Expansion of human γδ T cells for adoptive immunotherapy using a bisphosphonate prodrug

• Published in: Cancer science Vol. 109; no. 3; pp. 587 - 599
• Main Authors: Tanaka, Yoshimasa, Murata‐Hirai, Kaoru, Iwasaki, Masashi, Matsumoto, Kenji, Hayashi, Kosuke, Kumagai, Asuka, Nada, Mohanad H., Wang, Hong, Kobayashi, Hirohito, Kamitakahara, Hiroshi, Okamura, Haruki, Sugie, Tomoharu, Minato, Nagahiro, Toi, Masakazu, Morita, Craig T.
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.03.2018; John Wiley and Sons Inc
• Subjects: adoptive cancer immunotherapy; Adoptive immunotherapy; Adoptive transfer; Animals; bisphosphonate; Bisphosphonates; Breast cancer; Breast Neoplasms - immunology; Breast Neoplasms - therapy; Cancer immunotherapy; Cancer therapies; CD25 antigen; Clinical trials; Cytotoxicity; Diphosphonates - administration & dosage; Diphosphonates - chemistry; Diphosphonates - pharmacology; farnesyl diphosphate synthase; Female; Histocompatibility antigen HLA; Humans; Immunodeficiency; Immunotherapy; Immunotherapy, Adoptive; Interferon; Inventors; Kidney cancer; Lung cancer; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Male; Melanoma; Metabolites; Metastasis; Mice; Mutation; Original; Prodrugs - administration & dosage; Prodrugs - pharmacology; Prostate cancer; Prostatic Neoplasms - immunology; Prostatic Neoplasms - therapy; Purification; Receptors, Antigen, T-Cell, gamma-delta - metabolism; T cell receptors; T-Lymphocytes - immunology; T-Lymphocytes - transplantation; Treatment Outcome; Tumor cells; Tumors; Viral infections; Vγ2Vδ2 T cells; Xenograft Model Antitumor Assays; Zoledronic acid; Japan; Vγ2Vδ2 T cells; bisphosphonate; adoptive cancer immunotherapy; farnesyl diphosphate synthase; zoledronic acid
• DOI: 10.1111/cas.13491
• ISSN: 1347-9032; 1349-7006

Cancer immunotherapy with human γδ T cells expressing Vγ2Vδ2 T cell receptor (also termed Vγ9Vδ2) has shown promise because of their ability to recognize and kill most types of tumors in a major histocombatibility complex (MHC) ‐unrestricted fashion that is independent of the number of tumor mutations. In clinical trials, adoptive transfer of Vγ2Vδ2 T cells has been shown to be safe and does not require preconditioning. In this report, we describe a method for preparing highly enriched human Vγ2Vδ2 T cells using the bisphosphonate prodrug, tetrakis‐pivaloyloxymethyl 2‐(thiazole‐2‐ylamino)ethylidene‐1,1‐bisphosphonate (PTA). PTA stimulated the expansion of Vγ2Vδ2 cells to purities up to 99%. These levels were consistently higher than those observed after expansion with zoledronic acid, the most commonly used stimulator for clinical trials. Cell numbers also averaged more than those obtained with zoledronic acid and the expanded Vγ2Vδ2 cells exhibited high cytotoxicity against tumor cells. The high purity of Vγ2Vδ2 cells expanded by PTA increased engraftment success in immunodeficient NOG mice. Even low levels of contaminating αβ T cells resulted in some mice with circulating human αβ T cells rather than Vγ2Vδ2 cells. Vγ2Vδ2 cells from engrafted NOG mice upregulated CD25 and secreted tumor necrosis factor‐α and interferon‐γ in response to PTA‐treated tumor cells. Thus, PTA expands Vγ2Vδ2 T cells to higher purity than zoledronic acid. The high purities allow the successful engraftment of immunodeficient mice without further purification and may speed up the development of allogeneic Vγ2Vδ2 T cell therapies derived from HLA‐matched normal donors for patients with poor autologous Vγ2Vδ2 T cell responses. Adoptive transfer of Vγ2Vδ2 T cells for treatment of cancer patients has been shown to be safe.In this report, we describe a method for preparing large numbers of highly enriched human Vγ2Vδ2 T cells using a new bisphosphonate prodrug. When the expanded Vγ2Vδ2 cells were administered to immunodeficient mice, the cells remained circulating in the blood for more than 2 weeks and they were functionally active.