Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Animal or plant cell
Reexamination Certificate
2001-10-25
2004-05-11
Brumback, Brenda (Department: 1654)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Animal or plant cell
C424S442000, C424S439000
Reexamination Certificate
active
06733748
ABSTRACT:
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of Canadian Application Serial Number 2,324,199, filed Oct. 25, 2000, which is incorporated by reference in its entirety.
FIELD OF THE INVENTION
This invention relates to leukemia alleviation, and to processes and cellular compositions useful therein. More specifically, it relates to compositions and processes for alleviating chronic lymphocytic leukemia in mammalian patients, especially humans, and to processes for preparing such compositions.
BACKGROUND OF THE INVENTION
Chronic lymphocytic leukemia (hereinafter CLL) is one of the four major types of leukemia encountered by humans, the others being acute lymphocytic leukemia, acute myeloid leukemia and chronic myeloid leukemia. CLL is most commonly encountered in patients over the age of sixty. It has a gradual onset, and may not cause the patient discomfort or pain for several years. It is characterized by a large number of cancerous mature lymphocytes and enlarged lymph nodes. Cancerous cells crowd out the normal cells in the bone marrow and lymph nodes. Anemia develops in the patient and the number of normal white cells and platelets in the patient's blood decreases, whereas the total white cell count increases due to the proliferation of abnormal white cells. The level and activity of antibodies also decrease. As a result, the patient's immune system becomes compromised. It is more common for CLL sufferers to die from consequences of the compromised immune system, e.g. infections, than from the CLL itself.
The most common type of CLL is a B cell leukemia, and the malignant cell of origin is a CD5+B cell, i.e. a B cell expressing the marker CD5.
Clinical stage of CLL, characterized in the staging systems of Rai (stages O-IV) and Binet (stages A-C), remains the strongest predictor of survival in CLL patients. Both systems are based on the amount of involved lymphoid tissue and the presence of anemia and/or thrombocytopenia. In general, patients with later stages have a significantly worse prognosis and a shorter survival. Patients with Rai stage IV or Binet stage C have a median survival of only 1.5 to 2 years.
Chemotherapy (initially with alkylating agents such as chlorambucil and subsequently with fludarabine) is the standard treatment for CLL. A patient diagnosed with CLL is normally monitored by tracking the white cell count in the blood. Chemotherapy is not instituted until the patient starts to suffer symptoms such as fatigue, weight loss, fevers or pain as a result of the progression of the CLL. However, CLL is not curable with conventional methods of chemotherapy, even though initial response rates are high. The toxicities associated with the use of chemotherapy are well known and include nausea and myelosuppression with a risk of developing serious infections. Moreover, subsequent responses become inexorably short-lived, likely because drug-resistant tumor cells are selected by the use of cytotoxic agents.
Accordingly, it is an object of the present invention to provide novel procedures and compositions for alleviation of CLL in mammalian patients.
It is a further object of the invention to provide procedures and compositions which, on suitable administration to a CLL suffering patient, will significantly postpone the need for subjecting the patient to chemotherapy.
SUMMARY OF THE INVENTION
According to the present invention in its broad aspects, CLL in a mammalian patient is alleviated by administering to the patient oxidatively stressed CLL malignant cells. The source of the CLL malignant cells may be the mammalian patient himself or herself (e.g. a withdrawn blood sample from the patient), a compatible mammalian donor (e.g. a withdrawn blood sample from another, compatible CLL-suffering patient), or a cultured cell line of CLL malignant cells. Subjection of the CLL malignant cells to oxidative stress takes place in vitro. The oxidatively stressed CLL cells thus obtained are administered to the patient to result in an alleviation of the patient's CLL.
According to a preferred aspect of the present invention, CLL in a mammalian patient suffering therefrom is significantly alleviated by administering to the patient oxidatively stressed blood cells, including oxidatively stressed CLL malignant cells, obtained from the patient and subjected to oxidative stress in vitro and then reintroduced into the patient. The procedure thus involves extracting an appropriate quantity of blood containing CLL cells from the CLL patient, treating the blood or a selected portion of it extracorporeally with an oxidative stressor, and reintroducing it into the same patient. The result, after one or more of such treatments, is a significant alleviation of the patient's CLL condition, as indicated in a reduced white blood cell proliferation and a reduced swelling of lymph nodes of the patient.
Thus from one aspect, the present invention provides a process for treating a CLL suffering patient for alleviation of CLL, which comprises extracting an aliquot of blood containing CLL cells from the patient, subjecting at least a portion of the extracted blood cells extracorporeally to appropriate oxidative stress, and re-introducing the oxidatively-stressed material into the patient.
Another aspect of the present invention is oxidatively stressed mammalian CLL cells, useful for introduction into a mammalian patient suffering from CLL to alleviate the patient's CLL.
A further aspect of the present invention is the use in preparation of a medicament active against CLL in a mammalian patient, of oxidatively stressed autologous blood or blood fractions, including oxidatively stressed autologous malignant CLL cells.
Another aspect of this invention is a composition comprising stressed CLL cells. The cells may be oxidatively stressed and may further be autologous CLL cells.
While it is not intended that this invention should be limited to any particular mode of action or theory of mechanism or performance, it is postulated that appropriately oxidatively stressed blood cells activate the regulatory immune T cells controlling the CD5+B cells in the patient's blood, including the malignant CD5+B cells. The oxidatively stressed cells, on reintroduction into the CLL patient, are believed to activate certain T cells present in the patient's blood which then down-regulate the malignant CD5+B cells by acting directly on them or by secreting cytokines which then act on them. In any event, the result is a significant reduction in the rate of proliferation of the malignant CD5+B cells in the CLL patient and a consequent alleviation of the CLL condition and its symptoms.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
A preferred embodiment of the present invention subjects the blood cells, or the appropriate fraction of them including the CLL cells, to electromagnetic emission radiation as well as oxidative stress, either simultaneously or sequentially. Optionally also, a temperature stressor may be applied to the cells, simultaneously or sequentially with the oxidative stressor and the electromagnetic emission stressor, i.e. a temperature at, above or below body temperature. An aliquot of blood is drawn from the CLL patient, of volume up to about 400 ml, preferably from about 0.1 to 100 ml, more preferably from about 1 to about 15 ml, even more preferably from about 8 to about 12 ml. Either the whole blood is subjected to the stressor(s), or an appropriate cellular fraction thereof containing the CLL malignant B cell fraction is separated by known methods and subjected to the aforementioned stressor(s). The stressed cells are then reintroduced into the CLL patient from whom the original aliquot was drawn. The term “aliquot” as used herein refers to the sample subjected to the stressors; and embraces both the originally extracted whole blood and any fraction thereof subjected to stressors, before or after separation.
The modified aliquot is re-introduced into the patient's body by any suitable method, most preferably intramuscular
Brumback Brenda
Swiss Law Group
Vasogen Ireland Limited
Winston Randall
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