Method for sensitization of cancer cells for killer cell mediate

Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Animal or plant cell

Patent

Rate now

  [ 0.00 ] – not rated yet Voters 0   Comments 0

Details

4241841, 4241981, 424479, 424488, 424493, 424499, 435 723, A01N 6300, A61K 3900, A61K 3938, A61K 936

Patent

active

057889643

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/FI94/00333 which is a continuation of the U.S. application Ser. No. 08/103,519, filed Aug. 9, 1993, now abandoned.


BACKGROUND OF THE INVENTION

The invention relates to the treatment of cancer by sensitization of cancer cells by antiestrogens for lysis with killer cells, particularly with natural killer (NK) cells, lymphokine activated killer (LAK) cells and cytotoxic T lymphocytes (CTL).
The treatment of human cancer with autologous lymphokine activated killer (LAK) cells combined with recombinant-derived lymphokine, interleukin-2, has already been attempted with encouraging results (Rosenberg, 1987) as well as the treatment with activated cytotoxic T lymphocytes (CTL) (Fujimoto, 1992).
Nonsteroidal antiestrogens tamoxifen and toremifene belonging to the triphenylethylene class of compounds have gained wide therapeutic application for the treatment of estrogen receptor positive breast cancer. Tamoxifen and toremifene inhibit estrogen-induced growth by competitive antagonism of tumor estrogen receptors. Antiestrogen therapy is effective in prolonging a disease-free state and overall survival of women following primary surgery. Other well known triphenylethylene class antiestrogens are e.g. clomiphene and droloxifene (3-hydroxytamoxifen).
We have now discovered that estrogen receptor negative cancer cells are sensitized by triphenylethylene antiestrogens for lysis with NK, LAK and CTL effectors. This sensitization effect is thus not dependent on the presence of classical estrogen receptors. The use of the combination of antiestrogen treatment and killer cell therapy according to the invention is expected to significantly elevate the percentage of tumor remission and cure that has already been achieved by the above investigators with killer cells alone in a minor percentage of patients.


SUMMARY OF THE INVENTION

The invention relates to a method of sensitizing cancer cells for a killer cell mediated lysis which involves administering to a patient an effective amount of antiestrogen and killer cells either jointly or sequentially, wherein the killer cells are selected from the group of NK cells, LAK cells and CTL cells and the antiestrogen is selected from the group of triphenylethylene class antiestrogens, such as tamoxifen or toremifene or their pharmaceutically acceptable salt. Alternatively, killer cells may be induced in a host by one of known immunostimulation methods during the first treatment period and thereafter administering an effective amount of antiestrogen during the second treatment period.


BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph of a Winn assay with untreated, tamoxifen (TX) treated and toremifene (TO) treated P815 tumor cells.
FIGS. 2a, 2b and 2c are the survival curves for the experiment of FIG. 1.
FIG. 3 is a graph of the effect of oral TX and TO treatment alone or with LAK treatment on P815 tumor growth.
FIGS. 4a, 4b and 4c are the survival curves for the experiment of FIG. 3.
FIG. 5 is a graph of a winn assay with untreated, tamoxifen (TX) treated and toremifene (TO) treated P815 tumor cells.
FIGS. 6a, 6b and 6c are the survival curves for the experiment of FIG. 5.
FIG. 7 is a graph demonstrating the immunotherapy results of P815 mastocytoma with TX or TO and LAK cells.
FIGS. 8a, 8b and 8c are the survival curves for the experiment of FIG. 7.
FIG. 9 is a graph demonstrating the immunotherapy results of P815 mastocytoma with TX or TO given by gavage and LAK cells.
FIGS. 10a, 10b and 10c are the survival curves for the experiment of FIG. 9 .


DETAILED DESCRIPTION OF THE INVENTION

1. Detection of killer cells
The prerequisite for success of the treatment according to the invention is the presence of killer cells (e. g. NK, LAK or CTL) capable of destroying the patient's cancer cells in the body when the adjuvant therapy with an antiestrogen, e. g. tamoxifen (TX) or toremifene (TO), is initiated. Ideally, a suspension of cells would be prepared from the patient's tumor by digestion with collagenase as described by Freshney (1976) and used

