肿瘤细胞治疗研究
英文原题：Checkpoint antibody receptor modified ARMed CAR T circumvents the suppressive immunome in GBM.
Checkpoint antibody receptor modified ARMed CAR T circumvents the suppressive immunome in GBM.
这些发现表明，将靶向 EGFRvIII 的 CAR T 细胞改造为局部分泌检查点抑制剂，可克服胶质母细胞瘤中的免疫抑制屏障，并绕开全身性抗体递送的局限。
引言：胶质母细胞瘤（GBM）仍是致命癌症，初始放疗、切除和化疗均无法治愈。过去十年，GBM 标准治疗没有显著进步，预期寿命不足 18 个月，且无标准二线治疗。研究者此前开发了第二代、经 4-1BB 共刺激的 CAR，靶向表皮生长因子受体肿瘤特异性变体 EGFRvIII。该 CAR-T 用于 I 期临床试验，显示 CAR-T 细胞可快速迁移至肿瘤，并在遇到表达 EGFRvIII 的肿瘤细胞时产生初步抗肿瘤活性。但 CAR-T 细胞很快耗竭、丧失抗肿瘤功能，且未产生持久的客观肿瘤应答。方法：研究者在同基因可移植 GL261 小鼠模型中评估 GBM 免疫环境。移植肿瘤前，脑内常驻免疫细胞基本缺失；肿瘤植入后，免疫细胞浸润随时间推移及 GBM 增大显著增加。早期浸润细胞主要为较早到达的 T、NK 和 B 淋巴细胞，之后则转为巨噬细胞和髓源性抑制细胞增加。分析新鲜及存档患者 GBM 样本发现，浸润免疫细胞水平同样较高，且肿瘤和免疫细胞均表达 PD-L1。PD-1/PD-L1 抗体介导的检查点抑制（CPI）已革新多种实体瘤治疗；然而，GBM 位于血脑屏障后方，限制抗体进入，CPI 试验治疗 GBM 未获成功。为向 GBM 患者递送 PD-1/PD-L1 检查点抗体，研究者将 EGFRvIII 靶向 CAR-T 工程化改造为“生物工厂”，使其在 GBM 病灶原位产生并分泌抗 PD-1 微型抗体。结果：这些抗体受体修饰（ARMed）CAR-T 细胞在体外产生有功能的 PD-1 微型抗体，并在 NOD-Scid γC 缺失（NSG）小鼠 GBM 异种移植模型中显示体内抗肿瘤活性。全身给药时，可溶性抗体联合 CAR-T 及 ARMed CAR-T 均较单用 CAR-T 改善皮下 GBM 治疗；而原位 GBM 的治疗只有 ARMed CAR-T 得到改善。讨论：工程化 EGFRvIII 靶向 CAR-T 局部分泌检查点抑制剂，可克服 GBM 免疫抑制屏障并绕过全身抗体递送的局限。该策略增强 CAR-T 功能持久性，对 GBM 及其他中枢神经系统局部疾病具有较强转化潜力。
INTRODUCTION: Glioblastoma (GBM) remains a deadly cancer with non-curative upfront treatment of radiation, resection, and chemotherapy. Not only has the standard of care for GBM patients not improved significantly over the past decade, life expectancy is less than 18 months, with no standard second-line therapy. We previously developed a 2 nd generation 4-1BB co-stimulated chimeric antigen receptor (CAR) targeting tumor-specific variant of the epidermal growth factor receptor (EGFRvIII) for treating patients with GBM. This CAR T was used in Phase 1 clinical trials, and demonstrated that CAR T cells rapidly trafficked to tumors and showed initial anti-tumor activity upon encountering EGFRvIII-bearing tumor cells. However, the CAR T cells rapidly became exhausted, losing anti-tumor function, with no durable objective tumor responses. METHODS: Here, we evaluated the GBM immune environment in a syngeneic implantable GL261 murine model. Prior to tumor implantation, brain-resident immune cells were mostly absent. Following tumor engraftment, there was a pronounced increase in immune cell infiltration over time and with GBM size. Immune infiltrates were intitally comprised of early-arriving lymphocytes including T, NK, and B cells, later this shifted towards increased presence of macrophages and myeloid-derived suppressor cells. Evaluating both fresh and archival GBM samples from patients, we found similarly high levels of infiltrating immune cells, and PDL1 expression on both tumor and immune cells. PD1/PDL1-antibody (Ab) mediated checkpoint inhibition (CPI) has been transformative in treating several types of solid tumors; however the localization of GBM behind the blood-brain barrier limits Ab access, and CPI trials have been unsuccessful in treating GBM. To deliver PD1/PDL1 checkpoint Ab for patients with GBM, we engineered our EGFRvIII-targeted CAR T cells to function as bio-factories, producing and secreting anti-PD1 mini-Abs in situ at the site of GBM. RESULTS: These Ab receptor-modified (ARMed) CAR T cells produced functional PD1 minibodies in vitro and demonstrated anti-tumor activity in vivo in a GBM xenograft model using NOD-Scid gammaC-null (NSG) mice. Delivered systemically, both soluble Ab plus CAR T, and ARMed CAR T cells improved subcutaneously implanted GBM treatment over CAR T alone, while treatment of orthotopic GBM treatment was only improved with ARMed CAR T therapy. DISCUSSION: These findings demonstrate that engineering EGFRvIII-directed CAR T cells to secrete checkpoint inhibitors locally can overcome immunosuppressive barriers in GBM and bypass the limitations of systemic antibody delivery. This strategy enhances CAR T cell functional persistence and holds strong translational potential for treating GBM and other CNS-localized disease.
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