WO2002032463A1 - Methodes de traitement des cancers par stimulation de cellules dendritiques ou de lymphomes avec certaines molecules tnf - Google Patents

Methodes de traitement des cancers par stimulation de cellules dendritiques ou de lymphomes avec certaines molecules tnf Download PDF

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WO2002032463A1
WO2002032463A1 PCT/US2001/032302 US0132302W WO0232463A1 WO 2002032463 A1 WO2002032463 A1 WO 2002032463A1 US 0132302 W US0132302 W US 0132302W WO 0232463 A1 WO0232463 A1 WO 0232463A1
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cells
light
dendritic cells
cell
cd40l
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WO2002032463A9 (fr
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Regis T. Costello
Yannis Morel
Daniel Olive
Raymond W. Sweet
Alemseged Truneh
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Smithkline Beecham Corporation
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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
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4615—Dendritic cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/462—Cellular immunotherapy characterized by the effect or the function of the cells
    • A61K39/4622—Antigen presenting cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
    • A61K39/46449—Melanoma antigens
    • A61K39/464491—Melan-A/MART
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/525—Tumour necrosis factor [TNF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/53—DNA (RNA) vaccination
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
    • A61K2239/48—Blood cells, e.g. leukemia or lymphoma

Definitions

  • Dendritic cells are professional antigen-presenting cells (“APC”) that play a crucial role in the initiation of the immune response of both helper and cytotoxic T lymphocytes (Banchereau, et al , Nature, 392 245, 1998) Dendritic cells reside in many tissues in an immature state and are characterized by their ability to capture and process antigens Following antigen uptake, dendritic cells undergo a maturation process and migrate to the T cell areas of lymph nodes During maturation, dendritic cells decrease their antigen processing capacity, increase cell surface expression of MHC and costimulatory molecules, and acquire the ability to produce IL- 12 These phenotypic and functional changes correlate with their capacity to induce primary T cell responses
  • CD40 is member of the TNF receptor ("TNF-R") family that plays a pivotal role in both cell-mediated and humoral immune responses
  • TNF-R TNF receptor
  • CD40 has wide distribution in tissue and cells, including B lymphocytes, monocytes, hematopoietic progenitors, dendritic, endothelial and epithelial cells
  • CD40L (also known as CD 154), the ligand for CD40, is mainly expressed on activated CD4+ T lymphocytes
  • CD40 triggering on dendritic cells induces phenotypic and functional maturation of dendritic cells, ; e upregulation of costimulatory molecules (CD54, CD58, CD80 and CD86), enhanced capacity to induce T cell proliferation and cytokine secretion including IL-1 , IL-6, IL-8, IL 10 , IL- 12, TNF ⁇ and macrophage inhibitory protein ("MIP”) l ⁇ (Van Kooten, et al , Current Opinion m linmiiiiologv, 9 330, 1997)
  • MIP macrophage inhibitory protein
  • CD40 and its ligand, CD40L in the modulation of tumor cell antigen-presenting cell functions has been outlined.
  • the CD40 stimulation of tumor cells could be of major importance in eliciting an efficient anti-tumor effect since it both improves the initial phase of the immune response (antigen recognition) and the effector phase (cytotoxicity/cytokine secretion) Via adhesion/costimulatory molecule up-regulation, increased endogenous antigen presentation and cytokine secretion, or by mimicking T-lymphocyte CD40L signaling
  • lymphoid neoplasms Van den Hove L E , et al Leukemia, 1 1 572-580, 1997, Plumas J , et al Eur J Immunol , 25 3332-3341 1995, Schultze J , et al Blood Rev 10 1 1 1-127, 1996, Schultze J L , et al Proc Natl Acad Sci U S A 92 8200-8204 1995, Schultze J L , et al Journal of Clinical Investigation 100 2757- 2765 1997, Fisher, D C , et al American Society of Hematology 40th meeting, Miami 1010, 1998, Costello R T , et al Immunol Today, 20 488-493, 1999) by CD40 triggering Finding other ways to improve immunogenicity of lymphoid tumors is desirable
  • HVEM herpes virus entry mediator
  • LIGHT a 29 kDa type II transmembrane protein expressed by activated T-cells (Maun, et al , l ⁇ r ⁇ i ⁇ ut ⁇ , $ 21, 1998) is expressed on activated T lymphocytes (Morel, et
  • HVEM Herpes virus entry mediatoi
  • LIGHT lymphtoxim ⁇ receptor
  • DcR3 decoy receptor 3
  • HVEM is broadly expressed on cells of the immune system like T, B lymphocytes, natural killer cells (Harrop, et al , Journal of Immunology, 161 1786, 1998, Kwon, et al , Journal of Biological Chemistr , 272 14272, 1997) and dendritic cells (Salio, et al , European Journal of Immunology, 29 3245, 1999) but it is also expressed on endothelial cells
  • LT ⁇ R plays a key role in the development and organization of lymphoid tissue, but it is absent on mature T and B lymphocytes, primary monocytes and peripheral dendritic cells (Murphy, et al , Cell Death & Differentiation, 5 497, 1998) DcR3 , a TNF-R lacking a transmembrane region, is expressed in lung tissue and the colon carcinoma cell line SW480, and may serve to modulate LIGHT function in vivo
