Intraperitoneal injection of in vitro expanded Vγ9Vδ2 T cells together with zoledronate for the treatment of malignant ascites due to gastric cancer
Ikuo Wada, Hirokazu Matsushita, Shuichi Noji, Kazuhiko Mori, Hiroharu Yamashita, Sachiyo Nomura, Nobuyuki Shimizu, Yasuyuki Seto, Kazuhiro Kakimi, Ikuo Wada, Hirokazu Matsushita, Shuichi Noji, Kazuhiko Mori, Hiroharu Yamashita, Sachiyo Nomura, Nobuyuki Shimizu, Yasuyuki Seto, Kazuhiro Kakimi
Abstract
Malignant ascites caused by peritoneal dissemination of gastric cancer is chemotherapy-resistant and associated with poor prognosis. We conducted a pilot study to evaluate the safety of weekly intraperitoneal injections of in vitro expanded Vγ9Vδ2 T cells together with zoledronate for the treatment of such malignant ascites. Patient peripheral blood mononuclear cells were stimulated with zoledronate (5 μmol/L) and interleukin-2 (1000 IU/mL). After 14 days culture, Vγ9Vδ2 T-cells were harvested and administered intraperitoneally in four weekly infusions. The day before T-cell injection, patients received zoledronate (1 mg) to sensitize their tumor cells to Vγ9Vδ2 T-cell recognition. Seven patients were enrolled in this study. The number of Vγ9Vδ2 T-cells in each injection ranged from 0.6 to 69.8 × 10(8) (median 59.0 × 10(8)). There were no severe adverse events related to the therapy. Intraperitoneal injection of Vγ9Vδ2 T cells allows them access to the tumor cells in the peritoneal cavity. The number of tumor cells in the ascites was significantly reduced even after the first round of therapy and remained substantially lower over the course of treatment. IFN-γ was detected in the ascites on treatment. Computed tomography revealed a significant reduction in volume of ascites in two of seven patients. Thus, injection of these antitumor Vγ9Vδ2 T-cells can result in local control of malignant ascites in patients for whom no standard therapy apart from paracentesis is available. Adoptively transferred Vγ9Vδ2 T-cells do indeed recognize tumor cells and exert antitumor effector activity in vivo, when they access to the tumor cells.
Keywords: Gastric cancer; Vγ9Vδ2 T-cell; malignant ascites; peritoneal dissemination; zoledronate.
© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
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References
- Hayday AC. γδ cells: a right time and a right place for a conserved third way of protection. Annu. Rev. Immunol. 2000;18:975–1026.
- Carding SR, Egan PJ. γδ T cells: functional plasticity and heterogeneity. Nat. Rev. Immunol. 2002;2:336–345.
- Triebel F, Hercend T. Subpopulations of human peripheral T γδ lymphocytes. Immunol. Today. 1989;10:186–188.
- Bonneville M, Scotet E. Human Vgamma9Vdelta2 T cells: promising new leads for immunotherapy of infections and tumors. Curr. Opin. Immunol. 2006;18:539–546.
- Riganti C, Massaia M, Davey MS, Eberl M. Human gammadelta T-cell responses in infection and immunotherapy: common mechanisms, common mediators? Eur. J. Immunol. 2012;42:1668–1676.
- Wilhelm M, Kunzmann V, Eckstein S, Reimer P, Weissinger F, Ruediger T, et al. γδ T cells for immune therapy of patients with lymphoid malignancies. Blood. 2003;102:200–206.
- Dieli F, Vermijlen D, Fulfaro F, Caccamo N, Meraviglia S, Cicero G, et al. Targeting human γδ T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer. Cancer Res. 2007;67:7450–7457.
- Bennouna J, Bompas E, Neidhardt EM, Rolland F, Philip I, Galea C, et al. Phase-I study of Innacell gammadelta, an autologous cell-therapy product highly enriched in gamma9delta2 T lymphocytes, in combination with IL-2, in patients with metastatic renal cell carcinoma. Cancer Immunol. Immunother. 2008;57:1599–1609.
- Kobayashi H, Tanaka Y, Yagi J, Minato N, Tanabe K. Phase I/II study of adoptive transfer of gammadelta T cells in combination with zoledronic acid and IL-2 to patients with advanced renal cell carcinoma. Cancer Immunol. Immunother. 2011;60:1075–1084.
