PO.IM01.05 · 免疫学

AZD5851，一种TGF-beta抵抗性GPC3 CAR-T细胞产品，在髓母细胞瘤和非典型畸胎样横纹肌样瘤患者来源原位异种移植模型中延长动物生存期

AZD5851, a TGF-beta-resistant GPC3 CAR-T cell product, prolongs animal survival times in patient derived orthotopic xenograft models of medulloblastoma and atypical teratoid rhabdoid tumor

编号 1528 展板 10 时间 4/20 09:00–12:00 区域 Section 7 主讲 Milagros Suarez Palacios, PhD

分会场 CAR T Cell Targets and TME Reprogramming

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作者与单位 Authors & Affiliations

Milagros Suarez¹, Aalaa Abdallah¹, Xin Zhai¹, Zilu Huang¹, Yuchen Du¹, Nitin Wadhwani², Alicia Lenzen¹, Jee Young Kwon³, Steven B. Neuhauser³, Timothy Stearns⁴, Jeffrey H. Chuang³, Emily L. Jocoy⁴, Carol J. Bult⁴, Beverly Teicher⁵, Malcolm A. Smith⁶, Xiao Nan Li⁷

¹Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL,²Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL,³The Jackson Laboratory for Genomic Medicine, Farmington, CT,⁴The Jackson Laboratory, Bar Harbor, ME,⁵Molecular Pharmacology Branch, National Cancer Institute, Bethesda, MD,⁶Clinical Investigations Branch, National Cancer Institute, Bethesda, MD,⁷Departments of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL

摘要 Abstract

中文摘要

背景：磷脂酰肌醇蛋白聚糖3（GPC3）具有独特表达，并与多种儿童实体胚胎性肿瘤的发生相关，使其成为GPC3 CAR-T细胞杀伤的首要靶点。TGF-beta是一种与免疫抑制相关的细胞因子，也已被证明在这些肿瘤的微环境中高表达，可能阻碍CAR-T细胞的抗肿瘤活性。在本研究中，我们检测了AZD5851的治疗疗效，这是一种自体CAR-T产品，表达针对GPC3的CAR以及作为武装策略的显性负性（dn）TGFbetaRII。方法：为评估该药物的体内疗效，采用5个已建立的患者来源原位异种移植（PDOX）模型——儿童髓母细胞瘤（ICb-2123MB、-1299MB、-S1129MB）、非典型畸胎样横纹肌样瘤（IC-L1115ATRT）和一个高级别胶质瘤（IC-2664HGG），这些模型经免疫组化染色确认表达GPC3和TGF-beta，接受未转导T细胞[剂量为12×10⁶细胞/只小鼠，静脉注射（IV）一次]或GPC3 CAR-T细胞（剂量为5×10⁶细胞/只小鼠，IV一次）治疗。每个模型有20只8周龄SCID小鼠接受脑内（IC）或小脑内（ICb）肿瘤细胞植入，并被分为2个治疗组（每组n=10）：未转导T细胞组和GPC3 CAR-T细胞组。使用Gehan-Breslow-Wilcoxon分析对动物生存期进行分析。结果：GPC3 CAR-T细胞治疗在小鼠中耐受性良好，无体重减轻或其他毒性。GPC3 CAR-T细胞治疗显著改善了2/5个模型的中位生存期，包括ICb-2123MB从未转导T细胞组的90.5天延长至162.5天（P=0.02），以及IC-L1115ATRT从136天延长至174天（P=0.02）。结论：我们的数据确定了GPC3 CAR-T细胞对儿童髓母细胞瘤和非典型畸胎样横纹肌样瘤PDOX模型的单药抗肿瘤活性。这些结果支持进一步开展涉及AZD5851单用或与其他疗法联合用于治疗这些肿瘤的临床转化工作。

查看英文原文 English abstract

BACKGROUND: Glypican-3 (GPC3) is uniquely expressed and has been associated with the development of several pediatric solid embryonal tumors, making it a prime target for GPC3 CAR-T cell killing. TGF-beta, a cytokine associated with immunosuppression, has also been shown to be highly expressed in the microenvironment of these tumors, potentially hindering CAR-T cell antitumor activity. In this study, we examined the therapeutic efficacy of AZD5851, an autologous CAR-T product that expresses a CAR specific for GPC3 and a dominant negative (dn)TGFbetaRII as an armoring strategy. METHODOLOGY: To assess the drug's in vivo efficacy, 5 established patient-derived orthotopic xenograft (PDOX) models of pediatric medulloblastoma (ICb-2123MB, -1299MB, -S1129MB), atypical teratoid rhabdoid tumor (IC-L1115ATRT) and a high grade glioma (IC-2664HGG), with confirmed expression of GPC3 and TGF-beta through immunohistochemical staining, were treated with untransduced T cells [dosed at 12x10 6 cells/mouse, intravenously (IV) once] or GPC3 CAR-T cells (dosed at 5x10 6 cells/mouse, IV once). 20 eight-week-old SCID mice per model received intra-cerebral (IC) or intra-cerebellar (ICb) tumor cell implantation and were divided into 2 treatment groups (n=10 per group): Untransduced T cells and GPC3 CAR-T cells. Animal survival times were analyzed using Gehan-Breslow-Wilcoxon analysis. RESULTS: GPC3 CAR-T cell treatment was well tolerated in mice with no loss of body weight or other toxicities. GPC3 CAR-T cell treatment significantly improved the median survival time in 2/5 models, including ICb-2123MB from 90.5 days in the untransduced T cell group to 162.5 days (P=0.02) and IC-L1115ATRT from 136 days to 174 days (P=0.02). CONCLUSION: Our data identifies single agent antitumor activity for GPC3 CAR-T cells for PDOX models of pediatric medulloblastoma and atypical teratoid rhabdoid tumor. The results support further clinical translational efforts involving the use of AZD5851 alone or in combination with other therapies for the treatment of these tumors.

利益披露 Disclosure

M. Suarez, None.. A. Abdallah, None.. X. Zhai, None.. Z. Huang, None.. Y. Du, None.. N. Wadhwani, None.. A. Lenzen, None.. J. Kwon, None.. S. B. Neuhauser, None.. T. Stearns, None.. J. H. Chuang, None.. E. L. Jocoy, None.. B. Teicher, None.. M. A. Smith, None.. X. Li, None.

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