  • LIGHT can mediate apoptosis of some tumor cells in v itro and ;/; v ivo (Harrop, et al , Journal of Biological Chemistry, 273 27548, 1998, Zhai, et al , Join rial of Clinical Investigation, 102 1 142, 1998) Although this effect appeared to require co- expression at the cell surface of both HVEM and LT ⁇ R, recent studies demonstrated that LT ⁇ R expression is necessary and sufficient (Rooney, et al , Journal of Biological Chemistry, 275 14307, 2000) LIGHT mediated apoptosis activates death signals through selective recruitment of Tumor necrosis factor receptor-associated factor (TRAF)3 by LT ⁇ R, implicated by their co-localization Through its interaction with HVEM, LIGHT is also an important costimulatory molecule for T cell activation LIGHT stimulated T cell proliferation in a thiee way MLR (Hairop, et al , Journal of Biological 213 27548
  • This invention is directed to novel methods of treating cancers comprising improving tumor immunospecificity by stimulating dendritic cells and lymphomas with certain TNF molecules, such as LIGHT
  • the present invention is directed to a method for treating dendritic cell mediated cancers comprising improving tumor immunogenicity by stimulating the dendritic cells with LIGHT in vitro to reach dendritic cell maturation and administering the mature dendritic cells to a patient in need thereof
  • the present invention is directed to a method for treating dendritic cell mediated cancers comprising improving tumor immunogenicity by administering to a patient in need thereof an amount of LIGHT capable of stimulating the maturation of dendritic cells in the patient Further, the present invention is directed to a method for treating non-Hodgkin s lymphomas comprising improving tumor immunogenicity and increasing Fas-induced apoptosis by stimulating lymphomas with LIGHT ex vixo and administering the stimulated lymphomas to a patient in need thereof
  • the present invention is directed to a method for treating non-Hodgkin's lymphomas comprising improving tumor immunogenicity and increasing Fas induced apoptosis by administering to a patient in need thereof an amount of LIGHT capable of stimulating the lymphomas in the patient
  • FIG. 1 A shows that HVEM is constitutively expressed on immature dendritic cells and that LIGHT is expressed on activated T-cell
  • Human immature dendritic cells lDCs
  • lDCs Human immature dendritic cells
  • CD40, CD40L, HVEM and LIGHT were assessed by flow cytometry using mAbs followed by FITC conjugated goat anti-mouse IgG. Filled histogram depicts specific mAb staining. Open histogram correspond to the negative control (isotypic matched antibody). These data correspond to one representative experiment out of four performed with different healthy blood donors.
  • Figure I B shows that LIGHT and CD40L transfected L cells induce dendritic cells cluster formation.
  • iDC generated as described above were incubated with 75 Gray irradiated CD32 (negative control), CD40L or LIGHT transfected L cells for 72 hours at a ratio 1 stimulator cell for 10 dendritic cells.
  • Photomicrographs were taken on day 8 of culture with a resolution X10 and are representative of four experiments.
  • FIG. 2 shows that LIGHT induces partial maturation of dendritic cells assessed as changes in surface phenotype.
  • Final maturation of dendritic cells was induced by CD32 (negative control), CD40L, LIGHT or LIGHT+CD40L transfected L cells for 72h as described in Figure I B.
  • Cells were analysed by flow cytometry using PE conjugated mAbs and anti-HVEM mAb followed by FITC conjugated goat anti mouse IgG. Values represent % of positive cells or mean fluorescence intensity substrated of the value of matched isotype control mAb (open histogram). These data correspond to one representative experiment out of four performed with different healthy blood donors.
  • Figure 3A shows that LIGHT reduces macropinocytic activity of dendritic cells.
  • immature dendritic cells co-cultured with CD32 L cells or CD40L
  • LIGHT and LIGHT+CD40L matured dendritic cells ere incubated at 37°C or 4°C (negative control) for l h in the presence of FITC-dextran (0.5 mg/ml).
  • Results are expressed as % positive cells and represent the mean of three independent experiments performed with different healthy blood donors.
  • Figure 3B shows that CD83 positive LIGHT matured dendritic cells have reduced macropinocytic activity.
  • LIGHT matured dendritic cells were incubated at 37°C or 4°C (negative control) for l h in the presence of FITC-dextran (0.5 mg/ml) and were then stained with CD83-PE mAb.
  • the histograms show FITC-dextran uptake for the negative control (dotted line), CD83 negative LIGHT treated dendritic cells (solid line) and CD83 positive LIGHT treated dendritic cells (bold line).
  • FIG. 3C shows that LIGHT cooperates with CD40L to enhance the capacity of dendritic cells to activate allogenic naive T-cells.
  • l O" 1 purified peripheral naive T-cells (CD4 -, CD45RA+, CD45RO-) were stimulated by serial dilutions (3.10 ? to 14 cells / well) of irradiated (25 Gray) immature dendritic cells, CD40L-, LIGHT- or LIGHT+CD40L- matured dendritic cells on day 8.
  • the proliferative response was measured by [ 3 H] Thymidine incorporation during the last 16h of a 6 day culture. Background T-cell proliferation was ⁇ 100 cpm. Results are expressed as mean cpm ⁇ SD and are representative of four independent experiments.
  • Figure 4 shows that LIGHT synergizes with CD40L for cytokine secretion.
  • Immature dendritic cells CD40L-, LIGHT- or LIGHT+CD40L- matured dendritic cells Were generated as described above. On day 8, i.e. after 72h final maturation, supernatants were harvested and tested by ELISA for IL- 12p75, IL6,TNF ⁇ and IL-l ⁇ . Results are expressed as pg/10 ⁇ cells and are the mean of three experiments performed with different donor.
  • Figure 5A shows that LIGHT and CD40L synergize for induction of specific antitumoral CTL activity.
  • 10 6 CD8+ purified T-cells were cultured with 2.10 5 MelanA 26- 35 peptide pulsed immature dendritic cells, CD40L-, LIGHT- or LIGHT+CD40L- matured dendritic cells in the presence of IL-2 ( 10 Ul/ml) and IL7 (5ng/ml).
