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Journal of Clinical Oncology, Vol 23, No 16 (June 1), 2005: pp. 3865-3866 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.148
Gefitinib Has the Potential of Activating Cell Immunity Against Malignant CellsFirst Department of Internal Medicine, Kansai Medical University, Osaka, Japan To the Editor: We read with interest the recent correspondence about gefitinib by Normanno et al. They concluded that it is evident that the complex interactions existing between the receptors of the ErbB family and the occurrence of molecular alternations that might activate proliferating/survival pathways that are independent from the epidermal growth factor receptor (EGFR) make it difficult to find a single molecular marker that might predict for sensitivity or resistance to an anti-EGFR agent such as gefitinib.1 Cappuzzo et al reported that efficacy, toxicity, and symptom outcome in patients with non–small-cell lung cancer treated with gefitinib do not seem to be related to HER2 expression.2 In addition, there has previously been no report supporting the correlation between gefitinib and EGF. Incidentally, recently we reported that thromboxan B2 increased in patients receiving treatment with gefitinib and platelet agglutination was reduced by the EGF.3 Thromboxan B2 is a metabolite of thromboxan A2.3 In Japan, acute lung injury, including interstitial pneumonia and alveolar hemorrhage, has occasionally been reported as a severe adverse reaction in patients receiving gefitinib therapy.4 We think that gefitinib possesses action mechanisms of activating platelets and measured plasma concentrations of soluble P-selectin and E-selectin in patients treated with gefitinib. To our surprise, the concentration of P-selectin and E-selectin significantly increased two weeks after receiving gefitinib. (P-selectin: 265 ± 92 v 351 ± 177; P < .05; n = 19; E-selectin: 121 ± 51 v 139 ± 67; P < .05; n = 19) In other words, platelets seem to have been activated by the administration of gefitinib. It has been reported that activated platelets can release regulated on activation, normal T cells expressed and secreted (RANTES)5 and that activated platelets regulate chemokine secretion by monocytes in the inflammatory lesion.6 It is our view that gefitinib enhances platelet activation and RANTES is released from the activated platelets; and lymphocyte migration is induced at the focal tissue and monocytes are activated; and several immune responses to tumor cells are activated at the focal tissue. We conclude that the clinical efficacy of gefitinib therapy may be brought about in the following fashion. First, angiogenesis is reduced via blockade of EGFR and then causing tumor necrosis. On the other hand, lymphocytes and monocytes are activated by activated platelet and cell immunity against tumor is raised. Our clinical results and also the in vitro findings by Normanno et al suggest that the actional mechanism of gefitinib does not always depend on the EOF alone, and some vital reaction seems to be implicated in that actional mechanism. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Normanno N, Di Maio M, Perrone F: Molecular markers to predict response to gefitinib: EGFR, ErbB2, or more? J Clin Oncol 22:2035-2036, 2004
2. Cappuzzo F, Gregorc V, Rossi E, et al: Gefitinib in pretreated non-small-cell lung cancer (NSCLC): Analysis of efficacy and correlation with HER2 and epidermal growth factor receptor expression in locally advanced or metastatic NSCLC. J Clin Oncol 21:2658-2663, 2003 3. Kanazawa S, Yamaguchi K, Kinoshita Y, et al: Gefinitib affects functions of platelets and blood vessels via changes in the prostanoids balance. Clin Applied Thromb/Hemostas, 2005 (in press) 4. Okamoto I, Fujii K, Matsumoto M, et al: Diffuse alveolar damage after ZD1839 therapy in a patient with non-small cell lung cancer. Lung Cancer 40:339-342, 2003[CrossRef][Medline]
5. Kameyoshi Y, Dorschner A, Mallet AI, et al: Cytokine RANTES released by thrombin-stimulated platelets is a potent attractant for human eosinophils. J Exp Med 176:587-592, 1992 6. Weyrich AS, Elstad MR, McEver RP, et al: Activated platelets signal chemokine synthesis by human monocytes. J Clin Invest 97:1525-1534, 1996[Medline]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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