Lymphokine activated killer cells

Harker, W.G., et al., Human tumor cell line resistance to chemotherapeutic agents does not predict resistance to natural killer or lymphokine-activated killer cell-mediated cytolysis, Cancer. Res. 50, 18, 5931, 1990. 

Merluzzi, VJ. (1985). Comparison of murine lymphokine, activated killer cells, natural killer cells, and cytotoxic T lymphocytes. Cell Immunol. 95 95-104. 

M. M. Corsi, H. H. Maes, K. Wasserman, A. Fulgenzi, G. Gaja, M. E. Ferrero, Protection by L-2-Oxothiazohdine-4-carboxyhc Acid of Hydrogen Peroxide-Induced CD3 and CD 162 Chain Down-Regulation in Human Peripheral Blood Lymphocytes and Lymphokine-Activated Killer Cells , Biochem. Pharmacol. 1998, 56, 657 - 662. 

Apoptosis can be induced or prevented through different pathways (TNFa-induced, Fas-induced, TRAIL-induced). In lymphokine-activated killer cells Fas-mediated cytotoxicity could be dissociated from perforin-mediated cytotoxicity by their different requirement of TPA-sensitive PKC... 

O Driscoll KR, Teng KK, Fabbro D, Greene LA, Weinstein IB (1995) Selective translocation of protein kinase C-delta in PC12 cells during nerve growth factor-induced neuritogenesis. Mol Biol Cell 6 449-458 Ohmi Y, Ohta A, Sasakura Y, Sato N, Yahata T, Santa K, Habu S, Nishimura T (1997) The role of phorbol ester-sensitive protein kinase C isoforms in lymphokine-activated killer cell-mediated cytotoxicity dissociation between perforin-dependent and Fas-dependent c otoxicity. Biochem Biophys Res Commun 235 461-464... 

A third biological activity of IL-2 pertinent to immunostimulation is its ability to promote the growth of natural killer (NK) cells. It also promotes further dilferentiation of NK cells, forming lymphokine-activated killer cells (LAKs), which exhibit an enhanced ability to directly kill tumour cells or virally infected cells. NK cells express the /I and y IL-2 receptor subunits only, thus their stimulation by IL-2 requires elevated concentrations of this cytokine. NK cells are also activated by a variety of additional cytokines, including all IFNs as well as tumour necrosis factor (TNF). 

Several proteins that stimulate subsets of lymphocytes involved in various aspects of the immune response are now produced by recombinant DNA techniques. The pharmacology of these lymphokines as potential anticancer agents is being investigated. Interleukin (IL) 2, originally described as a T-cell growth factor, induces the production of cytotoxic lymphocytes (lymphokine-activated killer cells, or LAK cells). IL-2 produces remissions in 10 to 20% of patients with melanoma or renal cell carcinoma when infused at high doses either alone or with lymphocytes that were previously harvested from the patient and incubated with IL-2 in vitro. 

HCF, hematopoietic cofactor LAK, lymphokine-activated killer cell. 

Cell transfer therapy is a new approach to strengthening the innate ability of the immune system to fight against cancer (Figure 51.2). In this therapy, lymphocytes are isolated and cultured with interleukin-2 for 3 d to yield lymphokine-activated killer cells, which are then administered to patients along with interleukin-2. 

FIGURE 51.2 Cell transfer therapy with lymphokine-activated killer cells. 

IGIV Immunoglobulin intravenous LAK cell Lymphokine-activated killer cell LFA Lymphocyte functional antigen MAb Monoclonal antibody MHC Major histocompatibility complex MCP-1 Macrophage chemotactic protein-1 MIP-1 Macrophage inflammatory protein-1 NK cell Natural killer cell... 

Combination of low doses of cyclophosphamide, E. purpurea extract (Echinacin ) and thymostimulin enhanced the immune functions of terminally ill cancer patients (Lersch et al., 1990, 1992). NK cells increased between 17 and 29% whereas lymphokine activated killer cell activity increased from 180 to 195%. In contrast, polysaccharides isolated from cell cultures of E. purpurea did not enhance the phagocytic activity of granulocytes in chemotherapy patients (Melchart et al., 2002). 

Meresse B, Chen Z, Ciszewski C, Tretiakova M, Bhagat G, Krausz TN, et al. Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity 2004 21 357-366. 

Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA. Lymphokine-activated killer cell phenomenon lysis of natural killer resistant fresh solid tumor cells by interleukin-2 activated autologous human peripheral blood lymphocytes. J Exp Med 1982 155 1823-41. 

Rosenberg S. Lymphokine activated killer cells a new approach to the immunotherapy of cancer. J Cancer Inst 1985 75 595-603. 

Rosenberg SA, Lotze MT, Muul LM, Leitman S, Chang AE, Ettinghausen SE, Matory YL, Skibber JM, Shiloni E, Vetto JT, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 1985 313 1485-92. 

Bar MH, Snzol M, Atkins MB, et al. Metastatic malignant melanoma treated with combined bolus and continuous infusion interleukin-2 and lymphokine activated killer cells. J Clin Oncol 1990 8 1138-47. 

Denicoff KD, Rubinow DR, Papa MZ, Simpson C, Seipp CA, Lotze MT, Chang AE, Rosenstein D, Rosenberg SA. The neuropsychiatric effects of treatment with interleukin-2 and lymphokine-activated killer cells. Ann Intern Med 1987 107(3) 293-300. 

Kinase insert domain-containing receptor KDR is the hnman homolog of the monse FLK-1 receptor the KDR and FLK-1 receptors are also known asVEGFR2 seeVEGFR Mast/stem cell growth factor receptor, CD 117 Retroviral oncogene derived from HZ4 feline sarcoma Kruppel-like factor 5, a transcription factor Lymphokine-activated killer cells Linear-after-the-exponential-PCR Luria-Bertani... 

IL-2 is a lymphokine produced by activated helper T-lympho-cytes. It induces the proliferation of T cells and promotes the differentiation of lymphocytes into cytotoxic cells. IL-2 also induces interferon gamma production (Lewko and Oldham, 2003). Activation of peripheral leukocytes with the drug produces lymphokine-activated killer cells (LAK) that lyse a variety of tumor cells in vitro. IL-2 has been cloned in bacteria through recombinant DNA technology, thus allowing the production of large amounts. IL-2 alone or with LAK cells can cause regression of several established metastatic tumors in animals (Lewko and Oldham, 2003 Dorr, 1993). 

Law TM, Motzer RJ, Mazumdar M, Sell KW, Walther PJ, O Connell M, Khan A, Vlamis V, Vogelzang NJ, Bajorin DF. Phase III randomized trial of interleukin-2 with or without lymphokine-activated killer cells in the treatment of patients with advanced renal cell carcinoma. Cancer 1995 76(5) 824-32. 

Kung AW, Lai CL, Wong KL, Tam CF. Thyroid functions in patients treated with interleukin-2 and lymphokine-activated killer cells. Q J Med 1992 82(297) 33 2. 

Marcus SL, Dutcher JP, Paietta E, Ciobanu N, Strauman J, Wiernik PH, Hutner SH, Frank O, Baker H. Severe hypo-vitaminosis C occurring as the result of adoptive immunotherapy with high-dose interleukin 2 and lymphokine-activated killer cells. Cancer Res 1987 47(15) 4208-12. 

Feinfeld DA, D Agati V, Dutcher JP, Werfel SB, Lynn RI, Wiernik PH. Interstitial nephritis in a patient receiving adoptive immunotherapy with recombinant interleukin-2 and lymphokine-activated killer cells. Am J Nephrol 1991 ll(6) 489-92. 

Bryostatin 1 binds to the regulatory domain of protein kinase C short-term exposure promotes activation of protein kinase C, whereas prolonged exposure promotes significant down-regulation (4). In preclinical and phase I clinical studies it had promising antitumor and immuno-modulating effects. It amplifies expansion of myeloid and erythroid progenitor cells stimulated by the cytokines GM-CSF, M-CSF, and IL-3. Similarly, it induces the production of peripheral blood mononuclear cells with enhanced lymphokine-activated killer cell activity and proliferation in the presence of IL-2 (5). 

Rozenberg SA, Lotze MT et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokine activated killer cells and Interleukine 2 or high dose interleukine 2alone. N ehg J Med. 1987,316,889-897. 

Thompson JA, Shulman KL, Benyunes MC, Lindgren CG, Collins C, Lange PH, Bush WH Jr, Benz LA, Fefer A. Prolonged continuous intravenous infusion interleukin-2 and lymphokine activated killer cell therapy for metastatic renal cell carcinoma. J Clin Oncol 1992,10 960-968. 

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