Non-viral precision T cell receptor replacement for personalized cell therapy.
Non-viral precision T cell receptor replacement for personalized cell therapy.
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DOI：
10.1038/s41586-022-05531-1
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发表时间：
2023-03
影响因子：
120.1
通讯作者：
Mandl, Stefanie J. J.
中科院分区：
文献类型：
--
作者：
Foy, Susan P. P.;Jacoby, Kyle;Bota, Daniela A. A.;Hunter, Theresa;Pan, Zheng;Stawiski, Eric;Ma, Yan;Lu, William;Peng, Songming;Wang, Clifford L. L.;Yuen, Benjamin;Dalmas, Olivier;Heeringa, Katharine;Sennino, Barbara;Conroy, Andy;Bethune, Michael T. T.;Mende, Ines;White, William;Kukreja, Monica;Gunturu, Swetha;Humphrey, Emily;Hussaini, Adeel;An, Duo;Litterman, Adam J. J.;Quach, Boi Bryant;Ng, Alphonsus H. C.;Lu, Yue;Smith, Chad;Campbell, Katie M. M.;Anaya, Daniel;Skrdlant, Lindsey;Huang, Eva Yi-Hsuan;Mendoza, Ventura;Mathur, Jyoti;Dengler, Luke;Purandare, Bhamini;Moot, Robert;Yi, Michael C. C.;Funke, Roel;Sibley, Alison;Stallings-Schmitt, Todd;Oh, David Y. Y.;Chmielowski, Bartosz;Abedi, Mehrdad;Yuan, Yuan;Sosman, Jeffrey A. A.;Lee, Sylvia M. M.;Schoenfeld, Adam J. J.;Baltimore, David;Heath, James R. R.;Franzusoff, Alex;Ribas, Antoni;Rao, Arati V. V.;Mandl, Stefanie J. J.
T细胞受体（TCR）使T细胞能够特异性识别癌细胞中的突变。在这里，我们开发了一种基于CRISPR-Cas9非病毒精确基因组编辑的临床级方法，以同时敲除两种内源性TCR基因TRAC（编码TCRα）和TRBC（编码TCRβ）。我们还将从患者的循环T细胞分离的新抗原特异性TCR（neoTCR）的两条链插入TRAC位点。使用可溶性预测新抗原-HLA捕获试剂的个性化文库分离neoTCR。16名患有不同难治性实体癌的患者接受了多达三种不同的neoTCR转基因细胞产物。每种产品均表达患者特异性neoTCR，并在细胞剂量递增、首次人体I期临床试验（NCT 03970382）中给药。1例患者出现1级细胞因子释放综合征，1例患者出现3级脑炎。所有参与者都有淋巴细胞清除化疗的预期副作用。5名患者病情稳定，其他11名患者病情进展为治疗的最佳缓解。在输注后的肿瘤活检样品中检测到neoTCR转基因T细胞，其频率高于输注前的天然TCR。本研究证明了分离和克隆识别突变新抗原的多种TCR的可行性。此外，使用单步、非病毒精确基因组编辑实现了内源性TCR的同时敲除和neoTCR的敲入。还证明了临床级的neoTCR工程化T细胞的制造、输注多达三种基因编辑的neoTCR T细胞产物的安全性以及转基因T细胞运输至患者肿瘤的能力。首次人体I期临床试验证明了个性化过继细胞转移抗癌治疗的非病毒精确基因组工程的可行性和安全性。
T cell receptors (TCRs) enable T cells to specifically recognize mutations in cancer cells. Here we developed a clinical-grade approach based on CRISPR–Cas9 non-viral precision genome-editing to simultaneously knockout the two endogenous TCR genes TRAC (which encodes TCRα) and TRBC (which encodes TCRβ). We also inserted into the TRAC locus two chains of a neoantigen-specific TCR (neoTCR) isolated from circulating T cells of patients. The neoTCRs were isolated using a personalized library of soluble predicted neoantigen–HLA capture reagents. Sixteen patients with different refractory solid cancers received up to three distinct neoTCR transgenic cell products. Each product expressed a patient-specific neoTCR and was administered in a cell-dose-escalation, first-in-human phase I clinical trial (NCT03970382). One patient had grade 1 cytokine release syndrome and one patient had grade 3 encephalitis. All participants had the expected side effects from the lymphodepleting chemotherapy. Five patients had stable disease and the other eleven had disease progression as the best response on the therapy. neoTCR transgenic T cells were detected in tumour biopsy samples after infusion at frequencies higher than the native TCRs before infusion. This study demonstrates the feasibility of isolating and cloning multiple TCRs that recognize mutational neoantigens. Moreover, simultaneous knockout of the endogenous TCR and knock-in of neoTCRs using single-step, non-viral precision genome-editing are achieved. The manufacture of neoTCR engineered T cells at clinical grade, the safety of infusing up to three gene-edited neoTCR T cell products and the ability of the transgenic T cells to traffic to the tumours of patients are also demonstrated. A first-in-human phase I clinical trial demonstrates the feasibility and safety of non-viral precision genome-engineering of a personalized adoptive cell transfer anticancer therapeutic.
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DOI：
10.1093/annonc/mdu479
发表时间：
2015-01
期刊：
Annals of oncology : official journal of the European Society for Medical Oncology
影响因子：
--
作者：
Favero F;Joshi T;Marquard AM;Birkbak NJ;Krzystanek M;Li Q;Szallasi Z;Eklund AC
通讯作者：
Eklund AC
影响因子：
82.9
作者：
Gros A;Parkhurst MR;Tran E;Pasetto A;Robbins PF;Ilyas S;Prickett TD;Gartner JJ;Crystal JS;Roberts IM;Trebska-McGowan K;Wunderlich JR;Yang JC;Rosenberg SA
通讯作者：
Rosenberg SA
DOI：
10.1038/s41577-019-0218-4
发表时间：
2020-01
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Kalbasi A;Ribas A
通讯作者：
Ribas A
影响因子：
64.8
作者：
Matsushita, Hirokazu;Vesely, Matthew D.;Koboldt, Daniel C.;Rickert, Charles G.;Uppaluri, Ravindra;Magrini, Vincent J.;Arthur, Cora D.;White, J. Michael;Chen, Yee-Shiuan;Shea, Lauren K.;Hundal, Jasreet;Wendl, Michael C.;Demeter, Ryan;Wylie, Todd;Allison, James P.;Smyth, Mark J.;Old, Lloyd J.;Mardis, Elaine R.;Schreiber, Robert D.
通讯作者：
Schreiber, Robert D.
影响因子：
64.8
作者：
Eyquem J;Mansilla-Soto J;Giavridis T;van der Stegen SJ;Hamieh M;Cunanan KM;Odak A;Gönen M;Sadelain M
通讯作者：
Sadelain M