- Kondo M, Sakuta K, Noguchi A, Ariyoshi N, Sato K, Sato S, et al. Zoledronate facilitates large-scale ex vivo expansion of functional gammadelta T cells from cancer patients for use in adoptive immunotherapy. Cytotherapy. 2008;10:842–856.
- Sato K, Kondo M, Sakuta K, Hosoi A, Noji S, Sugiura M, et al. Impact of culture medium on the expansion of T cells for immunotherapy. Cytotherapy. 2009;11:936–946.
- Nakajima J, Murakawa T, Fukami T, Goto S, Kaneko T, Yoshida Y, et al. A phase I study of adoptive immunotherapy for recurrent non-small-cell lung cancer patients with autologous γδ T cells. Eur. J. Cardiothorac. Surg. 2010;37:1191–1197.
- Sakamoto M, Nakajima J, Murakawa T, Fukami T, Yoshida Y, Murayama T, et al. Adoptive immunotherapy for advanced non-small cell lung cancer using zoledronate-expanded gammadeltaTcells: a phase I clinical study. J. Immunother. 2011;34:202–211.
- Dupont JB, Jr, Lee JR, Burton GR, Cohn I., Jr Adenocarcinoma of the stomach: review of 1,497 cases. Cancer. 1978;41:941–947.
- Cavazzoni E, Bugiantella W, Graziosi L, Franceschini M, Donini A. Malignant ascites: pathophysiology and treatment. Int. J. Clin. Oncol. 2013;18:1–9.
- Imamoto H, Oba K, Sakamoto J, Iishi H, Narahara H, Yumiba T, et al. Assessing clinical benefit response in the treatment of gastric malignant ascites with non-measurable lesions: a multicenter phase II trial of paclitaxel for malignant ascites secondary to advanced/recurrent gastric cancer. Gastric Cancer. 2011;14:81–90.
- Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, et al. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 2008;9:215–221.
- Lenz HJ, Lee FC, Haller DG, Singh D, Benson AB, III, Strumberg D, et al. Extended safety and efficacy data on S-1 plus cisplatin in patients with untreated, advanced gastric carcinoma in a multicenter phase II study. Cancer. 2007;109:33–40.
- Ishigami H, Kitayama J, Kaisaki S, Hidemura A, Kato M, Otani K, et al. Phase II study of weekly intravenous and intraperitoneal paclitaxel combined with S-1 for advanced gastric cancer with peritoneal metastasis. Ann. Oncol. 2010;21:67–70.
- Heiss MM, Murawa P, Koralewski P, Kutarska E, Kolesnik OO, Ivanchenko VV, et al. The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: results of a prospective randomized phase II/III trial. Int. J. Cancer. 2010;127:2209–2221.
- Glimelius B, Hoffman K, Haglund U, Nyren O, Sjoden PO. Initial or delayed chemotherapy with best supportive care in advanced gastric cancer. Ann. Oncol. 1994;5:189–190.
- Pyrhonen S, Kuitunen T, Nyandoto P, Kouri M. Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Br. J. Cancer. 1995;71:587–591.
- Kang JH, Lee SI, Lim DH, Park K-W, Oh SY, Kwon H-C, et al. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J. Clin. Oncol. 2012;30:1513–1518.
- Gober HJ, Kistowska M, Angman L, Jeno P, Mori L, De Libero G. Human T cell receptor gammadelta cells recognize endogenous mevalonate metabolites in tumor cells. J. Exp. Med. 2003;197:163–168.
- Clézardin P. Bisphosphonates' antitumor activity: an unravelled side of a multifaceted drug class. Bone. 2011;48:71–79.
- Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer. 2011;14:101–112.
- Kondo M, Izumi T, Fujieda N, Kondo A, Morishita T, Matsushita H, et al. Expansion of human peripheral blood gammadelta T cells using zoledronate. J. Vis. Exp. 2011:e3182. doi: .
- Izumi T, Kondo M, Takahashi T, Fujieda N, Kondo A, Tamura N, et al. Ex vivo characterization of gammadelta T-cell repertoire in patients after adoptive transfer of Vgamma9Vdelta2 T cells expressing the interleukin-2 receptor beta-chain and the common gamma-chain. Cytotherapy. 2013;15:481–491.
