Tumor cells with increased immunogenicity and uses therefor

Details Tumor cells with increased immunogenicity and uses therefor Tumor cells with increased immunogenicity and uses therefor

1999-11-29

2001-11-20

Priebe, Scott D. (Department: 1632)

Chemistry: molecular biology and microbiology

Animal cell, per se ; composition thereof; process of...

C424S093210, C435S455000

Reexamination Certificate

active

06319709

ABSTRACT:

BACKGROUND OF THE INVENTION
Induction of a T lymphocyte response is a critical initial step in a host's immune response. Activation of T cells results in T cell proliferation, cytokine production by T cells and generation of T cell-mediated effector functions. T cell activation requires an antigen-specific signal, often called a primary activation signal, which results from stimulation of a clonally-distributed T cell receptor (hereafter TcR) present on the surface of the T cell. This antigen-specific signal is usually in the form of an antigenic peptide bound either to a major histocompatibility complex (hereafter MHC) class I protein or an MHC class II protein present on the surface of an antigen presenting cell (hereafter APC). CD4+ T cells recognize peptides associated with class II molecules. Class II molecules are found on a limited number of cell types, primarily B cells, monocytes/macrophages and dendritic cells, and, in most cases, present peptides derived from proteins taken up from the extracellular environment. In contrast, CD8+ T cells recognize peptides associated with class I molecules. Class I molecules are found on almost all cell types and, in most cases, present peptides derived from endogenously synthesized proteins. For a review see Germain, R.,
Nature
322, 687-691 (1986).
It has now been established that, in addition to an antigen-specific primary activation signal, T cells also require a second, non-antigen specific, signal to induce full T cell proliferation and/or cytokine production. This phenomenon has been termed costimulation. Mueller, D. L., et al.,
Annu. Rev. Immunol
. 7, 445-480 (1989). Like the antigen-specific signal, the costimulatory signal is triggered by a molecule on the surface of the antigen presenting cell. A costimulatory molecule, the B lymphocyte antigen B7, has been identified on activated B cells and other APCs. Freeman, G. J., et al.,
J. Immunol
. 139, 3260-3267 (1987); Freeman, G . J., et al.,
J. Immunol
. 143, 2714-2722 (1989). Binding of B7 to a ligand on the surface of T cells provides costimulation to the T cell. Two structurally similar T cell-surface receptors for B7 have been identified, CD28 and CTLA-4. Aruffo, A. and Seed, B.,
Proc. Natl. Acad. Sci. USA
84, 8573-8577 (1987); Linsley, P. S., et al.,
J. Exp. Med
. 173, 721-730, (1991); Brunet, J. F., et al.,
Nature
328, 267-270 (1987); Brunet, J. F., et al.,
Immunol Rev
. 103, 21-36 (1988). CD28 is expressed constitutively on T cells and its expression is upregulated by activation of the T cell, such as by interaction of the TcR with an antigen-MHC complex. In contrast, CTLA4 is undetectable on resting T cells and its expression is induced by activation.
A series of experiments have shown a functional role for a T cell activation pathway stimulated through the CD28 receptor. Studies using blocking antibodies to B7 and CD28 have demonstrated that these antibodies can inhibit T cell activation, thereby demonstrating the need for stimulation via this pathway for T cell activation. Furthermore, suboptimal polyclonal stimulation of T cells by phorbol ester or anti-CD3 antibodies can be potentiated by crosslinking of CD28 with anti-CD28 antibodies. Engagement of the TcR by an MHC molecule/peptide complex in the absence of the costimulatory B7 signal can lead to T cell anergy rather than activation. Damle, N. K., et al.,
Proc. Natl. Acad. Sci. USA
78, 5096-5100 (1981); Lesslauer, W., et al.,
Eur. J. Immunol
. 16, 1289-1295 (1986); Gimmi, C. D., et al.,
Proc. Natl. Acad. Sci. USA
88, 6575-6579 (1991); Linsley, P. S., et al.,
J. Exp. Med
. 173, 721-730 (1991); Koulova, L., et al.,
J. Exp. Med
. 173, 759-762 (1991); Razi-Wolf, Z., et al.,
Proc. Natl. Acad. Sci. USA
89, 4210-4214 (1992).