  • IL-2 10 Ul/ml
  • IL7 5ng/ml
  • Figure 5B shows that LIGHT costimulation induces enhanced IFN- ⁇ secretion by CTL upon restimulation.
  • the resulting CTL were harvested and restimulated at the initial ratio by autologous MelanA 26-35 pulsed irradiated (25Gray) PBMC.
  • supernatants were harvested and tested by ELISA for IFN- ⁇ secretion.
  • One representative experiment out of three performed is shown.
  • Figure 6 shows a model of CD4 - help for CD8+ CTL priming by dendritic cells.
  • CD4+ activated T cell interacts with immature dendritic cells and induce maturation through CD40L/CD40 and LIGHT/HVEM interactions. Mature dendritic cells are thus conditioned to prime CTL responses.
  • Figure 7A shows expression and regulation of HVEM expression in normal B lymphocytes. Resting peripheral blood mononuclear cells from a normal donor were double-stained with anti-HVEM mAb and anti-CD 19 mAb (one representative experiment of 15 performed).
  • Figure 7B shows expression and regulation of HVEM in B cell lymphoid malignancies
  • White curves correspond to the negative control (isotype-matched mAb), and black cuives to HVEM staining (CLL representative of 1 of 15 experiments performed, ALL 1 of 3, MCL 1 of 3)
  • Figure 7C shows lymphoma cell stimulation Lymphoma cells were incubated in medium alone ( 1 st column), IFN- ⁇ (2nd column), CD32 transfected L-cell controls (3rd column) or CD40L transfected L-cells (4th column) and analyzed by flow cytometry using specific antibodies
  • White curves correspond to the negative control (isotype-matched mAb), and black curves to the HVEM (1 st row), CD80 (2nd row) or CD86 (last row)
  • Figure 8A shows the results of flow cytometry analysis of lymphoma cell following stimulation via CD40 or via HVEM Lymphoma cells ere incubated with CD32 negative control transfected L cells (CD32 L-cells, black), or LIGHT-expressing transfectants (LIGHT L- cells, white) and analyzed after 48 hours by flow cytometry using specific antibodies Results are expressed here as % of positive cells (after subtraction of the background corresponding to the isotype-matched control) Data correspond to one representative experiments out of 5 performed with 3 different lymphomas
  • Figure 8B shows the results of flow cytometry analysis of lymphoma cells following stimulation via CD40 or via HVEM Lymphoma cells were incubated with CD32 L cells ("unstimulated", black histograms) or LIGHT transfectants (red histograms) in absence or presence of an anti-Fas mAb with pro-apoptotic effect Apoptosis was evaluated using flow cytometry analysis with the Apo2 7 mAb Data correspond to one representative experiments out of 3 performed
  • Figures 9A and B show the proliferation and IL-2 secretion of CD4+ T- lymphocytes in allogeneic mixed lymphocyte reaction against lymphoma cells Allogeneic purified CD4+ lymphocyte were incubated at a 1/1 ration with irradiated lymphoma cells pre-incubated for 48 hours in different conditions
  • the proliferation of responding T- lymphocytes was assessed after 6 days of culture by a [3H ] thymidine pulse in the last 18 hours of culture
  • Data represent the mean ⁇ standard deviation of triplicates and the experiments were performed with two different normal lymphocyte donors with two different lymphomas
  • Figure 9B the secretion of IL-2 by responding T-lymphocytes was assessed after 4 days of culture by an ELISA assay Data represent the mean ⁇ standard deviation of duplicates, and the experiments were performed with two different normal lymphocyte donors with two different lymphomas
  • Figures 10A and B show lymphoma proliferation and apoptosis
  • lymphoma cells 50,000/well)
  • Figure 1 1 shows schematically the pleiotropic immune anti-tumor effects of LIGHT
  • the various effects of stimulation by LIGHT shown in this figure summarize the development of an immune reaction from dendritic cell antigen loading, maturation and migration to lymph nodes to cytotoxic T-lymphocyte (CTL) stimulation and target cell killing
  • the immune response could be increased by increasing the presentation of exogenously processed tumour antigens by professional antigen-presenting cells such as dendritic cells
  • the antigen- presenting cell functions of cancer cells can be directly enhanced, thus improving both the presentation of endogenous peptides and the co-stimulation signals they provide to T-cells
  • the present invention is directed to novel methods of treating cancers comprising increasing tumor immunospecificity by stimulating dendritic cells or lymphomas with TNF molecules, such as LIGHT
  • TNF molecules such as LIGHT
  • soluble recombinant LIGHT, or LIGHT expressed on the surface of cells is used to stimulate the maturation of dendritic cells in conjunction with stimulation via the DC40 pathway During this period, the dendritic cells can be pulsed with tumor antigens, either as recombinant proteins, peptides or specially tieated tumor cells (e g apoptotic bodies generated from tumor cells)
  • Such dendritic cells can then induce generation of tumor specific CTL responses which would eventually result
  • Dendritic cells are potent antigen-presenting cells that control the development of T cell mediated immune responses (Banchereau, et al., Nature, 392: 245, 1998). In their immature state, dendritic cells capture antigen or apoptotic cells from sites of infection, inflammatory lesions or tissue damage and process the antigens for subsequent antigenic peptide loading to MHC Class I and Class II molecules and presentation to CD8 and CD4 T cells respectively.
  • the maturation process is a complex but sequentially highly ordered process.
