: 'Coexpression of CD40 and CD40 ligand in cutaneous T-cell lymphoma (mycosis fungoides)' CANCER RESEARCH vol. 61, 15 January 2001, pages 452 - 454, XP002955745 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10105426B2 (en) 2002-12-30 2018-10-23 Trustees Of Dartmouth College Immunostimulatory combinations
WO2006025028A2 (fr) * 2004-09-01 2006-03-09 H.J.L, Inc. Nouvelle methode de classification des globules sanguins servant de base a des activites therapeutiques et preventives sur mesure
WO2006025028A3 (fr) * 2004-09-01 2006-08-17 H J L Inc Nouvelle methode de classification des globules sanguins servant de base a des activites therapeutiques et preventives sur mesure
EP1977003A2 (fr) * 2005-12-22 2008-10-08 Dermagene Oy Méthodes et moyens relatifs à des maladies
EP1977003A4 (fr) * 2005-12-22 2009-11-11 Dermagene Oy Méthodes et moyens relatifs à des maladies
US8143029B2 (en) 2005-12-22 2012-03-27 Valipharma Methods and means related to diseases
WO2014107663A3 (fr) * 2013-01-07 2014-10-16 The Trustees Of The University Of Pennsylvania Compositions et procédé pour traiter un lymphome à cellules t cutané
RU2669941C2 (ru) * 2013-01-07 2018-10-17 Дзе Трастиз Оф Дзе Юниверсити Оф Пенсильвания Композиции и способы для лечения t-клеточной лимфомы кожи

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AU2002258519A1 (en) 2002-09-24

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