Integrative Immunotherapy as practiced at our Integrative Oncology Centers™ has an extensive history of complete long-term remissions of advanced cancers. It has further evolved by including research based novel protocols of immune enhancement using these specialized treatments.
Cytokines, NK Cells, LAK Cells, and Stem Cells Information and Use in Fighting Cancer
Cytokines in Cancer Therapy
In cancer therapy, cytokines are generally used to enhance immunity.
Cytokines(Greek cyto-, cell; and -kinos, movement) are substances that are secreted by specific cells of the immune system. They are proteins, peptides or glycoproteins. They carry signals between cells, and thus have an effect on other cells. They can function locally or at a distance to enhance or suppress immunity.
The term “cytokine” refers to the immune modulating agents such as interleukins, interferons, tumor necrosis factor, granulocyte-macrophage colony-stimulating factor (GM-CSF). These medications are also called biologic response modifiers.
One class of interleukins is Interleukin-2 (IL-2, Aldesleukin, Proleukin), which is normally produced in the body in small amounts. By increasing levels of IL-2, the increase in immune system components, specifically T-cells and Natural Killer Cells, will mount an attack against any cancer cells. The effect depends on the adhesion molecules or signals in the cells.
Due to the research by Steven A. Rosenberg of the US National Cancer Institute, Interleukin-2 is approved by the FDA for the treatment of cancer. Interferon-alfa 2b is approved by the FDA as well.
Other cytokines have shown great promise in cancer treatment, such as Interleukin-4 during the generation of Dendritic Cells and Interleukin-21 in the enhancement of Natural Killer Cell (NK Cell) activity, as well as in the activation of CD8 T-cells.
Interleukin-2 has demonstrated activity against renal cell cancer, melanoma, lymphoma, leukemia, and other cancers that have receptors for IL-2 in the membrane of the specific cell. The high pharmacological dosage generally used is toxic and poses the risk of side effects like fever, chills, nausea, diarrhea, fluid retention, low blood pressure and other reactions. Pre-medication can lower risks.
Interleukin-2 can also be given in low dose via a shot under the skin (subcutaneously). For qualified patients we administer a protocol with low dose Interleukin-2 that has shown activity against a variety of advanced solid tumors.
Natural Killer Cells (NK Cells)
Natural Killer Cells, also called NK cells, are very important cells of our immune system. They are our first line of defense. Natural Killer Cells kill tumor cells and cells infected by viruses by releasing small granules of proteins that cause the target cell to die. This process is called apoptosis or programmed cell death.
Natural Killer Cells evolve from lymphoid stem cells and are a major component of the innate immune system. It is the innate immune system which provides immediate defense against invaders whereas the adaptive immune system with its antigen-specific cytotoxic T-cells provides long-lasting immunity.
In view of NK Cells’ strong cytolytic (cell-dissolving) properties, NK Cell activity is tightly regulated. Natural Killer Cells have a variety of receptors that either activate or suppress their cytolytic activity. The latter has the purpose to prevent auto-immune diseases.
The activating signal for Natural Killer Cells comes in a variety of forms, of which Interferons and macrophage-derived Cytokines are the most potent ones. They are stress molecules released by cells upon viral infection and also in cancer.
Natural Killer Cells can also target cells against which a humoral immune response has been mobilized and can lyse cells through antibody-dependent cytotoxicity.
In our efforts to provide maximum immune enhancement to our patients, the comprehensive Issels Immunotherapy programs not only focus on cell-mediated immunity, but on all the different levels of the immune system. We address the adaptive and innate immune system.
Therefore, we integrate a specifically prepared Concentrate of Activated Autologous Natural Killer Cells into our treatment protocols. These are the patient’s own immune cells which do not cause adverse reactions such as allergies or rejection and do not require immune suppressive drugs. (Donor immune cells may cause adverse reactions and require immune suppressive drugs.)
Lymphokine-Activated Killer Cells (LAK Cells)
Lymphokine-Activated Killer Cells, also known as LAK cells, are lymphocytes that in the presence of Interleukin-2 are stimulated to kill tumor cells. Lymphocytes are one of the five kinds of white blood cells, or leukocytes, circulating in the blood. They play an integral role in the body’s defenses. The culture of lymphocytes in the presence of interleukin-2 results in effector cells which are cytotoxic to tumor cells.
The stem cells of lymphocytes (THO) have many receptors or adhesion molecules in their membrane for IL-2 and during our procedures they are stimulated to increase their cell division into the cytotoxic line (LTCD4, LTCD8, NK cells). When these lymphocytes are activated in the circulation they can destroy circulating malignant cells.
Mature lymphocytes are extraordinarily diverse in their functions. The most abundant lymphocytes are B lymphocytes (often simply called B-cells) and T lymphocytes (likewise called T-cells). B-cells are produced in the bone marrow. The precursors or stem cells of T-cells are also produced in the bone marrow but leave the bone marrow and mature in the Thymus (which accounts for their designation).
Our protocols of Immune Enhancement involve the administration of Autologous Lymphocytes. These are the patient’s own immune cells which do not cause adverse reactions such as allergies or rejection and do not require immune suppressive drugs. (Donor immune cells may cause such adverse reactions.)
Our Protocols Used in Integrative Immunotherapy
LAK Cells with Low Dose of Interleukin-2 in Patients with Solid Tumors
One of the procedures involves the separation of lymphocytes from the peripheral blood, culturing them in the patient’s own blood serum and expanding their numbers multifold before transfusing them back to the patient to yield maximum results.