  • factors that contribute to this process are bacterial and viral products such as LPS and double-stranded (ds) RNA (Cella, et al., Journal of Experimental Medicine, 189: 821 , 1999) which activate dendritic cells resulting in upregulation of adhesion and costimulatory molecules and down-regulation of endocytic activities.
  • Inflammatory cytokines TNF ⁇ and IL- 1 ⁇ (Cella, et al., Nature, 388: 782, 1997) or the activated T cell molecules CD40L and TRANCE (Josien, et al., Journal of Immunology, J_62: 2562, 1999; Anderson, et al., Nature, 390: 175, 1997) represent endogenous stimuli that enhance the stimulatory capacity of dendritic cells.
  • LIGHT like CD40L and TRANCE, is a member of the TNF family that is induced on T cells following activation (Morel, et al., Journal of Immunology, 167: 2479-2486, 2001 ).
  • LIGHT stimulation only a fraction of monocyte derived immature dendritic cells acquire the fully mature phenotype characterized by expression of CD83 and high levels of HLA-DR. This is not due to insufficient level of LIGHT since stimulation at increased ratios of LIGHT-L celkdendritic cells or with L cells expressing 3 fold higher levels of LIGHT on their surface does not improve the dendritic cell response (data not shown).
  • LT ⁇ R is not on T and B cells or dendritic cells
  • LIGHT presumably stimulates dendritic cells through its interaction with HVEM.
  • the signaling pathways involved in dendritic cell maturation are not fully elucidated.
  • Signal transduction pathways downstream of TNFR superfamily members have been extensively characterized in vitro.
  • the cytoplasmic region of HVEM interacts strongly with TRAF2 but weakly with TRAF5, TRAF3 and TRAF1 (Marsters, et al., Journal of Biological Chemistry, 272: 14029, 1997).
  • CD40 which shows significant cytoplasmic region homology to HVEM ( 12 identities), also interacts with TRAF2, TRAF3 and TRAF5 but, unlike HVEM, it recognizes TRAF6.
  • transfection of HVEM induces activation of the transcription factors NF-kB and AP- 1 (Hsu, et al., Journal of Biological Chemistry, 272: 13471 , 1997; Marsters, et al., Journal of Biological Chemistry, 272: 14029, 1997). This activation is likely to be mediated by TRAF5 rather than TRAF2.
  • CD40 activates NF-kB through a TRAF2 mediated pathway (Rothe, et al., Science, 269: 1424, 1995; Lee, et al., Proceedings of the National Academy of Sciences, USA, 96: 1421 , 1999).
  • TRAF2 TRAF2 mediated pathway
  • NF-kB activation is implicated in LPS-induced dendritic cell maturation (Rescigno, et al., Journal of Experimental Medicine, 188: 2175, 1998).
  • IkB-a degradation inhibitor it has been shown that nuclear translocation of NF-kB is necessary for upregulation of MHC class II and costimulatory molecules.
  • the maturation of only a subpopulation of iDCs in response to stimulation by LIGHT suggests that not all of the iDC express the required complement of TRAFs and other adaptors or that the expression level of HVEM on the non-responding cells is too low to recruit a sufficient level of second messengers.
  • the mixed phenotype of dendritic cells matured in response to LIGHT highlights the inverse correlation between CD83 expression and the capacity to internalize FITC-dextran by macropinocytosis. This correlation suggests that closely related signaling pathways are involved in these two steps during dendritic cell differentiation. LIGHT stimulated dendritic cells are unable to secrete the cytokines IL-12, IL-6,
  • TNF ⁇ and IL-l ⁇ TNF ⁇ and IL-l ⁇ .
  • the absence of cytokine secretion can not be attributed to insufficient stimulation (see above) or to a different kinetics than the CD40L stimulation (data not shown). It remains to be determined whether the failure to induce cytokine secretion occurs at the level of mRNA expression, protein synthesis or secretion.
  • signaling via HVEM alone is inefficient at inducing cytokine production, it strongly synerg ⁇ zes with CD40-mediated IL-12, IL-6 and TNF ⁇ but not IL-l ⁇ secretion.
  • IL-12 is a heterodimeric molecule produced by antigen-presenting cells that plays a pivotal role during immune responses by driving T cell differentiation towards the Th l cytokine pattern.
  • p38 MAPK Activation of p38 MAPK is critical for CD40 induced IL-12p40 production by human monocyte derived dendritic cells (Aicher, et al., Journal of Immunology, 163 : 5786, 1999).
  • the molecular basis of HVEM and CD40 synergy in cytokine regulation remains to be elucidated but activation of the p38 MAPK pathway represent a potential candidate.
  • LIGHT and CD40L synergizes in IL- 12 production, a p38 MAPK dependant cytokine but not in IL- 1 ⁇ production, a MEK/ERK dependant cytokine.
  • Cross-presentation is a mechanism that allows exogenous antigens like tumor, viral or transplantation antigens to be presented to class I-restricted cytotoxic T lymphocyte by the antigen-presenting cells (Sigal, et al., Nature, 398: 77, 1999; Huang, et aL, Science, 264: 961 , 1994). It has been demonstrated that induction of specific CD8+ CTL responses by such a cross-priming mechanism requires cognate CD4+ T cell help (Bennett, et al., Journal of Experimental Medicine, 186: 65, 1997).
  • This CD4+ T cell help is particularly necessary under non-inflammatory conditions, as occurs in most cancers, including non-inflammatory persistent tumor viruses (human papillomavirus or Epstein- Barr virus) (Toes, et al., Journal of Experimental Medicine, 189: 753, 1999).
