Natural Killer Cell (NKC) Activation Through the Issels Immunotherapy Protocol
by Walter H. Kim, Christian N. Issels
Issels Medical Center, Santa Barbara, California
Published June 30, 2009
Background: Immunotherapy for cancers is based on the principle that the host's immune system is capable of generating immune responses against tumor specific antigens. Of particular interest is the role of Natural Killer Cells (NKC), which are able to eliminate solid tumors and metastatic cells in the circulation through their cytotoxicity and cytokine production. 1 Modern cancer treatment strategy calls for integration of innovative non-toxic treatment regimens.
Methods: A retrospective analysis of NKC counts included 129 cancer patients with pathologic confirmation of disease who underwent the Issels Treatment program. Stage classification included: Stage I (5 patients), Stage II (15 patients), Stage III (11 patients), Stage IV (98 patients). Tumor types included: 42 breast, 18 colorectal, 6 lung, 9 ovarian, 14 prostate, 8 head and neck, 2 cholangiocarcinoma, 3 uterine, 1 brain, 3 thyroid, 1 testicular, 8 sarcoma, 3 urinary tract, 2 cervical, 2 gastroesophageal, 5 pancreatic. NKC levels were obtained on day 1 prior to start of the Issels treatments and upon completion of the 3-week intensive initiation of the Issels program.
Individualized proprietary treatment protocols consisted of: immunostimulants; autohemotherapy; intravenous high dose Vitamin C as a pro-oxidant 2,3,4; intravenous high dose nutritionals including enzymes, vitamins, antioxidants, amino acids, minerals, electrolytes; pleomorphic and homeopathic remedies; phytotherapy, hyperbaric oxygen chamber; far-infrared sauna; psychological counseling; acupuncture; massage; acid-alkaline balance diet; extensive oral supplementation, detoxification strategies 5; lifestyle/dietary modification.
Results: Statistical analysis of NKC response to Issels Treatment protocol revealed an average 48% increase in absolute NKC levels per patient in approximately three weeks.
Conclusion: The Issels Treatment protocol has shown statistically significant overall improvement in NKC levels following three weeks of intensive treatment which supports the premise that the anti tumor immunotherapy approach is beneficial to overall survival and quality of life.
The incidence of cancer is increasing at a dramatic rate worldwide. Many patients present with early-stage disease that is potentially curable with high success rates 6. However, the prognosis for patients with more advanced disease with involvement of regional lymph nodes or distant metastasis is poor. Current available treatments for cancer patients are limited. In patients with metastatic disease, chemotherapy, biologic therapy, and combination biochemotherapy have generally yielded low response rates. 7,8,9,10,11
One approach that holds promise is immune therapy. Of particular interest is the role of Natural Killer (NK) Cells which are able to eliminate metastatic cells in the circulation through their cytotoxicity and cytokine production 1. NK-Cells are also important mediators of anti-tumor immunity. This is clearly displayed in transgenic mice with severely decreased levels of NK Cells. Such mice have decreased resistance to B16 experimental lung metastases and RMA tumor outgrowth. Furthermore, protection from the development of carcinogen-induced tumors is dependent on NK Cells. 12
NK Cells use a large number of receptors to identify potential target cells. The highly polymorphic nature of NK Cell receptors for Class I molecules (KIR or Ly49) may provide a genetic explanation for why some mouse strains or human individuals are resistant or susceptible to various diseases.
NK-Cell responses toward tumor cells are controlled in part by expression of receptors for ligands often expressed on tumor cells such as the MIC/Rae1 stress-induced molecules recognized by the NKG 2D surface receptor. Also, the frequently observed reduction of class I major histocompatibility complex (MHC) expression on tumors confers susceptibility to NK Cell lysis. Normal class Ia and Ib MHC expression is thought to result in NK-Cell tolerance through inhibitory class I MHC receptors such as KIR, Ly49, and NKG2A. Finally, analogous to HIV infection, patients with cancer have decreased NK function as measured by cytotoxicity, production of cytokines, and proliferation. 14,15
NK Cells mediate their protective effect in 2 ways: cytotoxicity and cytokine production. Cytotoxicity in NK Cells (and cytotoxic T lymphocytes) is carried out by granule exocytosis of membrane pore-forming molecules (perforin) and proteases (granzymes) or death ligand interactions (FasL and TRAIL). Upon target-cell binding, NK Cells will also produce large amounts of cytokines, such as interferon (IFN) g, TNF, and granulocyte-macrophage colony-stimulating factor. Natural and induced mutations of cytokine (IFN-g and IL-2/IL-15Rb) and cytotoxicity-associated genes (perforin, granzyme A and B, FasL) that are expressed by NK Cells also negatively affect antiviral responses and the rejection of tumors 13.
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