美国德克萨斯大学安德森癌症中心Katayoun Rezvani课题组的一项最新研究使用CAR转导的自然杀伤细胞治疗CD19阳性淋巴瘤。相关论文2020年2月6日发表在国际顶尖学术期刊《新英格兰医学杂志》上。

抗CD19嵌合抗原受体（CAR）T细胞治疗B细胞瘤临床疗效显著。然而，T细胞会引起大量毒副作用，并且细胞制备复杂。经修饰可表达抗CD19CAR的自然杀伤细胞（NK）有可能克服这些限制。

在这项1期和2期临床试验中，研究组使用脐带血来源的HLA不匹配的抗CD19 CAR-NK细胞治疗11例复发或难治性CD19阳性肿瘤（非霍奇金淋巴瘤或慢性淋巴细胞性白血病[CLL]）。NK细胞通过逆转录病毒载体转导，表达编码抗CD19CAR、白细胞介素-15和诱导半胱天冬酶9的基因作为安全开关。

CAR-NK细胞治疗与细胞因子释放综合征，神经毒性或移植物抗宿主病的发生率无关，并且炎症细胞因子（包括白介素-6）水平与基线相比没有增加。没有达到最大耐受剂量。接受治疗的11名患者中，8例（73%）有效，7例完全缓解，1例Richter转化，但仍有持续性CLL。患者在输注30天内病情迅速缓解。输注的CAR-NK细胞低水平扩增和表达至少持续12个月。

总之，11例复发或难治性CD19阳性肿瘤患者经CAR-NK细胞治疗后，大多数显著改善，且未产生严重毒副作用。

附：英文原文

Title: Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors

Author: Enli Liu, M.D.,, David Marin, M.D.,, Pinaki Banerjee, Ph.D.,, Homer A. Macapinlac, M.D.,, Philip Thompson, M.B., B.S.,, Rafet Basar, M.D.,, Lucila Nassif Kerbauy, M.D.,, Bethany Overman, B.S.N.,, Peter Thall, Ph.D.,, Mecit Kaplan, M.S.,, Vandana Nandivada, M.S.,, Indresh Kaur, Ph.D.,, Ana Nunez Cortes, M.D.,, Kai Cao, M.D.,, May Daher, M.D.,, Chitra Hosing, M.D.,, Evan N. Cohen, Ph.D.,, Partow Kebriaei, M.D.,, Rohtesh Mehta, M.D.,, Sattva Neelapu, M.D.,, Yago Nieto, M.D., Ph.D.,, Michael Wang, M.D.,, William Wierda, M.D., Ph.D.,, Michael Keating, M.D.,, Richard Champlin, M.D.,, Elizabeth J. Shpall, M.D.,, and Katayoun Rezvani, M.D., Ph.D.

Issue&Volume: 2020-02-05

Abstract:

Background
Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable clinical efficacy in B-cell cancers. However, CAR T cells can induce substantial toxic effects, and the manufacture of the cells is complex. Natural killer (NK) cells that have been modified to express an anti-CD19 CAR have the potential to overcome these limitations.

Methods
In this phase 1 and 2 trial, we administered HLA-mismatched anti-CD19 CAR-NK cells derived from cord blood to 11 patients with relapsed or refractory CD19-positive cancers (non-Hodgkin’s lymphoma or chronic lymphocytic leukemia [CLL]). NK cells were transduced with a retroviral vector expressing genes that encode anti-CD19 CAR, interleukin-15, and inducible caspase 9 as a safety switch. The cells were expanded ex vivo and administered in a single infusion at one of three doses (1×105, 1×106, or 1×107 CAR-NK cells per kilogram of body weight) after lymphodepleting chemotherapy.

Results
The administration of CAR-NK cells was not associated with the development of cytokine release syndrome, neurotoxicity, or graft-versus-host disease, and there was no increase in the levels of inflammatory cytokines, including interleukin-6, over baseline. The maximum tolerated dose was not reached. Of the 11 patients who were treated, 8 (73%) had a response; of these patients, 7 (4 with lymphoma and 3 with CLL) had a complete remission, and 1 had remission of the Richter’s transformation component but had persistent CLL. Responses were rapid and seen within 30 days after infusion at all dose levels. The infused CAR-NK cells expanded and persisted at low levels for at least 12 months.

Conclusions
Among 11 patients with relapsed or refractory CD19-positive cancers, a majority had a response to treatment with CAR-NK cells without the development of major toxic effects. (Funded by the M.D. Anderson Cancer Center CLL and Lymphoma Moonshot and the National Institutes of Health; ClinicalTrials.gov number, NCT03056339.)

DOI: 10.1056/NEJMoa1910607

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1910607