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针对新诊断的 4 级星形细胞瘤的 I 期研究，采用双特异性抗体武装的 T 细胞（EGFR BATs）联合放疗和替莫唑胺。

Phase I study targeting newly diagnosed grade 4 astrocytoma with bispecific antibody armed T cells (EGFR BATs) in combination with radiation and temozolomide.

机构信息

Department of Neurology, Division of Neuro-Oncology, University of Virginia Health System, P.O. Box 800394, Charlottesville, VA, 22908, USA.

Bone Marrow Transplant Program, Division Hematology/Oncology, Department of Medicine, University of Virginia Cancer Center, Charlottesville, VA, USA.

出版信息

J Neurooncol. 2024 Jan;166(2):321-330. doi: 10.1007/s11060-024-04564-y. Epub 2024 Jan 23.

DOI:10.1007/s11060-024-04564-y

PMID:38263486

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10834565/

Abstract

PURPOSE

The purpose of this study was to determine the safety, feasibility, and immunologic responses of treating grade 4 astrocytomas with multiple infusions of anti-CD3 x anti-EGFR bispecific antibody (EGFRBi) armed T cells (EGFR BATs) in combination with radiation and chemotherapy.

METHODS

This phase I study used a 3 + 3 dose escalation design to test the safety and feasibility of intravenously infused EGFR BATs in combination with radiation and temozolomide (TMZ) in patients with newly diagnosed grade 4 astrocytomas (AG4). After finding the feasible dose, an expansion cohort with unmethylated O-methylguanine-DNA methyltransferase (MGMT) tumors received weekly EGFR BATs without TMZ.

RESULTS

The highest feasible dose was 80 × 10 EGFR BATs without dose-limiting toxicities (DLTs) in seven patients. We could not escalate the dose because of the limited T-cell expansion. There were no DLTs in the additional cohort of three patients with unmethylated MGMT tumors who received eight weekly infusions of EGFR BATs without TMZ. EGFR BATs infusions induced increases in glioma specific anti-tumor cytotoxicity by peripheral blood mononuclear cells (p < 0.03) and NK cell activity (p < 0.002) ex vivo, and increased serum concentrations of IFN-γ (p < 0.03), IL-2 (p < 0.007), and GM-CSF (p < 0.009).

CONCLUSION

Targeting AG4 with EGFR BATs at the maximum feasible dose of 80 × 10, with or without TMZ was safe and induced significant anti-tumor-specific immune responses. These results support further clinical trials to examine the efficacy of this adoptive cell therapy in patients with MGMT-unmethylated GBM.

CLINICALTRIALS

gov Identifier: NCT03344250.

摘要

目的

本研究旨在确定多次输注抗 CD3x 抗 EGFR 双特异性抗体（EGFRBi）武装 T 细胞（EGFRBATs）联合放疗和化疗治疗 4 级星形细胞瘤的安全性、可行性和免疫反应。

方法

这项 I 期研究采用 3+3 剂量递增设计，以测试静脉输注 EGFRBATs 联合放疗和替莫唑胺（TMZ）在新诊断的 4 级星形细胞瘤（AG4）患者中的安全性和可行性。在确定可行剂量后，一个未甲基化 O-甲基鸟嘌呤-DNA 甲基转移酶（MGMT）肿瘤的扩展队列接受每周一次的 EGFRBATs 治疗，而不使用 TMZ。

结果

在 7 名患者中，最高可行剂量为 80×10EGFRBATs，无剂量限制毒性（DLT）。由于 T 细胞扩增有限，我们无法增加剂量。在另外 3 名未甲基化 MGMT 肿瘤患者的队列中，接受 8 次每周 EGFRBATs 输注而不使用 TMZ 也没有 DLT。EGFRBATs 输注可体外诱导外周血单核细胞（p<0.03）和 NK 细胞活性（p<0.002）增加，诱导肿瘤特异性抗肿瘤细胞毒性，血清中 IFN-γ（p<0.03）、IL-2（p<0.007）和 GM-CSF（p<0.009）浓度增加。