Melanoma cell lines expressing shared immunodominant...

Details Melanoma cell lines expressing shared immunodominant... Melanoma cell lines expressing shared immunodominant...

1997-08-05

2001-02-13

LeGuyader, John L. (Department: 1633)

Drug, bio-affecting and body treating compositions

Whole live micro-organism, cell, or virus containing

Genetically modified micro-organism, cell, or virus

C424S093200, C424S277100, C435S325000, C435S455000, C514S04400A

Reexamination Certificate

active

06187306

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The present invention pertains to a method of treating or protecting against melanoma using as a vaccine one or more melanoma tumor cell lines that express multiple immunodominantshared melanoma antigens. In particular, the invention pertains to the method of using an allogeneic melanoma cell line as a vaccine. The present invention also relates to a melanoma cell line that expresses shared immunodominant melanoma antigens, and to a composition comprising cells of the melanoma cell line.
BACKGROUND OF THE INVENTION
It generally is accepted that tumor cells contain multiple specific alterations in the cellular genome responsible for their cancerous phenotype. These alterations affect the expression or function of genes that control cell growth and differentiation. For instance, typically these mutations are observed in oncogenes, or positive effectors of cellular transformation, such as ras, and in tumor suppressor genes (or recessive oncogenes) encoding negative growth regulators, the loss of function of which results in expression of a transformed phenotype. Such recessive oncogenes include p53, p21, Rb1, DCC, MCC, NFI, and WTI.
Immunotherapy is a potential therapeutic approach for the treatment of cancer. Immunotherapy is based on the premise that the failure of the immune system to reject spontaneously arising tumors is related to the failure of the immune system to appropriately respond to tumor antigens. In a functioning immune system, tumor antigens are processed and expressed on the cell surface in the context of major histocompatibility complex (MHC) class I and II molecules, which, in humans, also are termed “human leukocyte associated” (HLA) molecules. Complexes of MHC class I and II molecules with antigenic peptides are recognized by CD8
+
and CD4
+
T cells, respectively. This recognition generates a set of secondary cellular signals and the paracrine release of specific cytokines or soluble so-called “biological response modifiers”, that mediate interactions between cells and stimulate host defenses to fight off disease. The release of cytokines then results in the proliferation of antigen-specific T cells.
Thus, active immunotherapy involves the injection of tumor cells to generate either a novel or an enhanced systemic immune response. The ability of this immunotherapeutic approach to augment a systemic T cell response against a tumor has been previously disclosed, e.g., amongst others, see International Application WO 92/05262, Fearon et al.,
Cell,
60, 397-403 (1990), and Dranoff et al.,
Proc. Natl. Acad. Sci.,
90, 3539-43 (1993). The injected tumor cells usually are altered to enhance their immunogenicity, such as by admixture with non-specific adjuvants, or by genetic modification of the cells to express cytokines, or other immune co-stimulatory molecules. The tumor cells employed can be autologous, i.e., derived from the same host as is being treated. Alternately, the tumor cells can be MHC-matched, or derived from another host having the same, or at least some of the same, MHC complex molecules.
Most whole cell cancer vaccines are produced using the patient's own tumor cells. There are two reasons for the use of such autologous vaccines. First, based on the results with murine tumors, it previously had been postulated that each tumor expresses tumor-associated-antigens (TAA) that are unique to each patient's tumor. Second, because T cell recognition depends on both the MHC allele as well as the specific antigen, use of cells from a patient's own tumor circumvents any need for matching of tumor or MHC antigens.
However, the in vitro expansion of fresh human tumor explants necessary for the production of autologous tumor cell vaccines is labor-intensive, technically demanding, and frequently impossible for most histologic types of human tumors, even with highly specialized research facilities. Moreover, the production of a vaccine from each patient's tumor is quite expensive. There also is a substantial likelihood that after extended passage of autologous cells in culture, the antigenic composition of such cells will change relative to the primary tumor from which the cell line originated, making the cells ineffective as a vaccine. While such change is frequent with all established cell lines, as regarding the use of autologous cells as a tumor vaccine, it potentially will require the maintenance of freezer stocks of each initially-isolated cell line for each patient being treated using this approach.
The recent results of Huang et al.,
Science,
264, 961-65 (1994), are relevant to the treatment of cancer using vaccines. Namely, prior to the study of Huang et al., tumor vaccine strategies were based on the understanding that the vaccinating tumor cells function as the antigen presenting cells (APCs) that present the tumor antigens on their MHC class I and II molecules, and directly activate the T cell arm of the immune response. In contrast, the results of Huang et al. indicate that the professional APCs of the host rather than the vaccinating tumor cells prime the T cell arm of the immune response. In the study of Huang et al., tumor vaccine cells secreting the cytokine GM-CSF recruit to the region of the tumor bone marrow-derived APCs. The bone marrow-derived-APCs take up the whole cellular protein of the tumor for processing, and then present the antigenic peptide(s) on their MHC class I and II molecules. In this fashion, the APCs prime both the CD4
+
and the CD8
+
T cell arms of the immune system, resulting in the generation of a systemic antitumor immune response that is specific for the antigenic epitopes of the host tumor. These results suggest that it may not be necessary to use autologous or MHC-matched tumor cells in cancer treatment.
Also relevant to the use of tumor vaccines, it has been confirmed that T cells are the critical mediator of systemic antitumor immunity induced by tumor vaccines (reviewed by Pardoll,
Trends in Pharmacological Sciences,
14, 202-08 (1993)). Thus, the production of a universal tumor vaccine, i.e., a vaccine that is applicable to the majority of patients with a particular type of cancer, requires knowledge of the existence of shared immunodominant tumor antigens recognized by T cells. Currently, shared immunodominant tumor antigens recognized by T cells have been identified in only one human cancer, melanoma. Melanoma is a malignant neoplasm derived from cells that are capable of forming melanin, and may occur in the skin of any part of the body, in the eye, or, less commonly, in the mucous membranes of the genitalia, anus, oral cavity, or other sites. Melanomas frequently metastasize widely, and the regional lymph nodes, liver, lungs, and brain are likely to be involved. Primary malignant melanoma of the skin is the leading cause of death from all diseases arising in the skin. Metastatic melanoma is frequently thought of as resistant to treatment. In fact, the most effective single agent for treatment of disseminated melanoma, dacarbazine (dimethyltriazenoimidazolecarboxamide or DTIC), induces a partial remission in only 20 percent of cases, and a complete response in less than 5 percent of cases (Fitzpatrick et al., “Malignant Melanoma of the Skin”,
In Harrison's Principles of Internal Medicine
, Braunwald et al., eds., Eleventh Ed. (McGraw-Hill Book Company: NY, 1987) 1595-97)).
The shared immunodominant melanoma antigens recognized by T cells fall into two main categories. One category of antigens encompasses proteins that are produced in melanoma cells, and are not produced in any other adult tissues with the exception of testis. These so-called tumor-specific shared antigens include the MAGE family antigens MAGE-1 and MAGE-3. Of these two antigens, MAGE-3 appears to be more widely produced and immunodominant than MAGE-1. MAGE-3 also is produced in other nonmelanotic tumors such as small cell lung cell carcinoma (SCLC), non-small cell lung cell carcinoma (non-SCLC), squamous cell carcinoma of the head and neck (SCCHN), colon can

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