Sourasky Medical Center, Tel-Aviv university, Tel-Aviv, Israel.
Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
Cancer Immunol Immunother. 2024 Aug 6;73(10):205. doi: 10.1007/s00262-024-03790-7.
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.
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).
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.
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).
JNJ-78306358 是一种双特异性抗体，可将 T 细胞重定向杀伤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。
纳入了 HLA-G 高表达转移性/不可切除实体瘤的成年患者。采用每周一次皮下给药进行剂量递增，以减轻细胞因子释放综合征（CRS）。
共有 39 名预处理较多的患者（结直肠癌：n=23，卵巢癌：n=10，肾细胞癌：n=6）在 7 个队列中接受了治疗。大多数患者（94.9%）经历了≥1 次治疗相关不良事件（TEAE）；87.2%有≥1 次相关的 TEAEs。约一半的患者（48.7%）发生了 CRS，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。4 名患者报告了剂量限制性毒性（DLTs），包括肝转氨酶升高、肺炎和因 CRS 而需要减少剂量，这些毒性与 CRS 有关。未报告治疗相关死亡。未观察到客观缓解，但有 2 名患者的疾病稳定时间超过 40 周。JNJ-78306358 刺激外周 T 细胞激活和细胞因子释放。45%的可评估患者检测到抗药物抗体，对暴露有影响。大约一半的存档肿瘤样本（48%）通过免疫组织化学检测到 HLA-G 的表达。
JNJ-78306358 表现出药效学效应，诱导细胞因子和 T 细胞激活。JNJ-78306358 与 CRS 相关的毒性相关，包括肝转氨酶升高和肺炎，限制了其剂量递增至潜在有效的水平。试验注册编号ClinicalTrials.gov（编号：NCT04991740）。