REFERENCES:
patent: 5024833 (1991-06-01), Del Blanco
patent: 5057423 (1991-10-01), Hiserodt et al.
patent: 5189212 (1993-02-01), Ruenitz
The Merck Index, 11th edition, pp. 373, 1430, and 1504, 1989.
Osband et al. "Problems in the invetigational study and clinical use of cancer immunotherapy" Immunotherapy, p. 1930-195, 1990.
Chaterjee et al. "Idiotype antibody immunotherapy of cancer" Cancer Immunol. Immunother. vol. 38, pp. 75-82, 1994.
Mallmann et al, "Effect of Tamoxifen and high-does medroxyprogesterone acetate (MPA) on cell mediated immune functions in breast cancer patients" Meth. Find. Exp. Clin. Pharmocol. vol. 12, No. 10, pp. 699-706, 1990.
Berry et al. "Modulation of natural killer cell activity by Tamoxifen in stage I post-menopausal breast cancer" Eur. J. Cancer Clin. Oncol., vol. 23, No. 5, pp. 517-520, 1987.
Kangas et al, "Additive and synergistic effects of a novel antiestrogen, toremifene (Fc-1157a), and human interferons on estrogen responsive MCF-7 cells in vitro" Med. Biol. vol. 63, pp. 187-190, 1985.
Robertson et al, "Biology and clinical relevance of human natural killer cells" Blood, vol. 76, No. 12, pp. 2421-2438, 1990.
Michael Andersson et al., "Incidence of New Primary Cancers After Adjuvant Tamoxifen Therapy and Radiotherapy for Early Breast Cancer", J. Natl. Cancer Institute, vol. 83, No. 14, Jul. 17, 1991.
R.I. Freshney, "B. Monolayer Cultures", Short Term Culture of Human Tumours. Techniques and Clinical Applications, PP. Dendy, ed. Academic Press, London, 1976.
Shigeyoshi Fujimoto et al., "Development of Specific Immunotherapy for Cancer", (translation from abstract), Human Cell, 5, 247-55, 1992.
Tenho Hietanen et al., "High Dose Toremifene (240 mg daily) is Effective as First Line Hormonal Treatment in Advanced Breast Cancer -An Ongoing Phase II Multicenter Finnish-Latvian Cooperative Study", Breast Cancer Research and Treatment, 16, S-37-40, 1990.
Steven A. Rosenberg, M.D. et al., "A Progress Report on the Treatment of 157 Patients with Advanced Cancer Using Lymphokine-Activated Killer Cells and Interleukin-2 or High Dose Interleukin-2 Alone", New England Journal of Medicine, vol. 316, No. 15, Apr. 1987, pp. 889-897.
Ichiro Yoshino et al., "Cytolytic Potential of Peripheral Blood T-Lymphocytes Following Adoptive Immunotherapy with Lymphokine-Activated Killer Cells and Low-Dose Interleukin-2", Cancer Research, 51, 1494-1498, Mar. 1, 1991.
Herbert C. Hoover, Jr. et al., "Adjuvant Active Specific Immunotherapy for Human Colorectal Cancer: 6.5 Year Median Follow-up of a Phase III Prospectively Randomized Trial", Journal of Clinical Oncology, vol. 11, No. 3, (Mar.), 1993: pp. 390-399.
Alfred E. Chang et al., "Clinical Observations on Adoptive Immunotherapy with Vaccine-primed T-Lymphocytes Secondarily Sensitized to Tumor in Vitro", Cancer Research, 53, 1043-1050, Mar. 1, 1993.
Philip O. Livingston, "Construction of Cancer Vaccines with Carbohydrate and Protein (Peptide) Tumor Antigens", Current Opinion in Immunology, 4,5, 624-9, 1992.
Masashi Komatsumoto et al., "The Improved Effects of Specific Active Immunotherapy on a Rat Fibrosarcoma by Antitumor Drugs", Cancer Immunology Immunotherapy, 33, 279-284, 1991.
Kroum T. Kassabov et al., "Inhibition of Spontaneous Pulmonary Metastases of Lewis Lung Carcinoma by Oral Treatment with Respivax and Broncho-Vaxom", Cancer Immunology Immunotherapy, 33, 307-313, 1991.
Mary Nel Saarloos et al., "Effects of Cancer Immunotherapy with Indomethacin and Interleukin-2 on Murine Hemopoietic Stem Cells", Cancer Research, 52, 6452-6462, Dec. 1, 1992.
Hisashi Aso et al., "Impaired NK Response of Cancer Patients to IFN-.alpha. but Not to IL-2: Correlation with Serum Immunosuppressive Acidic Protein (IAP) and Role of Suppressor Macrophage", Microbiological Immunology, vol. 36, (10), 1087-1097, 1992.
Teruhiro Utsugi et al., "Comparative Efficacy of Liposomes Containing Synthetic Bacterial Cell Wall Analogues for Tumoricidal Activation of Monocytes and Macrophages", Cancer Immunology Immunotherapy, 33, 28

LandOfFree

Say what you really think

Search LandOfFree.com for the USA inventors and patents. Rate them and share your experience with other people.

Rating

Method for sensitization of cancer cells for killer cell mediate does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Method for sensitization of cancer cells for killer cell mediate, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for sensitization of cancer cells for killer cell mediate will most certainly appreciate the feedback.

Rate now

     

Profile ID: LFUS-PAI-O-1174301

  Search
All data on this website is collected from public sources. Our data reflects the most accurate information available at the time of publication.