Expansion of human γδ T cells for adoptive immunotherapy using a bisphosphonate prodrug.
Expansion of human γδ T cells for adoptive immunotherapy using a bisphosphonate prodrug.
复制标题
DOI：
10.1111/cas.13491
复制
发表时间：
2018-03
期刊：
影响因子：
5.7
通讯作者：
Morita CT
中科院分区：
文献类型：
--
作者：
Tanaka Y;Murata-Hirai K;Iwasaki M;Matsumoto K;Hayashi K;Kumagai A;Nada MH;Wang H;Kobayashi H;Kamitakahara H;Okamura H;Sugie T;Minato N;Toi M;Morita CT
用表达Vγδ2Vγ2 T细胞受体的人δT细胞(也称为Vγ9Vδ2)进行肿瘤免疫治疗已显示出良好的前景，因为它们能够以主要组织能力复合体识别和杀死大多数类型的肿瘤--一种不受肿瘤突变数量限制的方式。在临床试验中，过继转移Vγ2Vδ2T细胞已被证明是安全的，且不需要预适应。在这篇报道中，我们描述了一种用双膦酸类前药四氢呋喃氧甲基2‐(thiazole‐2‐ylamino)ethylidene‐1，1‐bisphosphonate(PTA)制备高浓缩人Vγ2Vδ2T细胞的方法。PTA刺激V-γ-2V-δ-2细胞扩增，纯度可达99%以上。这些水平始终高于用唑来膦酸扩张后观察到的水平，唑来膦酸是临床试验中最常用的刺激剂。扩增后的V-γ-2V-δ-2细胞对肿瘤细胞具有较高的杀伤活性。经PTA扩增的V-γ-2V-δ-2细胞纯度高，可提高免疫缺陷小鼠的移植成功率。即使是低水平的αβT细胞污染，也会导致一些小鼠出现循环中的人类αβT细胞，而不是Vγ2Vδ2细胞。移植瘤小鼠的Vγ2Vδ2细胞上调CD2 5，并分泌肿瘤坏死因子α和干扰素γ。因此，PTA可使Vγ2Vδ2T细胞扩增至比唑来膦酸更高的纯度。这种高纯度使免疫缺陷小鼠无需进一步纯化即可成功植入，并可能加速Vγ2Vδ2T细胞疗法的发展，该疗法来自于人类白细胞抗原匹配的正常供者，用于自体Vγ2Vδ2T细胞反应差的患者。
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.
登录
查看更多内容
影响因子：
82.9
作者：
Klebanoff CA;Rosenberg SA;Restifo NP
通讯作者：
Restifo NP
影响因子：
5.4
作者：
MORITA, CT;VERMA, S;BRENNER, MB
通讯作者：
BRENNER, MB
影响因子：
82.9
作者：
Heslop, HE;Ng, CYC;Rooney, CM
通讯作者：
Rooney, CM
DOI：
10.1056/nejmoa1200694
发表时间：
2012-06-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Brahmer JR;Tykodi SS;Chow LQ;Hwu WJ;Topalian SL;Hwu P;Drake CG;Camacho LH;Kauh J;Odunsi K;Pitot HC;Hamid O;Bhatia S;Martins R;Eaton K;Chen S;Salay TM;Alaparthy S;Grosso JF;Korman AJ;Parker SM;Agrawal S;Goldberg SM;Pardoll DM;Gupta A;Wigginton JM
通讯作者：
Wigginton JM
影响因子：
5.8
作者：
Kobayashi, Hirohito;Tanaka, Yoshimasa;Tanabe, Kazunari
通讯作者：
Tanabe, Kazunari