Chemistry: molecular biology and microbiology – Vector – per se
Reexamination Certificate
2001-04-04
2004-05-04
Falk, Anne-Marie (Department: 1632)
Chemistry: molecular biology and microbiology
Vector, per se
Reexamination Certificate
active
06730512
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to immunotherapy for the treatment of tumors. In particular the present invention provides combinations of immune-modulating proteins that induce systemic immunity against tumors and provides humanized animal models for immunogene therapy.
BACKGROUND OF THE INVENTION
Conventional treatment of cancer typically involves the use of chemotherapeutic agents. The father of chemotherapy, Paul Ehrlich, imagined the perfect chemotherapeutic as a “magic bullet;” such a compound would kill invading organisms without harming the host. This target specificity is sought in all types of chemotherapeutics, including anticancer agents.
However, specificity has been the major problem with conventional anticancer agents. In the case of anticancer agents, the drug needs to distinguish between host cells that are cancerous and host cells that are not cancerous. The vast majority of anticancer drugs are indiscriminate at this level. Typically anticancer agents have negative hematological affects (e.g., cessation of mitosis and disintegration of formed elements in marrow and lymphoid tissues) and immunosuppressive action as well as a severe impact on epithelial tissues (e.g., intestinal mucosa), reproductive tissues and the nervous system [Calabresi and Chabner, In: Goodman and Gilman,
The Pharmacological Basis of Therapeutics
(Pergamon Press, 8th Edition) pp. 1209-1216].
Success with chemotherapeutics as anticancer agents has also been hampered by the phenomenon of multiple drug resistance, resistance to a wide range of structurally unrelated cytotoxic anticancer compounds [Gerlach et al. (1986) Cancer Surveys 5:25]. In addition, certain cancers are non-responsive to known chemotherapeutics agents and patients with these cancers invariably die within a short period following diagnosis (e.g., glioblastoma multiforme, recurrent metastatic melanoma, breast, lung and pancreatic cancers).
To address the drawbacks of chemotherapy for the treatment of cancer, immune system-based therapies or cancer immunotherapies have been developed. The goal of cancer immunotherapy is to harness the patient's own immune system to recognize and attack tumors. The recognition and rejection of tumor cells requires the participation of T lymphocytes (T cells).
T cells play a crucial role in a number of immune responses including the recognition of foreign antigens, destruction of virally infected cells and providing help to B cells to permit the production of antibodies that neutralize foreign antigens. In order for a T cell to recognize its target antigen, the antigen must be presented to the T cell by an antigen-presenting cell (APC) such as dendritic cells, macrophages, Langerhans cells and B cells. The APC presents the target antigen as part of a complex containing immune molecules termed major histocompatibility complex (MHC) in mice and human leukocyte antigens (HLA) in humans. Two classes of MHC molecules are known: MHC class I molecules which are expressed on all nucleated cells and MHC class II molecules which are expressed only on APCs. Class I molecules present endogenous protein fragments (not recognized as foreign) and viral antigens (recognized as foreign) while class II molecules present protein fragments derived from proteins that entered the cell by endocytosis or phagocytosis (i.e., proteins which are mainly derived from infectious agents such as parasites and bacteria).
T cells recognize MHC-antigen complexes on APCs via their T cell receptor (TCR)/CD3 complex; the TCR complex together with the CD4 or CD8 coreceptors bind to MHC class II or I, respectively. Occupancy of the TCR alone is not sufficient to active the T cell to respond; activation also requires antigen-independent signals provided by the engagement of costimulatory molecules present on the surface of the T cell with their cognate ligands present on the surface of the APC. The costimulatory proteins serve to stabilize the interaction of the T cell with the APC and to transduce costimulatory signals that lead to the secretion of cytokines, proliferation of the T cell and induction of the T cell's effector function. Engagement of the TCR in the absence of costimulation results in anergy (i.e., nonresponsiveness) of the T cell [Schwartz (1992) Cell 71:1065; Liu and Linsley (1992) Curr. Opin. Immunol. 4:265; Allison (1994) Curr. Opin. Immunol. 6:414 and Linsley and Ledbetter (1993) Annu. Rev. Immunol. 11:191]. In addition to the requirement for costimulatory signals, T cells require growth factors (i.e., cytokines such as interleukin-2) in order to cause proliferation of antigen-reactive T cells.
Several cell surface proteins have been identified as potential costimulatory molecules including LFA-3, ICAM-1 and members of the CD28/CTLA-4 family. The CD28/CTLA-4 family of proteins, present on the surface of T cell, has been shown to be an important costimulator required for interleukin-2 (IL-2) driven proliferation of T cells. The ligands for the CD28/CTLA-4 proteins are members of the B7 family (e.g., B7-1, B7-2 and B7-3).
Cancer immunotherapy aims to induce tumor-specific T cell response that will be effective in the rejection of tumors. The notion that the immune system is naturally involved in identifying and suppressing tumors is supported by the fact that immunocompromised patients have an increased incidence of tumors [Frei et al. (1993) Transplant. Proc. 25:1394]. However, given the incidence of cancer, even in seemingly immunologically normal individuals, it is clear that the immune system fails to recognize and destroy all tumor cells. Indeed animal studies have shown that the majority of tumors fail to provoke an immune response even when these tumors express potentially recognizable tumor-specific antigens [Boon et al. (1994) Annu. Rev. Immunol. 12:337 and Houghton (1994) J. Exp. Med. 180:1]. Several reasons for the lack of immunogenicity of tumor cells have been proposed including failure to express MHC class I molecules, downregulation of transporters for antigen processing and the lack of costimulatory molecules on tumor cells [Garrido et al. (1993) Immunol. Today 14:491; Restifo et al. 91993) J. Exp. Med. 177:265; Cromme et al. (1994) J. Exp. Med. 179:335; Chong et al. (1996) Human Gene Ther. 7:1771].
In order to provide effective cancer immunotherapy, the art needs means to increase the immunogenicity of human tumors as well as animal models predictive of human anti-tumor immune responses.
SUMMARY
The present invention provides novel humanized animal models that permit the identification of immune-modulating genes and combinations thereof useful for the treatment of human tumors. In addition, the present invention provides methods of treating subjects having a tumor with one or more immune-modulating genes and provides tumor cell vaccines comprising tumor cells modified to express immune-modulating genes.
Accordingly, the present invention provides an imniunodeficient mouse comprising human T lymphocytes expressing the CD45 antigen wherein at least 5% of the human T lymphocytes expressing the CD45 antigen represent immature naive T lymphocytes. The invention is not limited by the nature of the immunodeficient mouse strain employed. In a preferred embodiment, the immunodeficient mouse is a SCID/beige mouse.
In another preferred embodiment, the immunodeficient mouse comprising human T lymphocytes further comprising human tumor cells. The invention is not limited by the nature of the human tumor cells employed. The human tumor cells may be established tumor cells, primary tumors cells or tumor cells (established or primary) modified to express one or more immune-modulating genes, genes encoding cell cycle regulators and genes encoding inducers of apoptosis.
In another embodiment, the present invention provides a SCID/beige mouse comprising human immune cells. The invention is not limited by the nature of the human immune cells, these cells may be human PBLs, splenocytes, cells isolated from lymph nodes and/or p
Amdl, Inc.
Cullman Louis C.
Falk Anne-Marie
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