  • non-inflammatory persistent tumor viruses human papillomavirus or Epstein- Barr virus
  • Recent publications Schoenberger, et al., Nature, 393: 480, 1998; Bennett, et al., Nature, 393: 478, 1998; Ridge, et al., Nature, 393: 474, 1998) have demonstrated that the CD4+ T cell help for the cytotoxic T cell response can be bypassed by activation of antigen-presenting cells through CD40.
  • Antigen-presenting cells also function as a "temporal bridge" in that once activated, antigen-presenting cells are conditioned to deliver, a "license to kill” to CD8+ CTLs. Ridge et al (Ridge, et al., Nature, 393: 474, 1998) have implicated dendritic cells in this model, suggesting that the activation state of dendritic cells is more important than the CD4+ T cell help itself (Toes, et al., Journal of Experimental Medicine, J_89: 753, 1999).
  • the present inventors used phenotypically-defined dendritic cell populations in in vitro CTL induction experiments, as underscored by Schuurhuis et al (Schuurhuis, et ah, Journal of Experimental Medicine, 192: 145, 2000).
  • Human monocyte derived iDCs called immature dendritic cells, express low levels of HLA class II and costimulatory molecules.
  • these dendritic cells Upon co-culture with CD40-L, these dendritic cells exhibit the characteristic phenotype of mature dendritic cells (Banchereau, et al.. Nature, 392; 245, 1998), i.e. expression of CD83 and high level of HLA class II and costimulatory molecules.
  • the LIGHT plus CD40L costimulated dendritic cells show a new phenotype of mature dendritic cells with enhanced functional capacity.
  • the present inventors developed an /; vitro model of cross-priming against the human melanoma antigen MelanA/Mart-l in order to test the specific CTL priming capacity of these differentially matured dendritic cell.
  • This invention is further directed at a method of treating non-Hodgkin's lymphoma by using an alternate and safe way to improve tumor immunogenicity and increase Fas- induced apoptosis B cell lymphoid malignancies are inefficient at stimulating immune responses
  • One way to improve their immunogenicity is stimulation via CD40
  • stimulation can be deleterious since in ' low-grade' malignancies it induces a protective effect against apoptosis and/or a prohferative signal
  • this pro-tumo ⁇ genic effects can be avoided and tumor immunogenicity can be improved by stimulation of the constitutively expressed HVEM using its ligand LIGHT
  • Primary antigen-specific T cell response requires not only antigen presentation but also costimulatory signals delivered by antigen-presenting cells, in particular via the CD28- CD80/CD86 pathway, in order to obtain effective T cell immunity instead of alloantigen- specific anergy (Guinan E.C., et. al. Blood.1994; 84: 3261-3282; Bou.ssiotis V.A., et. al., Res Immunol. 146: 140- 149.; 1995; Bou.ssiotis V.A., et. al., J Exp Med. 178: 1753- 1763 1993; Gribben J.G., et. al., Blood. 87: 4887-4893, 1996).
  • HVEM is expressed on all normal B-cells and in "low grade" lymphoma cells or chronic lymphocytic leukemia. This expression is long-lasting, even when lymphoma cells are stimulated.
  • CD86 expression can explain the improved in vitro allogeneic immune recognition we observed following stimulation of lymphoma cells by LIGHT.
  • in vitro stimulation via the CD40 pathway improves tumor immunogenicity but also induces tumour cell proliferation and/or protection against apoptosis (Costello R.T., et. al. Immunol Today, 20: 488-493, 1999).
  • These effects partially mimic those observed in normal B-cells (Schattner E.J., et. al., J Exp Med. 182: 1557- 1565, 1995; Garrone P., et. al., J Exp Med. 182: 1265-1273, 1995).
  • the CD40 system appears to be an interesting approach for an ex vivo immunotherapy, i.e. in vitro treatment of irradiated tumor cells which are subsequently re-infused to the patient, but it raises safety problems for a direct in vivo use.
  • the intracellular signaling delivered via HVEM contemplated by the present invention which does not contain intracellular death domain, involves TRAF 1 ,2,3 and 5 and is able to activate NF- ⁇ B (Green J.M., et. al., Cell Immunol. 171 : 126- 131 , 1996) and avoids the problems associated with CD40 immunotherapy.
  • the stimulation of HVEM by LIGHT failed to induce any lymphoma proliferation, even in the presence of other cytokines such as IL-4 (data not shown), in sharp contrast to the CD40/CD40L system.
  • cytokines such as IL-4 (data not shown)
  • some data in solid tumors suggest that, despite the absence of a death domain, stimulation via HVEM in conjunction with IFN- ⁇ induces programmed cell death There was no induction of apoptosis by LIGHT treatment, even in association with IFN ⁇ (not shown)
  • LIGHT triggering was not protective against spontaneous apoptosis of lymphoma cells
  • LIGHT stimulation increased Fas expiession A parallelism between Fas expression and sensitivity to Fas- induced apoptosis is not always observed in lymphoid malignancies (Plumas J , et al , Blood 91 2875-2885, 1998, Iijima N , et al , Blood 90 4901-4909, 1997)
  • LIGHT stimulation may also amplify other pivotal pathways of the immune network ( Figure 1 1 ) since LIGHT co-stimulates CD3- ⁇ nduced T-cell proliferation (Harrop J A , et al J Biol Chem 273 27548-27556, 1998), participates in dendritic cell maturation 31 and amplifies IL-12 secretion (Morel Y , et al .
