Drug – bio-affecting and body treating compositions – Nonspecific immunoeffector – per se ; or nonspecific...
Reexamination Certificate
1998-12-17
2004-10-19
Ewoldt, G. R. (Department: 1644)
Drug, bio-affecting and body treating compositions
Nonspecific immunoeffector, per se ; or nonspecific...
42, C435S455000, C435S375000, C435S383000, C435S384000, C435S386000
Reexamination Certificate
active
06805869
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides a method for enhancing the immunogenicity of weakly immunogenic or non-immunogenic cells in order to provide the immune system with an immunogenic signal capable of stimulating T cell activation leading to an effective immune response. The method of the invention generates cellular vaccines which are useful for the prevention and treatment of diseases which develop and/or persist by escaping the immune response triggered by T cell activation. Such diseases include, for example, all cancers, natural and induced immune-deficiency states, and diseases caused by infections with a variety of pathogens.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 5,484,596 by Hanna et al. describes using tumor tissue as a vaccine. U.S. Pat. No. 4,844,893 by Honsik et al. describes arming IL-2-activated leukocytes with Mabs directed to antigens preferentially expressed on tumor cells for killing the target cells. Both patents are incorporated by reference herein.
Anti-tumor immune responses are mediated primarily by T lymphocytes. Down regulation of both the major histocompatibility complex (MHC) and the molecules that costimulate the immune response is associated with defective T cells activation signaling by tumor cells (Luboldt et al.,
Cancer Res.
56:826-830, 1996; L. Chen et al., 1992, Cell 1: 1093; P. S. Linsley, J. A. Ledbetter, 1993, Ann. Rev. Immunol 11: 191; G. J. Freeman et al., 1993, Science 262: 909; C. H. June et al., 1994, Immune. Today 15: 321; J. T. Gerge et al., 1993, Cancer Res. 53: 2374; Ostrand-Rosenberg, 1993, S. Curr. Opin. Immune. 6: 772; B. E. Elliot et al., 1989, Adv. Cancer Res. 53: 181).
T cell receptor (TCR) recognition of MHC-bound antigen is not a sufficient signal for T cell activation. Costimualtory molecules, such as B7-1 and B7-2, are cell surface proteins of antigen presenting cells (APCs), and other cells targeted by the immune response, that provide critical signals for T cell activation (for review, see L. Chen et al., 1995, Immunol. Rev. 145: 123; T. Tykocinski et al., 1996, Am. J. Path. 148: 1). B7 signaling via the T cell surface molecule CD28 appears to be the major costimulatory pathway for T cell activation. However, recent studies show that costimulation is a more complex event which involves both cytokines and adhesion molecules (G. Yang et al., 1995, J. Immune. 154: 2794; M. Kubin et al., 1994, J. Exp. Med. 180: 211; Y. Li et al., 1996, J. Exp. Med. 183: 639).
Many approaches have been used to enhance the immunogenicity of tumor cells (see, for example, the references cited in this section). The major approaches presently under investigation involve gene transfer. In this regard, most of the methods employed to date have required ex vivo or in vivo transfection with genes such as MHC or B7, or modification of tumor cells with antigen presenting cells (APCs) (Y. J. Guo et al., 1994, Science 263: 518; M. Tykocinski, 1996, A. J. Path. 148: 1; J. Young and K. Inaba, 1996, J. Exp. Med. 183: 7; L. Zitvogel et al., 1996, J. Exp. Med. 183: 87; C. M. Celluzzi et al., 1996, J. Exp. Med. 183: 283). These approaches are time consuming and problematic because of the poor transfectability of primary tumor cells and because of the requirement for large numbers of APCs.
In vitro treatment of tumor cells with cytokines increases the expression of MHC and adhesion molecules (R. Mattsson et al., 1992, Biol-Reprod 46: 1176; R. J. Ulevitch et al., 1991, Am. J. Pathol. 139: 287; F. Willems et al., 1994, Eur. J. Immune. 24: 1007; I. Saito et al., 1993, J. Clin. Lab. Anal. 7: 180; R. A. Panettieri et al., 1994, J. Immune. 154: 1358; M. Ikeda et al., 1994, J. Invest. Dermatol. 103: 791). Transfection of tumor cells with MHC, B7-1 and B7-2 genes converts low immunogenic tumor cell lines to immunogenic cell lines (S. E. Townsend and J. P. Allison, Science 259: 368; J. P. Allison et al., 1995, Curr. Opin. Immune. 7: 682; G. Yang et al., 1995, J. Immune. 154: 2794; M. Kubin et al., 1994, J. Exp. Med. 180: 211). Non-immunogenic tumor cells are not responsive to transfection with the B7 gene alone but can become responsive by co-expression of CD48 molecules at the cell surface (Y. Li et al., 1996, J. Exp. Med. 183: 639).
