Safety and clinical activity of JNJ-78306358, a human leukocyte antigen-G (HLA-G) x CD3 bispecific antibody, for the treatment of advanced stage solid tumors.

IF 4.6 2区医学 Q2 IMMUNOLOGY Cancer Immunology, Immunotherapy Pub Date : 2024-08-06 DOI:10.1007/s00262-024-03790-7

Ravit Geva, Maria Vieito, Jorge Ramon, Ruth Perets, Manuel Pedregal, Elena Corral, Bernard Doger, Emiliano Calvo, Jorge Bardina, Elena Garralda, Regina J Brown, James G Greger, Shujian Wu, Douglas Steinbach, Tsun-Wen Sheena Yao, Yu Cao, Josh Lauring, Ruchi Chaudhary, Jaymala Patel, Bharvin Patel, Victor Moreno

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Abstract

Background: JNJ-78306358 is a bispecific antibody that redirects T cells to kill human leukocyte antigen-G (HLA-G)-expressing tumor cells. This dose escalation study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of JNJ-78306358 in patients with advanced solid tumors.

Methods: Adult patients with metastatic/unresectable solid tumors with high prevalence of HLA-G expression were enrolled. Dose escalation was initiated with once-weekly subcutaneous administration with step-up dosing to mitigate cytokine release syndrome (CRS).

Results: Overall, 39 heavily pretreated patients (colorectal cancer: n = 23, ovarian cancer: n = 10, and renal cell carcinoma: n = 6) were dosed in 7 cohorts. Most patients (94.9%) experienced ≥ 1 treatment-emergent adverse events (TEAEs); 87.2% had ≥ 1 related TEAEs. About half of the patients (48.7%) experienced CRS, which were grade 1/2. Nine patients (23.1%) received tocilizumab for CRS. No grade 3 CRS was observed. Dose-limiting toxicities (DLTs) of increased transaminases, pneumonitis and recurrent CRS requiring a dose reduction were reported in 4 patients, coinciding with CRS. No treatment-related deaths reported. No objective responses were noted, but 2 patients had stable disease > 40 weeks. JNJ-78306358 stimulated peripheral T cell activation and cytokine release. Anti-drug antibodies were observed in 45% of evaluable patients with impact on exposure. Approximately half of archival tumor samples (48%) had expression of HLA-G by immunohistochemistry.

Conclusion: JNJ-78306358 showed pharmacodynamic effects with induction of cytokines and T cell activation. JNJ-78306358 was associated with CRS-related toxicities including increased transaminases and pneumonitis which limited its dose escalation to potentially efficacious levels. Trial registration number ClinicalTrials.gov (No. NCT04991740).

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用于治疗晚期实体瘤的人类白细胞抗原-G (HLA-G) x CD3 双特异性抗体 JNJ-78306358 的安全性和临床活性。

背景：JNJ-78306358是一种双特异性抗体，它能引导T细胞杀死表达人类白细胞抗原-G（HLA-G）的肿瘤细胞。这项剂量递增研究评估了 JNJ-78306358 在晚期实体瘤患者中的安全性、药代动力学、药效学和初步抗肿瘤活性：方法：研究人员招募了患有转移性/不可切除实体瘤且HLA-G表达率较高的成年患者。开始剂量升级，每周一次皮下注射，同时加大剂量以减轻细胞因子释放综合征（CRS）：共有 39 名重度预处理患者（结直肠癌：23 人；卵巢癌：10 人；肾细胞癌：6 人）在 7 个队列中接受了治疗。大多数患者（94.9%）发生了≥1次治疗突发不良事件（TEAEs）；87.2%发生了≥1次相关TEAEs。约半数患者（48.7%）出现了CRS，均为1/2级。9名患者（23.1%）因CRS接受了托珠单抗治疗。未观察到 3 级 CRS。有4名患者报告了转氨酶升高、肺炎和复发性CRS等剂量限制性毒性（DLTs），需要减少剂量，并与CRS同时发生。没有与治疗相关的死亡报告。未发现客观反应，但有 2 名患者病情稳定超过 40 周。JNJ-78306358 可刺激外周 T 细胞活化和细胞因子释放。在 45% 的可评估患者中观察到了抗药性抗体，并对暴露产生了影响。约有一半的存档肿瘤样本（48%）通过免疫组化表达了 HLA-G：结论：JNJ-78306358 具有诱导细胞因子和 T 细胞活化的药效学效应。JNJ-78306358与CRS相关毒性有关，包括转氨酶升高和肺炎，这限制了其剂量升级到潜在有效水平。试验注册号为 ClinicalTrials.gov（NCT04991740 号）。

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来源期刊

Cancer Immunology, Immunotherapy 医学-免疫学

CiteScore

10.50

自引率

1.70%

发文量

207

审稿时长

1 months

期刊介绍： Cancer Immunology, Immunotherapy has the basic aim of keeping readers informed of the latest research results in the fields of oncology and immunology. As knowledge expands, the scope of the journal has broadened to include more of the progress being made in the areas of biology concerned with biological response modifiers. This helps keep readers up to date on the latest advances in our understanding of tumor-host interactions. The journal publishes short editorials including "position papers," general reviews, original articles, and short communications, providing a forum for the most current experimental and clinical advances in tumor immunology.