  • LIGHT stimulation is a good candidate for a "total immune therapy” approach that may simultaneously 1 ) enhance the intrinsic tumor immunogenicity 2) restore tumor sensitivity to apoptosis, 3) participate in dendritic cell functional maturation, 4) directly stimulate T-lymphocyte activation, and 5) indirectly enhance T lymphocyte cytotoxicity potential via amplification of dendritic cell IL-12 secretion EXAMPLES
  • PBMCs Peripheral blood mononuclear cells
  • T-lymphocytes were isolated as the CD2+ PBMC population, corresponding to cells which adhere to sheep erythrocytes (Kamoun, et al., Journal of Experimental Medicine, 153: 207, 1981) in the E-rosetting technique but fail to adhere to plastic dishes after overnight incubation in medium plus 30% FCS.
  • PBMCs 10% fetal bovine serum (Bioproducts).
  • PBMCs were depleted of non-adherent cells by 4-hour adhesion on plastic dishes.
  • Adherent cells were extensively washed and then cultured in RPMI 1640 (Bioproducts) 10% FCS with GM-CSF (Sandoz, Copenhagen, Denmark) at 100 ng/ml and IL-4 (Genzyme Corp., Cambridge, MA) at 10 ng/mL for 5 days.
  • the medium was replenished with cytokines every 2-3 days.
  • final maturation was induced by the addition of irradiated (75Gy) L cells at a ratio of 1 : 10 for an additional 72 hours.
  • the mAbs directed against HVEM 12C5 and 20D4, both murine IgG 1 ) and LIGHT (2C8, murine IgG2b) were generated at SmithKline Beecham by conventional hybridoma methodology from mice immunized with the respective recombinant proteins and screening the hybridomas by ELISAs.
  • the mAbs to CD la, CD3, CD4, CD8, CD 14, CD 19, CD25, CD40, CD54, CD56, CD69, CD83 and HLA- DR were purchased from Beckman Coulter (Marseille, France).
  • the mAb to CD80 was from Beckton Dickinson, and the mAbs to CD86 and CD 154 from Pharmingen.
  • Cell surface CD40 and HVEM were quantified on immature dendritic cells by indirect immunofluorescence staining using QIFIKIT (Dako, Glostrup, Denmark).
  • Thymidine uptake was counted on a gas-phase ⁇ -counter (Matrix 9600, Packard). Immature dendritic cells or dendritic cells matured by co-incubation with L cells expressing CD 154, LIGHT or LIGHT plus CD 154 were used as stimulators.
  • Mannose Receptor-mediated fluid phase macropinocytosis measured by the cellular uptake of FITC-dextran, was used as a surrogate marker for antigen capture.
  • 10 5 of the immature and matured dendritic cells were incubated in media containing FITC-dextran (0.5 mg/ml) (m.w. 40000; Sigma) for 1 h at 37°C or 4°C (negative control). After four washes with cold PBS, cells were analysed by flow cytometry for uptake of the FITC-dextran.
  • IL- 12p75 IL- 12p75
  • IL- l ⁇ R&D Systems, Minneapolis, MN
  • IL6, TNF ⁇ Beckman Coulter, France
  • Immature and matured dendritic cells were pulsed for 2h at 37°C in serum free X- Vivo 15 (Biowhittaker) with MelanA 26-35 peptide (ELAGIGILTV) ( lO ⁇ g/ml) together with b2 microglobulin (3 ⁇ g/ml).
  • ELAGIGILTV MelanA 26-35 peptide
  • b2 microglobulin 3 ⁇ g/ml.
  • 2.10 ⁇ peptide pulsed dendritic cells were cultured with 10 & CD8+ purified T-cells (>95% by flow cytometry), obtained by two round of negative selection (reference - or state antibody used) from purified T-cells, in 2 ml CTL medium in the presence of IL-2 ( 10 Ui/ml) and IL7 (5ng/ml).
  • the CTL medium is IMDM (Biowhittaker) supplemented with L-Arg 550 ⁇ M, L-Asn 240 ⁇ M, L-Gln 1 5mM 1 % Penicillin-Streptomycin and 10% pooled human serum
  • CTLs were harvested and restimulated at the initial ratio With the corresponding peptide pulsed dendritic cells Cytotoxic activity was measured on day 13- 14 in the 'Cr release assay described below / Cytotoxi itv assay
  • the T2 cell line was labeled by incubating 10 6 cells in lOO ⁇ Ci sodium [ ,! Cr] chromate for 2h at 37°C and washing three times Labeled target cells (10 ) and serial dilutions of effector cells in triplicate were incubated in RPMI 10%FCS in 96-well V bottom plates at 37°C for 4h in the presence or absence of MelanA 26-35 ( l ⁇ g/ml) and a 30 fold excess of unlabeled K562 cells Supernatants were then analysed in microplate scintillation counter (Topcount, Packard) Percentage lysis was determinated for each triplicate experiment as [(experimental 51 Cr release - spontaneous Cr release)/( maximal 5l Cr release - spontaneous 51 Cr release)]x 100 Results are expressed in % specific lysis (% lysis in the presence of peptide - % lysis in the absence of peptide) One representative experiment out of three performed is shown J IFN ⁇ secretwn assay
  • HVEM like CD40, is expressed on peripheral blood monocyte derived immature dendritic cells but at a lower level Using the QIFIKIT quantification system (unlabelled mAbs followed by FITC conjugated goat anti mouse IgG), we estimate that there are 510,000 ⁇ 50,000 molecules of CD40 and 30 000 ⁇ 8,000 molecules of HVEM at the cell surface (data not shown) LIGHT and CD 1 4 are not expressed on resting T-lymphocytes but both are upregulated at the cell surface following activation (Morel, et al , Journal of Immunology, 167 2479-2486, 2001 and figure 1 A) These cellular distributions suggest that, similarly to CD40L and CD40, the interaction of LIGHT with HVEM is important in T cell communication with dendritic cells L.