- Fischer K, Andreesen R, Mackensen A. An improved flow cytometric assay for the determination of cytotoxic T lymphocyte activity. J. Immunol. Methods. 2002;259:159–169.
- Idrees ASM, Sugie T, Inoue C, Murata-Hirai K, Okamura H, Morita CT, et al. Comparison of γδ T cell responses and farnesyl diphosphate synthase inhibition in tumor cells pretreated with zoledronic acid. Cancer Sci. 2013;104:536–542.
- Chen T, Berenson J, Vescio R, Swift R, Gilchick A, Goodin S, et al. Pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with bone metastases. J. Clin. Pharmacol. 2002;42:1228–1236.
- Kunzmann V, Bauer E, Feurle J, Weissinger F, Tony HP, Wilhelm M. Stimulation of gammadelta T cells by aminobisphosphonates and induction of antiplasma cell activity in multiple myeloma. Blood. 2000;96:384–392.
- Roelofs AJ, Jauhiainen M, Monkkonen H, Rogers MJ, Monkkonen J, Thompson K. Peripheral blood monocytes are responsible for gammadelta T cell activation induced by zoledronic acid through accumulation of IPP/DMAPP. Br. J. Haematol. 2009;144:245–250.
- Monkkonen H, Auriola S, Lehenkari P, Kellinsalmi M, Hassinen IE, Vepsalainen J, et al. A new endogenous ATP analog (ApppI) inhibits the mitochondrial adenine nucleotide translocase (ANT) and is responsible for the apoptosis induced by nitrogen-containing bisphosphonates. Br. J. Pharmacol. 2006;147:437–445.
- Benzaid I, Monkkonen H, Stresing V, Bonnelye E, Green J, Monkkonen J, et al. High phosphoantigen levels in bisphosphonate-treated human breast tumors promote Vgamma9Vdelta2 T-cell chemotaxis and cytotoxicity in vivo. Cancer Res. 2011;71:4562–4572.
- Ismaili J, Olislagers V, Poupot R, Fournie JJ, Goldman M. Human gamma delta T cells induce dendritic cell maturation. Clin. Immunol. 2002;103:296–302.
- Brandes M, Willimann K, Lang AB, Nam KH, Jin C, Brenner MB, et al. Flexible migration program regulates gamma delta T-cell involvement in humoral immunity. Blood. 2003;102:3693–3701.
- Poccia F, Gougeon ML, Agrati C, Montesano C, Martini F, Pauza CD, et al. Innate T-cell immunity in HIV infection: the role of Vgamma9Vdelta2 T lymphocytes. Curr. Mol. Med. 2002;2:769–781.
- Norton JT, Hayashi T, Crain B, Cho JS, Miller LS, Corr M, et al. Cutting edge: nitrogen bisphosphonate-induced inflammation is dependent upon mast cells and IL-1. J. Immunol. 2012;188:2977–2980.
- Agrati C, Cimini E, Sacchi A, Bordoni V, Gioia C, Casetti R, et al. Activated Vγ9Vδ2 T cells trigger granulocyte functions via MCP-2 release. J. Immunol. 2009;182:522–529.
- Caccamo N, Orlando C, La Mendola V, Meraviglia S, Todaro M, Stassi G, et al. Differentiation, phenotype, and function of interleukin-17-producing human Vγ9Vδ2 T cells. Blood. 2011;118:129–138.
- Yamao T, Shimada Y, Shirao K, Ohtsu A, Ikeda N, Hyodo I, et al. Phase II study of sequential methotrexate and 5-fluorouracil chemotherapy against peritoneally disseminated gastric cancer with malignant ascites: a report from the Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group, JCOG 9603 Trial. Jpn. J. Clin. Oncol. 2004;34:316–322.
- Oh SY, Kwon HC, Lee S, Lee DM, Yoo HS, Kim SH, et al. A phase II study of oxaliplatin with low-dose leucovorin and bolus and continuous infusion 5-fluorouracil (modified FOLFOX-4) for gastric cancer patients with malignant ascites. Jpn. J. Clin. Oncol. 2007;37:930–935.
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