LAK- STEM Cells with Low Dose of Interleukin-2 in Patients with Solid Tumors
The stem cell procedure that we administer consists of the stimulation of lymphocytes in vivo. During this stem cell procedure the sample is taken from the patient’s bone marrow of the head of the tibia bone and provides in addition to lymphocytes, stem cells, mature and immature leukocytes.
This combination renders the therapy even more powerful. As the stroma of bone marrow contains IL-7, which increases the effect of IL-2 by 5 times, we can decrease the dose of IL-2 while maintaining its potency.
Interleukin-2 stimulates the stem cells of the lymphocytes that then divide into T-Helper cells, such as THO, TH1 and TH2, which secrete lymphokines, various cytokines, such as interleukins and interferons.
TH1 secretes mainly IL-2, interferon gamma, GM-CSF, TNA-alpha, ligand CD40, which can activate macrophages. The LTC or cytotoxic CD8+ lymphocytes produce perforins, gamzymes, interferon gamma, TNF alpha and beta, and can in this way destroy circulating abnormal cells.
Stem cells are the human body’s master cells with the ability to renew themselves through cell division and grow into any one of its 200 cell types, except for cells of the placenta. They have the potential to multiply indefinitely, become highly specialized and replace cells that die or are lost.
Thus these specialized Stem Cells, aid in the repair of organs and tissue damaged by cancer progression, previous cancer treatments, or chronic degenerative conditions. They also maintain the normal turnover of regenerative organs, such as blood, skin, and intestinal tissues. Autologous Stem Cells from the patient’s own bone marrow do not have any adverse side effects.
Under normal conditions, we have less than 0.1% of stem cells in circulation, which is sometimes not sufficient for regenerative processes. The objective is, therefore, to increase the number of stem cells in circulation without the use of potent toxic drugs.
The immune-stimulatory effect of our therapy is sometimes quickly seen in the improvement of the overall condition of the patient, quality of life, reduction of pain, etc. Tumor shrinkage may take four weeks or longer. The procedure can be repeated after two months.
The protocols with autologous stem cells and low-dose Interleukin-2 that we administer do usually not cause any adverse effects.
Butterfield LH. Recent advances in immunotherapy for hepatocellular cancer. Swiss Med Wkly. 2007 Feb 10;137(5-6):83-90.
Cheever MA, Thompson JA, Peace DJ, Greenberg PD. Potential uses of interleukin 2 in cancer therapy. Immunobiology. 1986 Sep;172(3-5):365-82.
Coquet JM, Kyparissoudis K, Pellicci DG, Besra G, Berzins SP, Smyth MJ, Godfrey DI. IL-21 is produced by NKT cells and modulates NKT cell activation and cytokine production. J Immunol. 2007 Mar 1;178(5):2827-34.
de Rham C, Ferrari-Lacraz S, Jendly S, Schneiter G, Dayer JM, Villard J. The proinflammatory cytokines IL-2, IL-15 and IL-21 modulate the repertoire of mature human natural killer cell receptors. Arthritis Res Ther. 2007;9(6):R125.
GACETA MEXICANA DE ONCOLOGIA, SOCIEDAD MEXICANA DE ONCOLOGIA. A.C. Vol. 5, Num. 3 Mayo-Junio 2006.
Gryllis C, Wainberg MS, Bentwich Z, Gornitsky M, and Brenner BG. Increased LAK activity against HIV-infected cell lines in HIV-1+ individuals. Clin Exp Immunol. 1992 September; 89(3): 356–361.
Ferris RL. Progress in head and neck cancer immunotherapy: can tolerance and immune suppression be reversed? ORL J Otorhinolaryngol Relat Spec. 2004;66(6):332-40.
Li YG, Wang ZP, Tian JQ, Tian BQ, Rodrigues R, Shang PF, Zhang T. Dendritic cell transfected with secondary lymphoid-tissue chemokine and/or interleukin-2 gene-enhanced cytotoxicity of T-lymphocyte in human bladder tumor cell S in vitro. Cancer Invest. 2009 Nov;27(9):909-17.
Liu Z, You Y, Chen Z, Zou P. Measurement of the activation of IL-2 on bone marrow by flow cytometry. J Tongji Med Univ. 1999;19(4):264-6.
Mårlind J, Kaspar M, Trachsel E, Sommavilla R, Hindle S, Bacci C, Giovannoni L, Neri D. Antibody-mediated delivery of interleukin-2 to the stroma of breast cancer strongly enhances the potency of chemotherapy. Clin Cancer Res. 2008 Oct 15;14(20):6515-24.
Miller JS, Tessmer-Tuck J, Pierson BA, Weisdorf D, McGlave P, Blazar BR, Katsanis E, Verfaillie C, Lebkowski J, Radford J Jr, Burns LJ.
Low dose subcutaneous interleukin-2 after autologous transplantation generates sustained in vivo natural killer cell activity. Biol Blood Marrow Transplant. 1997 Apr;3(1):34-44.
Rosenberg SA. Immunotherapy of cancer using interleukin 2: current status and future prospects. Immunol Today. 1988 Feb;9(2):58-62.
Smith FO, Downey SG, Klapper JA, et al. Treatment of Metastatic Melanoma Using Interleukin-2 Alone or in Conjunction with Vaccines. Clinical Cancer Research September 2008 14; 5610.
Wagner K, Schulz P, Scholz A, Wiedenmann B, Menrad A. The targeted immunocytokine L19-IL2 efficiently inhibits the growth of orthotopic pancreatic cancer. Clin Cancer Res. 2008 Aug 1;14(15):4951-60.