  • LIGHT induces phenotypically mature dendritic cells
  • Immature dendritic cells Immature dendritic cells (iDCs) were generated from T-cell-depleted adherent PBMC by a five day culture in the presence of GM-CSF and IL4. They were then incubated for 72 hrs with irradiated stable L cell transfectants expressing similar levels of CD32 (negative control), CD40L, LIGHT or LIGHT plus CD40L at a 1 : 10 ratio of iDCs.'stimulator. LIGHT transfected L cells induced small cell clusters ( Figure I B) whereas co-cultures with of CD40L ( Figure I B) or CD40L plus LIGHT (not shown) transfected L cells formed large homotypic cell clusters.
  • Immature dendritic cells co-cultured with L cells expressing both LIGHT and CD40L acquired a mature phenotype distinct from that obtained by CD40L or LIGHT stimulation alone.
  • these dendritic cells expressed higher levels of HLA-DR, CD54 and costimulatory molecules (particularly CD86) and showed down modulation of HVEM.
  • HLA-DR high-density lipoprotein
  • CD54 costimulatory molecules
  • CD86 costimulatory molecules
  • the dendritic cell maturation process is associated with cytokine synthesis
  • Secretion of immunoregulatory and pro-inflammatory cytokines plays a pivotal role during T cell priming in the lymphoid organs
  • CD40L stimulation induced high levels of secreted IL-12, IL-6, TNF ⁇ and IL-l ⁇ compared to those produced by immature dendritic cells (figure 4)
  • LIGHT matured dendritic cells only modestly induced IL-12 and TNF ⁇ and had no effect on IL-6 and IL-l ⁇ , relative to control iDCs
  • This low response could not be attributed to a toxic effect of LIGHT on cytokine secretion pathways since IL-8 secretion was not inhibited (data not shown)
  • LIGHT cooperated with CD40L to induce 5 to 15 fold higher levels of IL- 12, IL-6 and TNF ⁇ than observed for CD40L alone In contrast, this combination had little effect on IL-l
  • IFN- ⁇ levels were measured to further assess the relative priming activity of the dendritic cells matured in the presence of LIGHT and/or CD40L
  • T cells were harvested, challenged for 48 hrs with autologous irradiated MelanA pulsed PBMC and tested for the levels of IFN- ⁇ level secretion Consistent with the cytotoxicity assays LIGHT matured dendritic cells, much like immature dendritic cells, failed to prime T cells for IFN- ⁇ secretion CD8 + T cells obtained by co-culture with CD40L matured dendritic cells produced only a modest level of IFN- ⁇ In sharp contrast, CD8 + T cells primed by LIGHT plus CD40L dendritic cells secreted large amounts of IFN- ⁇
  • PBMCs peripheral normal blood mononuclear cells
  • T- lymphocytes from normal donors were isolated as the CD2-pos ⁇ t ⁇ ve PBMC population, corresponding to cells which adhered to sheep erythrocytes (Kamoun M , et al J Exp Med 1 3 207-212, 1981 ) in E-rosettmg technique but failed to adhere to plastic dishes after overnight incubation in medium + 30% FCS
  • the CD4+ T cells were isolated by two rounds of negative selection using magnetic beads (Beckman Coulter, France) and anti CD8 (8E17, D Olive)
  • lymphoma proliferation culture experiments ere performed in RPMI 1640 (Bioproducts, MA, USA) with 10% fetal bovine serum (Bioproducts) Lymphocytes were cultured at 106/mL For MHC-unmatched MLR against lymphoma cells, responding CD4+ T lymphocytes were isolated from 3 unrelated healthy blood donors as previously described Culture experiments Were performed in RPMI 1640 (Bioproducts) With 107c fetal bovine serum (Bioproducts), 1 % L-glutamme (Life Technologies, Gaithersburg, MA, U S A), 1 % Na pyruvate (Life Technologies) and 5 10-5 ⁇ -mercaptoethanol (Sigma Chemical Co, Saint-Louis, MO, U S A) Lymphoma cells had ⁇ irradiation at 50 Gy, were then incubated (from 5 x 104 per well) With T-lymphocytes (5 x 104 per well) for 6 days and pulse
  • mAbs were used: the anti-HVEM 12C5 and 20D4 (mouse IgG 1 , SmithKline Beecham), anti-CD3, anti-CD4, anti-CD8, anti-CD 14, anti-CD 19 (Beckman Coulter), anti- CD80, anti-CD54, anti-CD58 (Beckton Dickinson), anti-CD86, anti-CD40L and anti-Fas (Pharmingen).
  • Apoptosis was detected using the AP02.7 mAb (Immunotech), that recognizes a 38 kDa protein localized on the membrane of mitochondria whose expression appears to be restricted to cells undergoing programmed cell death.
  • AP02.7 mAb Immunotech
  • T-lymphocytes were incubated with lymphoma cells in RPMI 1640 (Bioproducts, MA, U.S.A) with 10% fetal bovine serum and supernatants were harvested after a 2-day incubation.
  • the JL-2 was measured using an immunoenzymatic assay with a sensitivity of 5 pg/ml (Immunotech).
  • E. HVEM expression by lymphoid cells (Table I and Fig. 1)
  • HVEM baseline expression in a panel of lymphoid cells was examined. As seen in Table I below, HVEM as not expressed in the most differentiated B cells, i.e. in the two plasma cell lines we evaluated (U266BL and XG7). In contrast, HVEM was expressed in all peripheral blood B-lymphocytes from all the healthy donors we tested (Table I, and Fig. 1 panel A, one representative experiment) and in all the eight Epstein-Barr Virus cell lines derived from PBMCs (data not shown). HVEM expression on Burkitt's lymphoma depended on the cell line tested since it was positive on Raji cells but not on Daudi. We failed to detect HVEM on the Hodgkin cell line we tested.