The costimulatory molecule B7 can under some circumstances deliver a negative signal through its binding to CTLA-4, a second receptor for B7 on T cells. Cross-linking CTLA-4 molecules in vitro has been shown to inhibit T cell proliferation. Furthermore, mice deficient in CTLA-4 develop severe T cell proliferative disorders (K. Kawai et al., 1993, Science 261: 609; J. P. Allison, M. K. Krummel, 1995, Science 270: 932; J. M. Green et al., 1994, Immunity 1: 501). A recent report showed that the introduction of anti-CTLA-4 monoclonal antibody (MAb), which blocks CTLA-4 mediated signaling, resulted in enhanced T cell-dependent rejection of tumors in certain mouse models (D. R. Leach et al., 1996, Science 271: 1734). These data provide evidence that CTLA-4 may be counter-regulatory to the CD28 costimulatory signal. Thus, transfected tumor cells expressing B7 molecules may fail to elicit effective immunity due to CTLA-4 mediated negative signaling.
In addition to T cell activation using B7 gene transfection, bispecific monoclonal antibodies (Bi-MAbs) in combination with pre-stimulated lymphocytes have been used to induce T cell activation under certain circumstances. For example, one study reports that costimulatory signals can be delivered by a combination of Bi-MAbs to CD28:CD30 (CD30 is a Hodgkin's tumor-associated antigen) and CD3:CD30 in combination with peripheral blood lymphocytes (PBLs) pre-stimulated with the CD3:CD30 Bi-MAb in the presence of CD30
+
Hodgkin's tumor-derived cells; however, the combination of CD28:CD30 and CD3:CD30 Bi-MAbs alone did not induce significant in vitro cytotoxicity of resting human PBLs against a Hodgkin's tumor-derived cell line, and stimulation with the CD28:CD30 Bi-MAb alone was not effective (C. Renner et al., 1994, Science 264: 833). Similarly, regression of Hodgkin's derived tumor xenografts was observed only when both the CD28:CD30 and CD3:CD30 Bi-MAbs were used in combination with PBLs prestimulated in vitro with CD30
+
cells and CD3:CD30 Bi-MAb; no significant effect was observed in xenografts treated with either of the Bi-MAbs alone, or a combination of the two Bi-MAbs without prestimulated human PBLs (Renner et al., supra).
SUMMARY OF THE INVENTION
The present invention features immunogenic tumor cells and other immunogenic autologous cells, convenient methods of making such immunogenic cells, methods of using such immunogenic cells to activate or enhance immune response against diseased cells with minimum effect on normal or healthy cells, and methods of avoiding the negative T cell signaling pathway.
The present invention provides a method for enhancing the immunogenicity of weakly-immunogenic or non-immunogenic cells, resulting in a cellular vaccine that can stimulate T cell activation, which in turn leads to an effective immune response against diseased cells. The cellular vaccines of the present invention can be used as vaccines to prevent diseases and as immunotherapeutics to treat diseases. The starting materials for the cellular vaccine can be a target diseased cell (e.g., autologous or in vivo diseased cells and in vitro transformed cell lines), or an antigen presenting cell presenting one or more antigens associated with a disease (e.g., dendritic cells, macrophages, B cells, and other cells fused with diseased cell, pulsed with antigens or transfected with antigen expressing nucleic acid).
In summary, the method of the invention involves the steps of (1) treating weakly- or non-immunogenic autologous cells (target cells) in order to amplify primary and costimulatory T cell activation signals in the cells, and (2) attaching to the treated cells a substance capable of binding to one or more antigens on the treated cells and to one or more T cell activation costimulatory molecules on the surface of T cells (such as CD28), thereby prov
Ewoldt G. R.
Shanghai CP Guojian Pharmaceutical Co., Ltd.
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