PO.CT01.02 · 临床试验

E-SYNC T细胞（一种自体抗EGFRvIII SynNotch受体诱导的抗EphA2/IL13Ra2 CAR T细胞）治疗成人EGFRvIII+胶质母细胞瘤的首次人体试验

First-in-human trial of E-SYNC T-cells, an autologous anti-EGFRvIII SynNotch receptor-induced anti-EphA2/IL13Ra2 CAR T-cells, in adult patients with EGFRvIII+ glioblastoma

编号 CT042 展板 2 时间 4/20 09:00–12:00 区域 Section 50 主讲 Payal Watchmaker, PhD

分会场 First-in-Human Phase I Clinical Trials

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作者与单位 Authors & Affiliations

Payal B. Watchmaker¹, Jennifer L. Clarke², Ricardo Almeida³, Akane Yamamichi¹, Abigail Hansen⁴, Harika T. Gopi⁵, Karishma Kumar-Wessel¹, Megna Reddy¹, David Y. Oh⁵, Jacob S. Young¹, Nicholas Butowski¹, Nancy A. Oberheim Bush², Jennie W. Taylor¹, John de Groot¹, Joanna Phillips¹, Annette M. Molinaro¹, Brain R. Shy⁶, Wendell Lim⁷, Hideho Okada¹

¹Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA,²Department of Neurology, University of California, San Francisco, San Francisco, CA,³Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA,⁴California Institute for Regenerative Medicine Alpha Clinic at University of California, San Francisco, San Francisco, CA,⁵Cancer Immunotherapy Program, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA,⁶Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA,⁷4 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA

摘要 Abstract

中文摘要

背景：为胶质母细胞瘤（GBM）开发安全有效的CAR-T疗法一直受到抗原异质性、靶向非肿瘤毒性以及CAR-T细胞耗竭的阻碍。我们开发了一种新型基于合成Notch（synNotch）受体的"引发-杀伤"双抗原识别T细胞回路。由GBM细胞亚群表达的EGFRvIII引发T细胞表达一种识别IL-13Ralpha2和EphA2的CAR，这两种抗原在GBM中广泛表达，从而清除表达EphA2或IL-13Ralpha2的GBM细胞（E-SYNC T细胞）。我们开展了一项I期临床试验，以评估静脉输注E-SYNC T细胞的安全性。方法：本研究包含2个序贯患者队列。队列1是一个2剂量水平的剂量递增队列，针对新诊断的EGFRvIII突变、MGMT非甲基化GBM患者。E-SYNC细胞通过用慢病毒E-SYNC载体对自体T细胞进行离体转导来制造，随后在清淋化疗后静脉输注。队列2将是一个组织分析队列。在复发时，参与者将在计划的临床手术切除前接受来自队列1的最大耐受/推荐剂量的E-SYNC T细胞输注。主要目标是安全性；次要目标是可行性以及（仅队列2）确定GBM组织和外周血中E-SYNC T细胞的引发状态。我们目前正在为队列1招募患者。结果：已成功为9名患者制造自体E-SYNC细胞。迄今为止，我们已在剂量水平1（DL1：5×10^7 CAR+细胞）治疗6名患者、在剂量水平2（DL2：1.5×10^8 CAR+细胞）治疗2名患者，未出现严重不良事件或剂量限制性毒性。DL1的6名患者中有2名自初次切除以来分别20个月和15个月保持无进展。基于数字PCR的外周血评估显示E-SYNC T细胞在输注后至少持续存在40周。血清分析显示输注后CCL2、CCL5、CXCL9和CCL22升高。在2名输注后两个月内复发的患者中，尽管有E-SYNC细胞浸润，复发肿瘤组织仍显示EGFRvIII缺失。结论：我们已安全地用自体E-SYNC细胞治疗了8名EGFRvIII+ GBM患者，迄今为止无显著毒性。考虑到MGMT非甲基化GBM患者预后不良，2名患者的无进展生存期令人鼓舞。为克服作为引发信号的EGFRvIII缺失，我们还正在开发第二代synNotch-CAR研究，使用脑特异性细胞外基质蛋白Brevican来诱导CAR表达（Simic, Watchmaker等，Science, 386, 2024）。

查看英文原文 English abstract

Background: Developing safe and effective CAR-T therapy for glioblastoma (GBM) has been hindered by antigen heterogeneity, on-target off-tumor toxicity, and CAR-T cell exhaustion. We have developed a novel synthetic Notch ( syn Notch) receptor-based “prime-and-kill” dual antigen recognition T cell circuit. E GFRvIII, which is expressed by a subset of GBM cells, primes the T-cells to express a C AR that recognizes IL-13Ralpha2 and EphA2, which are broadly expressed in GBM, thereby eradicating GBM cells expressing either EphA2 or IL-13Ralpha2 (E-SYNC T-cells). We developed a Phase I clinical trial to evaluate the safety of intravenously infused E-SYNC T-cells. Methods: The study has 2 sequential patient cohorts. Cohort 1 is a 2-level dose-escalation cohort, targeting newly diagnosed patients with EGFRvIII-mutant, MGMT-unmethylated GBM. The E-SYNC cells are manufactured by ex vivo transduction of autologous T-cells with a lentiviral E-SYNC vector, and then intravenously infused after lymphodepleting chemotherapy. Cohort 2 will be a tissue analysis cohort. At the time of recurrence, participants will receive an infusion of E-SYNC T-cells at the maximum tolerated/recommended dose from Cohort 1 prior to a planned clinical surgical resection. The primary objective is safety; secondary objectives are feasibility and (for Cohort 2 only) to determine the priming status of E-SYNC T-cells in the GBM tissues and peripheral blood. We are currently enrolling patients in cohort 1. Results: Autologous E-SYNC cells have been successfully manufactured for 9 patients. To date, we have treated six patients at dose level 1 (DL1: 5x10 7 CAR + cells) and two patients at dose level 2 (DL2: 1.5x10 8 CAR + cells), with no serious adverse events or dose-limiting toxicities. Two of six patients at DL1 remain progression-free for 20 months and 15 months since the initial resection. Digital PCR-based evaluation of the peripheral blood demonstrated the post-infusion persistence of E-SYNC T-cells for at least 40 weeks. Serum analyses show post-infusion increases in CCL2, CCL5, CXCL9, and CCL22. In two patients who recurred within two months following the infusion, the recurrent tumor tissues showed the loss of EGFRvIII, despite the infiltration of E-SYNC cells. Conclusions: We have safely treated eight patients with EGFRvIII+ GBM with autologous E-SYNC cells, with no significant toxicity thus far. Considering the poor prognosis of MGMT-unmethylated GBM patients, the progression-free survival in two patients is promising. To overcome the loss of EGFRvIII as the priming signal, we are also developing a second-generation synNotch-CAR study using Brevican, a brain-specific extracellular matrix protein, to induce the CAR expression (Simic, Watchmaker et al., Science, 386, 2024).

利益披露 Disclosure

P. B. Watchmaker, None.. J. L. Clarke, None.. R. Almeida, None.. A. Yamamichi, None.. A. Hansen, None.. H. T. Gopi, None.. K. Kumar-Wessel, None.. M. Reddy, None.. D. Y. Oh, None.. J. S. Young, None.. N. Butowski, None.. N. A. Oberheim Bush, None.. J. W. Taylor, None.. J. de Groot, None.. J. Phillips, None.. A. M. Molinaro, None.. B. R. Shy, None.. W. Lim, None.. H. Okada, None.

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