  • HVEM was not expressed at the surface of acute lymphoblastic leukemias (Table I, and Fig. 7B, first row, phenotype of three representative samples). In contrast, we observed a consistent expression of HVEM in all the chronic lymphocytic leukemia and mantle cell lymphomas we tested (Table I, and Fig. 7B, second and third rows, phenotype of three representative samples). We choose to focus our study on this latter type of lymphoma that represents a lymphoid malignancy with very poor prognosis in the absence of a curative therapy. HVEM expression time-course on lymphoma cells during a ten days culture period was tested. The 48-hour data are shown here (Fig. 7C).
  • HVEM expression was still detectable with no significant differences between the various conditions, and no difference regarding the baseline level (not shown). A decrease of HVEM expression was observed by day 6 (not shown), and may reflect impaired viability of lymphoma cells.
  • the up-regulation of the CD80 and CD86 adhesion/costimulation molecules controls the efficiency of the IFN- ⁇ and CD40L stimulation.
  • lymphoma cells In order to better define the effects of HVEM triggering, the surface phenotype of lymphoma cells after a 48-hours incubation with LIGHT or CD32 (control) transfected L cells (Fig. 8A) was analyzed.
  • CD32 expressing control fibroblast or IFN- ⁇ did not have any synergistic or additive effect
  • IFN- ⁇ ⁇ 60 pgml
  • lymphoma cells stimulated by CD40L-transfected cells displayed high level proliferation
  • LIGHT-translected cells did not induce any proliferation (even with higher level of stimulating cells l e 50,000/wells, which correspond to a 1 / 1 ration data not shown)
  • panel B shows that CD40L stimulation (striped bar) decreases the spontaneous apoptosis of lymphoma cells cultured for 24 hours in the absence of cytokines
  • no apoptosis prevention is observed with LIGHT transfectant, with a percentage of apoptotic cells comparable to control obtained by lymphoma cell culture with CD32 expressing fibroblasts

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Abstract

La présente invention concerne de nouvelles méthodes de traitement des cancers, consistant à améliorer l'immunospécificité de la tumeur par la stimulation de cellules dendritiques et de lymphomes avec certaines molécules TNF, comme la protéine LIGHT.
PCT/US2001/032302 2000-10-18 2001-10-18 Methodes de traitement des cancers par stimulation de cellules dendritiques ou de lymphomes avec certaines molecules tnf WO2002032463A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1364653A1 (fr) * 2001-02-23 2003-11-26 Takeda Chemical Industries, Ltd. Inhibiteurs de caspase 3
WO2005002628A1 (fr) * 2003-06-11 2005-01-13 The University Of Chicago Infiltration accrue de lymphocytes t dans une tumeur provoquee par le mutant light
US7811983B2 (en) 2003-06-11 2010-10-12 The University Of Chicago Increased T-cell tumor infiltration and eradication of metastases by mutant light
WO2011139629A2 (fr) * 2010-04-26 2011-11-10 Biogen Idec Ma Inc. Molécules ciblant light et ses utilisations

Citations (1)

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Publication number Priority date Publication date Assignee Title
US6140467A (en) * 1997-07-07 2000-10-31 La Jolla Institute For Allergy And Immunology Ligand for herpes simplex virus entry mediator and methods of use

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US6140467A (en) * 1997-07-07 2000-10-31 La Jolla Institute For Allergy And Immunology Ligand for herpes simplex virus entry mediator and methods of use

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HARROP J.A.: "Herpesvirus entry mediator ligand (HVEM-L), a novel ligand for HVEM/TR2, stimulates proliferation of T cells and inhibits HT29 cell growth", J. BIOL. CHEM., vol. 273, October 1998 (1998-10-01), pages 27548 - 27556, XP002947574 *
ZHAI ET AL.: "LIGHT, a novel ligand for lymphotoxin beta receptor and TR2/HVEM induces apoptosis and suppresses in vivo tumor formation via gene transfer", J. CLIN. INVEST., vol. 102, no. 6, September 1998 (1998-09-01), pages 1142 - 1151, XP002947576 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1364653A1 (fr) * 2001-02-23 2003-11-26 Takeda Chemical Industries, Ltd. Inhibiteurs de caspase 3
EP1364653A4 (fr) * 2001-02-23 2005-01-26 Takeda Pharmaceutical Inhibiteurs de caspase 3
WO2005002628A1 (fr) * 2003-06-11 2005-01-13 The University Of Chicago Infiltration accrue de lymphocytes t dans une tumeur provoquee par le mutant light
US7807784B2 (en) 2003-06-11 2010-10-05 The University Of Chicago Increased T-cell tumor infiltration by mutant LIGHT
US7811983B2 (en) 2003-06-11 2010-10-12 The University Of Chicago Increased T-cell tumor infiltration and eradication of metastases by mutant light
US9272025B2 (en) 2003-06-11 2016-03-01 The University Of Chicago Increased T-cell tumor infiltration and eradication of metastases by mutant light
WO2011139629A2 (fr) * 2010-04-26 2011-11-10 Biogen Idec Ma Inc. Molécules ciblant light et ses utilisations
WO2011139629A3 (fr) * 2010-04-26 2012-04-19 Biogen Idec Ma Inc. Molécules ciblant light et ses utilisations

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