To the Editor:
We read with great interest the article by Krause et al. (1)
. They report on the role played by activated natural killer cells in the treatment of colon and lung cancer patients. With respect to the above, we would like to inform readers of our experience with this issue.
In 1987, we found that neuropharmacological therapy was able to improve different types of cancer patients (2)
. In addition, we showed that the clinical improvement was paralleled by an increase in the cytoxicity activity of natural killer cells against the K-562 target cells (3)
. This first report was confirmed by further research published in 1989 (4)
and 1990 (5)
. All our patients were submitted to neuroautonomic and immunological investigations. Neuroautonomic research included the assessment of circulating neurotransmitters: noradrenaline, adrenaline, dopamine, platelet serotonin, and plasma serotonin. We showed that clinical severity correlated negatively with the noradrenaline/adrenaline ratio, which in our experience is associated with “uncoping stress” situation (6
, 7)
. Conversely, clinical improvement correlated positively with the noradrenaline/adrenaline ratio. According to the above, the neuropharmacological manipulations we prescribed were addressed to enhance central noradrenergic activity (8, 9, 10)
.
The above findings were also the subject of lectures in many cancer hospitals and departments (M. D. Anderson, Ohio State University, University of South Florida, Rosewell Hospital, Hospital de Buenos Aires, and others).
Up to the present, we have treated more than 2,000 advanced cancer patients, which include many types. Prostate, gastric, mammary cancer, and non-Hodgkin’s lymphoma patients were shown to obtain maximal improvement by our neuropharmacological therapy. Our long experience dealing with this issue has been summarized in our recently published book (11)
.
References
- ↵
Krause SW, Gastpar R, Andreesen R, et al Treatment of colon and lung cancer patients with ex vivo heat shock protein 70-peptide-activated, autologous natural killer cells: a clinical phase I trial. Clin Cancer Res 2004;10:3699-707.
- ↵
Lechin F, van der Dijs B, Azocar J, et al Stress, immunology and cancer: effect of psychoactive drugs. Arch Ven Farm Clin Terap 1987;6:28-43.
- ↵
Lechin F, van der Dijs B, Jakubowicz D, et al Role of stress in the exacerbation of chronic illness. Effects of clonidine administration on blood pressure, nor-epinephrine, cortisol, growth hormone and prolactin plasma levels. Psychoneuroendocrinology 1987;12:117-29.
- ↵
Lechin F, van der Dijs B, Lechin S, Vitelli G, Lechin ME, Cabrera A. Neurochemical, hormonal and immunological views of stress: clinical and therapeutic implications in Crohn’s disease and cancer Velazco M eds. . Recent advances in pharmacology and therapeutics. International Congress Series 1989;volume 839:p. 57-70. Excerpta Medica Amsterdam
- ↵
Lechin F, van der Dijs B, Vitelli G, et al Psychoneuroendocrinological and immunological parameters in cancer patients: involvement of stress and depression. Psychoneuroendocrinology 1990;15:435-51.
- ↵
Lechin F, van der Dijs B, Lechin AE, et al Plasma neurotransmitters and cortisol in chronic illness: role of stress. J Med 1994;25:181-92.
- ↵
Lechin F, van der Dijs B, Lechin M. Plasma neurotransmitters and functional illness (review). Psychother Psychosom 1996;65:293-318.
- ↵
Lechin F, van der Dijs B, Orozco B, et al Plasma neurotransmitters, blood pressure and heart rate during supine-resting, orthostasis and moderate exercise stress test in healthy humans before and after parasympathetic blockade with atropine. Res Comm Biol Psychol Psychiatry 1996;21:55-72.
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Lechin F, van der Dijs B, Orozco B, Jahn E, Rodriguez S, Baez S. Neuropharmacological treatment of refractory idiopathic thrombocytopenic purpura: roles of circulating catecholamines and serotonin. Thromb Haemost 2004;91:1254-6.
- ↵
Lechin F, van der Dijs B, Pardey-Maldonado B, et al Enhancement of noradrenergic neural transmission: an effective therapy of myasthenia gravis. Report of 52 consecutive patients. J Med 2000;31:333-61.
