雙特異性CD20、CD19 CAR T細胞可用於復發性B細胞惡性腫瘤治療

雙特異性CD20、CD19 CAR T細胞可用於復發性B細胞惡性腫瘤治療

作者：

小柯機器人

發布時間：2020/10/11 21:21:05

美國Lentigen公司Boro Dropuli、威斯康辛醫學院Nirav N. Shah等研究人員發現，雙特異性CD20、CD19 CAR T細胞可用於復發性B細胞惡性腫瘤治療。 相關論文於2020年10月5日發表於國際學術期刊《自然—醫學》。

據研究人員介紹，靶向CD19的嵌合抗原受體（CAR）T細胞是復發難治性B細胞惡性腫瘤的突破性療法。儘管結果令人印象深刻，但CD19疾病的復發仍然是一個挑戰。

 

通過使用雙特異性抗CD20、抗CD19（LV20.19）CAR T細胞來治療復發難治性B細胞惡性腫瘤的首次人類試驗，研究人員解決了這一局限性。對成人B細胞非霍奇金淋巴瘤或慢性淋巴細胞性白血病患者進行了1期劑量遞增和擴增試驗（NCT03019055），用以評估4-1BB–CD3ζ LV20.19 CAR T細胞的安全性以及現場製造的可行性（使用CliniMACS Prodigy系統來評估）。 CAR T細胞劑量範圍為每公斤2.5×10⁵至2.5×10⁶個細胞。

 

為注入非冷凍保存的LV20.19 CAR T細胞，細胞製造時間被設定為14天。在所有未接受過CAR的患者中均達到了LV20.19 CAR T細胞的目標劑量，並且有22例患者在治療方案中接受了LV20.19 CAR T細胞。在沒有劑量限制性毒性的情況下，選擇每公斤2.5×10⁶個細胞進行擴增。一名（5％）患者發生3-4級細胞因子釋放症候群，三名（14％）患者發生3-4級神經毒性。18例（82％）患者在第28天獲得了總體緩解，其中14例（64％）完全緩解，4例（18％）部分緩解。非冷凍保存的輸注對每公斤2.5×10⁶個細胞劑量的總緩解率為100％（完全緩解率為92％；部分緩解率為8％）（n = 12）。

 

值得注意的是，在復發或經歷治療失敗的患者中未觀察到CD19抗原的丟失。總之，非冷凍保存的LV20.19 CAR T細胞的現場製造和輸注是可行且治療安全的，且顯示出低毒性和高療效。雙特異性CAR可以通過減輕靶抗原下調作為復發機制來改善臨床反應。

 

附：英文原文

Title: Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial

Author: Nirav N. Shah, Bryon D. Johnson, Dina Schneider, Fenlu Zhu, Aniko Szabo, Carolyn A. Keever-Taylor, Winfried Krueger, Andrew A. Worden, Michael J. Kadan, Sharon Yim, Ashley Cunningham, Mehdi Hamadani, Timothy S. Fenske, Boro Dropuli, Rimas Orentas, Parameswaran Hari

Issue&Volume: 2020-10-05

Abstract: Chimeric antigen receptor (CAR) T cells targeting CD19 are a breakthrough treatment for relapsed, refractory B cell malignancies1,2,3,4,5. Despite impressive outcomes, relapse with CD19 disease remains a challenge. We address this limitation through a first-in-human trial of bispecific anti-CD20, anti-CD19 (LV20.19) CAR T cells for relapsed, refractory B cell malignancies. Adult patients with B cell non-Hodgkin lymphoma or chronic lymphocytic leukemia were treated on a phase 1 dose escalation and expansion trial (NCT03019055) to evaluate the safety of 4-1BB–CD3ζ LV20.19 CAR T cells and the feasibility of on-site manufacturing using the CliniMACS Prodigy system. CAR T cell doses ranged from 2.5×105–2.5×106 cells per kg. Cell manufacturing was set at 14d with the goal of infusing non-cryopreserved LV20.19 CAR T cells. The target dose of LV20.19 CAR T cells was met in all CAR-naive patients, and 22 patients received LV20.19 CAR T cells on protocol. In the absence of dose-limiting toxicity, a dose of 2.5×106 cells per kg was chosen for expansion. Grade 3–4 cytokine release syndrome occurred in one (5%) patient, and grade 3–4 neurotoxicity occurred in three (14%) patients. Eighteen (82%) patients achieved an overall response at day 28, 14 (64%) had a complete response, and 4 (18%) had a partial response. The overall response rate to the dose of 2.5×106 cells per kg with non-cryopreserved infusion (n=12) was 100% (complete response, 92%; partial response, 8%). Notably, loss of the CD19 antigen was not seen in patients who relapsed or experienced treatment failure. In conclusion, on-site manufacturing and infusion of non-cryopreserved LV20.19 CAR T cells were feasible and therapeutically safe, showing low toxicity and high efficacy. Bispecific CARs may improve clinical responses by mitigating target antigen downregulation as a mechanism of relapse.

DOI: 10.1038/s41591-020-1081-3

Source: https://www.nature.com/articles/s41591-020-1081-3