Malignant transformation of a cell is commonly associated with phenotypic changes in the cell. Such changes can include loss or gain of expression of some proteins or alterations in the level of expression of certain proteins. It has been hypothesized that in some situations the immune system may be capable of recognizing a tumor as foreign and, as such, could mount an immune response against the tumor. Kripke, M.,
Adv. Cancer Res
. 34, 69-75 (1981). This hypothesis is based in part on the existence of phenotypic differences between a tumor cell and a normal cell, which is supported by the identification of tumor associated antigens (hereafter TAAs). Schreiber, H., et al.
Ann. Rev. Immunol
. 6, 465-483 (1988). TAAs are thought to distinguish a transformed cell from its normal counterpart. Three genes encoding TAAs expressed in melanoma cells, MAGE-1, MAGE-2 and MAGE-3, have recently been cloned. van der Bruggen, P., et al.
Science
254, 1643-1647 (1991). That tumor cells under certain circumstances can be recognized as foreign is also supported by the existence of T cells which can recognize and respond to tumor associated antigens presented by MHC molecules. Such TAA-specific T lymphocytes have been demonstrated to be present in the immune repertoire and are capable of recognizing and stimulating an immune response against tumor cells when properly stimulated in vitro. Rosenberg, S. A., et al.
Science
233, 1318-1321 (1986); Rosenberg, S. A. and Lotze, M. T.
Ann. Rev. Immunol
. 4, 681-709 (1986).
However, in practice, tumors in vivo have generally not been found to be very immunogenic and appear to be capable of evading immune response. This may result from an inability of tumor cells to induce T cell-mediated immune responses. Ostrand-Roscnberg, S., et al.,
J. Immunol
. 144, 4068-4071 (1990); Fearon, E. R., et al.,
Cell
60, 397-403 (1990). A method for increasing the immunogenicity of a tumor cell in vivo would be therapeutically beneficial.
SUMMARY OF THE INVENTION
Although most tumor cells are thought to express TAAs which distinguish tumor cells from normal cells and T cells which recognize TAA peptides have been identified in the immune repertoire, an anti-tumor T cell response may not be induced by a tumor cell due to a lack of costimulation necessary to activate the T cells. It is known that many tumors are derived from cells which do not normally function as antigen-presenting cells, and, thus, may not trigger necessary signals for T cell activation. In particular, tumor cells may be incapable of triggering a costimulatory signal in a T cell which is required for activation of the T cell. This invention is based, at least in part, on the discovery that tumor cells modified to express a costimulatory molecule, and therefore capable of triggering a costimulatory signal, can induce an anti-tumor T cell-mediated immune response in vivo. This T cell-mediated immune response is effective not only against the modified tumor cells but, more importantly, against the unmodified tumor cells from which they were derived. Thus, the effector phase of the anti-tumor response induced by the modified tumor cells of the invention is not dependent upon expression of a costimulatory molecule on the tumor cells.
Accordingly, the invention pertains to methods of inducing or enhancing T lymphocyte-mediated anti-tumor immunity in a subject by use of a modified tumor cell having increased immunogenicity. In one aspect of the invention, a tumor cell is modified to express a T cell costimulatory molecule on its surface. Prior to modification, the tumor cell may lack the ability to express a T cell costimulatory molecule, may be capable of expressing a T cell costimulatory molecule but fail to do so, or may express insufficient amounts of a T cell costimulatory molecule to activate T cells. Therefore, a tumor cell can be modified by providing a costimulatory molecule to the tumor cell surface, by inducing the expression of a costimulatory molecule on the tumor cell surface or by increasing the level of expression of a costimulatory molecule on the tumor cell surface. In one embodiment, the tumor cell is modified by transfecting the cell with a nucleic acid encoding a T cell costimulatory molecule in a form suitable for expression of the molecule on the cell surface. Alternat

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