- ↵
Lechin F, van der Dijs B, Lechin ME. Illustrations of some therapeutic results Lechin F van der Dijs B Lechin ME eds. . Neurocircuitry and neuroautonomic disorders: reviews and strategies of therapy 2002p. 75-94. S. Karger AG Basel
In Response:
We want to thank Dr. Fuad Lechin for his comments about the impact of natural killer (NK) cells in different tumor types including prostate, gastric, mammary and non-Hodgkin lymphoma. His finding that clinical improvement correlated with an increased cytotoxicity against K562 cells, a classical NK target cell line, is of major interest and further confirmed our hypothesis that Hsp70 plasma membrane expression serves as a tumor-specific, stress-inducible recognition site for NK cells. Screening of more than 800 different tumor samples and corresponding normal tissues including lung, colorectal, stomach, pancreas, mammary, head and neck cancers, and leukemic blasts revealed that Hsp70 membrane localization was frequently detected on human tumors (50–80% of the cases) but never on normal tissues (refs. 1
and 2
; Gabriele Multhoff, Lydia Rossbacher, Mathias Gelermann unpublished observation). Also K562 cells present Hsp70 on their plasma membrane (3)
. This Hsp70 membrane expression could be further enhanced by exogenous stress induced by chemotherapy (4
, 5)
. High Hsp70 levels have been found to exert dual functions: i.e., on the one hand, they mediate protection against chemotherapy-induced effects (6)
; on the other hand, they serve as a danger signal for NK cells (7)
. Incubation of NK cells with the Hsp70-derived peptide “TKD” (TKDNNLLGRFELSG, amino acid 450–463), mimicking the danger signal, was able to enhance the cytolytic and migratory capacity of NK cells toward Hsp70 membrane-positive tumor cells (8)
. Granzyme B could be identified as the effector protease inducing programmed cell death in Hsp70 membrane-positive tumor cells (9)
. After reinfusion of ex vivo Hsp70-activated autologous NK cells in tumor patients, granzyme B serum levels were found to be elevated (10)
. Furthermore, Hsp70 but neither Hsp60 nor Hsp65 antibody levels in the serum also seemed to be affected. The prognostic value of these serum parameters and the clinical efficacy of “TKD”-activated NK cells will be addressed in a multicenter clinical phase II trial in the near future.
Acknowledgments
Sponsored by EU-TRANS-EUROPE Grant QLK3-CT-2002–1936
References
- ↵
Multhoff G, Botzler C, Wiesnet M, et al A stress-inducible 72 kDa heat shock protein is expressed on the cell surface of human tumor cells but not on normal cells. Int J Cancer 1995;61:272-9.
- ↵
Hantschel M, Pfister K, Jordan A, et al Hsp70 plasma membrane expression on primary tumor biopsy material and bone marrow of leukemic patients. Cell Stress Chaperones 2000;5:438-42.
- ↵
Gehrmann M, Pfister K, Hutzler P, et al Effects of anti-neoplastic agents on cytoplasmic and membrane-bound Hsp70 levels. Biol Chem 2002;383:1715-25.
- ↵
Gehrmann M, Brunner M, Pfister K, et al Differential up-regulation of cytosolic and membrane-bound Hsp70 in tumors by anti-inflammatory drugs. Clin Cancer Res 2004;10:3354-64.
- ↵
Botzler C, Ellwart J, Günther W, et al Synergistic effects of ET-18-OCH3 on membrane expression of Hsp70 and lysis of leukemic K562 cells. Exp Hematol 1999;27:470-8.
- ↵
Nylandsted J, Gyrd-Hansen M, Danielewicz A, et al Heat shock protein 70 promotes cell survival by inhibiting lysosomal membrane permeabilization. J Exp Med 2004;200:425-35.
- ↵
Gastpar R, Gross C, Rossbacher L, et al Soluble Hsp70-peptide induces both, migration and cytolytic activity in CD3-CD94+CD56+ NK cells. J Immunol 2004;172:972-80.
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Multhoff G, Pfister K, Gehrmann M, et al A 14-mer Hsp70 peptide stimulates NK cell activity. Cell Stress Chaperones 2001;6:337-44.
- ↵
Gross C, Koelch W, Arispe N, et al Cell surface-bound Hsp70 mediates perforin-independent apoptosis by specific binding and uptake of granzyme B. J Biol Chem 2003;17:41173-81.
- ↵
Krause S, Gastpar R, Andreesen R, et al Treatment of cancer patients with autologous ex vivo Hsp70-peptide activated NK cells. A clinical phase I trial. Clin Cancer Res 2004;10:3699-707.
