Phase I/II study of adoptive transfer of γδ T cells in combination with zoledronic acid and IL-2 to patients with advanced renal cell carcinoma
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Human Vγ2 Vδ2-bearing T cells have recently received much attention in cancer immunotherapy. In this study, we conducted a phase I/II clinical trial of the adoptive transfer of γδ T cells to patients with advanced renal cell carcinoma. Eleven patients who had undergone nephrectomy and had lung metastasis were enrolled. Peripheral blood γδ T cells obtained from the patients were stimulated ex vivo with 2-methyl-3-butenyl-1-pyrophosphate (2M3B1PP), a synthetic pyrophosphomonoester antigen, and transferred in combination with zoledronic acid (Zol) and teceleukin (recombinant human interleukin-2). Expanded γδ T cells exhibited potent cytotoxic activity against tumor cells in vitro, and the proportion of peripheral blood γδ T cells among CD3+ cells typically peaked three to 5 days after transfer. Tumor doubling time was prolonged in all 11 patients, and the best overall responses were 1 CR, 5 SD, and 5 PD, as defined based on Response Evaluation Criteria in Solid Tumors (RECIST). Although ten patients developed adverse reactions of grade ≥3, they were likely to have been the result of the concomitant infusion of Zol and IL-2, and most symptoms swiftly reverted to normal during the course of treatment. In conclusion, this clinical trial demonstrated that our regimen for the adoptive transfer of γδ T cells in combination with Zol and IL-2 was well tolerated and that objective clinical responses could be achieved in some patients with advanced renal cell carcinoma.
Keywordsγδ T cell Nitrogen-containing bisphosphonate Pyrophosphomonoester Isopentenyl pyrophosphate Renal cell carcinoma Cancer immunotherapy
This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Culture, Sports, and Technology of Japan (MEXT) and by Special Coordination Funds for Promoting Science and Technology from MEXT and Astellas Pharma Inc. as part of the “Formation of Innovation Center for Fusion of Advanced Technologies” program. The authors wish to acknowledge the support provided by the staff from the Translational Research Informatics Center (TRI), Kobe, Hyogo, Japan, and would like to thank Ms Clare Dover for providing English correction prior to paper submission.
- 14.Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE, Szubert AJ, Navarro-Coy N, Drayson MT, Owen RG, Feyler S, Ashcroft AJ, Ross F, Byrne J, Roddie H, Rudin C, Cook G, Jackson GH, Child JA, On behalf of the National Cancer Research Institute Haematological Oncology Clinical Study Group (2010) First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet 376:1989–1999PubMedCrossRefGoogle Scholar
- 16.Kobayashi H, Tanaka Y, Nakazawa H, Yagi J, Minato N, Tanabe K (2011) A new indicator of a favorable progress in locally advanced renal cell carcinomas: γδ T-Cells in peripheral blood. Anticancer Res (in press)Google Scholar
- 18.Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216PubMedCrossRefGoogle Scholar
- 21.Bellmunt J (2009) Future developments in renal cell carcinoma. Ann Oncol 20(Suppl 1):113–117Google Scholar
- 23.Escudier B, Szczylik C, Hutson TF, Demkow T, Staehler M, Rolland F, Negrier S, Laferriere N, Scheuring UJ, Cella D, Shah S, Bukowski RM (2009) Randomized phase II trial of first-line treatment with sorafenib versus interferon α-2a in patients with metastatic renal cell carcinoma. J Clin Oncol 27:1280–1289PubMedCrossRefGoogle Scholar
- 30.Wilhelm M, Kunzmann V, Eckstein S, Reimer P, Weissinger F, Ruediger T, Tony HP (2003) γδ T cells for immune therapy of patients with lymphoid malignancies Blood 102:200–206Google Scholar
- 31.Dieli F, Vermijlen D, Fulfaro F, Caccamo N, Meraviglia S, Cicero G, Roberts A, Buccheri S, D’Asaro M, Gebbia N, Salerno A, Eberl M, Hayday AC (2007) Targeting human γδ T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer. Cancer Res 67:7450–7457PubMedCrossRefGoogle Scholar
- 33.Santini D, Martini F, Fratto ME, Galluzzo S, Vincenzi B, Agrati C, Turchi F, Piacentini P, Rocci L, Manavalan JS, Tonini G, Poccia F (2009) In vivo effects of zoledronic acid on peripheral γδ T lymphocytes in early breast cancer patients. Cancer Immunol Immunother 58:31–38PubMedCrossRefGoogle Scholar
- 42.Bivi N, Romanello M, Harrison R, Clarke I, Hoyle DC, Moro L, Ortolani F, Bonetti A, Quadrifoglio F, Tell G, Delneri D (2009) Identification of secondary targets of N-containing bisphosphonates in mammalian cells via parallel competition analysis of the barcoded yeast deletion collection. Genome Biol 10:R93.1–R93.11CrossRefGoogle Scholar
- 44.Eble JN, Sauter G, Epstein JI, Sesterhenn IA (eds) (2004) World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of the Urinary System and Male Genital Organs, IRAC Press, LyonGoogle Scholar