Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Cancer cell or component thereof
Reexamination Certificate
2000-03-16
2002-06-11
Huff, Sheela (Department: 1642)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Cancer cell or component thereof
C424S093100, C424S093700
Reexamination Certificate
active
06403104
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to mammalian cells conjugated to a hapten, and methods of making and using thereof. Conjugating hapten to mammalian cells is an alternative strategy to prevent cells from proliferating, which may be used instead of conventional irradiation treatment. Compositions comprising hapten-modified tumor cells and tumor cell extracts, and methods of treating cancer by administering a therapeutically effective amount of a composition comprising a tumor cell or tumor cell extract to a subject in need of such treatment, are also within the scope of the invention. The invention also provides an effective vaccination schedule useful for inducing an antitumor response in a patient suffering from cancer.
BACKGROUND OF THE INVENTION
Preventing Growth of Mammalian Cells
In various in vitro and in vivo procedures using mammalian cells, there is a need to prevent the mammalian cells from growing and dividing, i.e., proliferating. Traditionally, irradiation of mammalian cells has been used for this purpose. For example, mammalian tumor cells were irradiated prior to administration as a vaccine to a melanoma patient (Berd et al., Cancer Res., 1986; 46:2572-77). Similarly, McCune et al. (Cancer, 1981; 47:1984-87) describe irradiation of renal carcinoma cells for purposes of therapy. However, there remains a need in the art for strategies to prevent cell proliferation which does not involve cell irradiation.
Hapten-conjugated Tumor Cell Vaccines
An autologous whole-cell vaccine modified with the hapten dinitrophenyl (DNP) has been shown to produce inflammatory responses in metastatic sites of melanoma patients. Post-surgical adjuvant therapy with DNP-modified vaccine produces survival rates that are markedly higher than those reported for surgery alone. Intact or viable cells are preferred for the vaccine.
U.S. Pat. No.5,290,551, to David Berd, discloses and claims vaccine compositions comprising haptenized melanoma cells. Melanoma patients who were treated with these cells developed a strong immune response. This response could be detected in a delayed-type hypersensitivity (DTH) response to haptenized and non-haptenized tumor cells. More importantly, the immune response resulted in increased survival rates of melanoma patients.
Haptenized tumor cell vaccines have also been described for other types of cancers, including lung cancer, breast cancer, colon cancer, pancreatic cancer, ovarian cancer, and leukemia (see U.S. patent application Ser. No. 08/203,004, filed Feb. 28, 1994; International Patent Application No. PCT/US96/09511; U.S. patent application Ser. No. 08/899,905, filed Jul. 24, 1997).
Although the above studies describe successful immunotherapy methods using hapten-conjugated tumor cells, there remains a need in the cancer treatment art for additional and improved methods for inducing an anti-tumor response and improved hapten-modified tumor-cell. Applicant has now surprisingly discovered a simplified method for preparing hapten-modified tumor cell which eliminates the need for irradiation, thereby offering procedural and financial advantages in the production of hapten-modified tumor-cell vaccines.
SUMMARY OF THE INVENTION
The present invention relates to mammalian cells in a substantially non-proliferative state compositions containing hapten-modified tumor cells and methods for inducing an antitumor response in a patient suffering from cancer by administering the compositions of the invention.
In one embodiment, the invention relates to a mammalian cell, including a tumor cell, in a substantially non-prolierative state.
In another embodiment, the present invention relates to a method for placing a mammalian cell in a substantially non-proliferative state, which does not comprise irradiating the cell.
In yet another embodiment, the present invention is directed to a composition comprising a hapten modified mammalian tumor cell substantially in a non-proliferative state.
In still another embodiment, the invention provides for a vaccine composition comprising a therapeutically effective amount of a hapten-modified mammalian, preferably human, tumor cell which is substantially in a non-proliferative state.
In another aspect, the present invention is directed to a method of treating cancer comprising administering to a mammal, preferably a human, a composition comprising a therapeutically effective amount of a hapten modified human tumor cell, which has not been exposed to irradiation, wherein said mammal suffers from a malignant tumor of the same type as said tumor cell membrane.
In a further aspect, the invention is directed to a method of treating cancer according to weekly vaccinations using the non-proliferative hapten-modified tumor cell compositions described herein.
In yet another aspect, the invention relates to a simplified method for making the non-proliferative hapten-modified tumor cell compositions of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to mammalian cells conjugated to a hapten and methods of making and using thereof. Conjugating hapten to mammalian cells is an alternative strategy for preventing cells from growth, i.e., multiplication and may be used instead of a conventional irradiation treatment. Thus, the invention relates generally to mammalian cells, for example human cells, which are substantially in a non-proliferative state and a method of placing the cells in such a state by conjugating them to a hapten. Further, the compositions and methods described in the following PCT applications can advantageously be modified according to the present invention: PCT/US96/09511 (WO 96/40173), PCT/US97/15741 (WO 98/14206), PCT/US98/20888, PCT/US98/16660, PCT/US99/27442, PCT/US99/07725 (WO 99/52546), and PCT/US99/31297.
The present invention is also directed to cancer immunotherapy. A tumor composition and methods of treating cancer are included in the scope of the invention. The invention further relates to a method of inducing an antitumor response according to a weekly vaccinations with non-proliferative hapten-conjugated tumor cell compositions produced by the simplified method of the invention.
For purposes of the present invention an antitumor response is at least one of the following: tumor necrosis, tumor regression, tumor inflammation, tumor infiltration by activated T lymphocytes, delayed-type hypersensitivity response, and prolongation of patient survival. The tumor cells and extracts of the invention and compositions thereof are capable of eliciting T lymphocytes that have a property of infiltrating a mammalian tumor, eliciting an inflammatory immune response to a mammalian tumor, eliciting a delayed-type hypersensitivity response to a mammalian tumor and/or stimulating T lymphocytes in vitro.
An anti-tumor response resulting from the treatment according to the present invention may be a partial or a complete regression of the metastatic tumor or a stable disease. A “complete” regression indicates about 100% regression for a period of at least one month, more preferably for a period of at least three months. A “partial” regression indicates more than about 50% regression for a period of at least one month, more preferably for a period of at least three months. A “stable” disease indicates a condition in which there is no significant growth of the tumor after the vaccine treatment. Another anti-tumor response that may be observed following the treatment of the invention is prolongation of survival.
Any malignant tumor may be treated according to the present invention including metastatic and primary cancers and solid and non-solid tumors. Solid tumor include carcinomas, and non-solid tumors include hematologic malignancies. Carcinomas include and are not limited to adenocarcinomas and epithelial carcinomas. Hematologic malignancies include leukemias, lymphomas, and multiple myelomas. The following are non-limiting examples of the cancers treatable with isolated modified tumor cell membranes according to the methods of the present invention: ovarian, including adv
Darby & Darby
Huff Sheela
Thomas Jefferson University
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