Background: This first-in-human proof-of-concept study aimed to check whether safety and preclinical results obtained by intratumoral administration of BQ788, an endothelin receptor B (EDNRB) antagonist, can be repeated in human melanoma patients.
Methods: Three patients received a single intralesional BQ788 application of 3 mg. After 3-7 days, the lesions were measured and removed for analysis. The administered dose was increased to a cumulative dosage of 8 mg in patient 4 (4 × 2.0 mg, days 0-3; lesion removed on day 4) and to 10 mg in patient 5 (3 × 3.3 mg, days 0, 3, and 10; lesion removed after 14 days). Control lesions were simultaneously treated with phosphate-buffered saline (PBS). All samples were processed and analyzed without knowledge of the clinical findings.
Results: No statistical evaluation was possible because of the number of patients (n = 5) and the variability in the mode of administration. No adverse events were observed, regardless of administered dose. All observations were in accordance with results obtained in preclinical studies. Accordingly, no difference in degree of tumor necrosis was detected between BQ788- and PBS-treated samples. In addition, both EDNRB and Ki67 showed decreased expression in patients 2 and 5 and, to a lesser extent, in patient 1. Similarly, decreased expression of EDNRB mRNA in patients 2 and 5 and of BCL2A1 and/or PARP3 in patients 2, 3, and 5 was found. Importantly, semiquantitatively scored immunohistochemistry for CD31 and CD3 revealed more blood vessels and lymphocytes, respectively, in BQ788-treated tumors of patients 2 and 4. Also, in all patients, we observed inverse correlation in expression levels between EDNRB and HIF1A. Finally, in patient 5 (the only patient treated for longer than 1 week), we observed inhibition in lesion growth, as shown by size measurement.
Conclusion: The intralesional applications of BQ788 were well tolerated and showed signs of directly and indirectly reducing the viability of melanoma cells.
经验
• 病灶内注射 BQ788 治疗黑色素瘤皮肤转移的耐受性非常好。
• 观察到了有效性的迹象, 包括直接效应 [内皮素受体 B (EDNRB) 和存活因子的表达下调, 增殖减少] 和间接效应 (免疫细胞浸润及血管生成增加)。
• 将来的临床试验应在开始前对患者 EDNRB 表达水平进行筛查, 因为只有 EDNRB 高表达的黑色素瘤患者 (4/5 例) 对 BQ788 有治疗反应。
• 将来的研究应该至少持续 2 周, 因为我们只在治疗超过 1 周的患者中观察到病灶生长抑制。
摘要
背景. 本研究为首次应用于人体的概念验证研究, 旨在检验肿瘤内注射内皮素受体 B (EDNRB) 拮抗剂 BQ788 的安全性及其临床前结果在人类黑色素瘤患者中是否具有重现性。
方法. 3 例患者接受单次肿瘤内注射 BQ788 3 mg。3 ∼ 7 天后对病灶进行测量和切除以进行分析。第 4 例患者的给药剂量上调至累积剂量 8 mg (4×2.0 mg, 0 ∼ 3天, 在第 4 天切除病灶), 第 5 例患者上调至 10 mg(3×3.3 mg, 0、3、 10 天, 14 天后切除病灶)。同时使用磷酸盐缓冲液 (PBS) 治疗对照病灶。所有标本均在研究者不知晓临床结果的情况下进行处理和分析。
结果. 由于患者数少 (n = 5) 以及给药模式的变异性, 我们无法进行统计学评价。我们在所有给药剂量水平均未观察到不良事件。所有观察结果均与临床前研究获得的结果相一致。相应地, 在 BQ788 和 PBS 处理标本中未观察到肿瘤坏死的程度存在差异。此外, 患者 2 和 5 的 EDNRB 和 Ki67 表达下调, 而患者 1 的下调幅度较小。与此相似, 患者 2 和 5 的 EDNRB mRNA 表达下调, 患者 2 、 3 和 5 的 BCL2A1 和/或 PARP3 表达下调。CD31 和 CD3 免疫组化结果的半定量评分分别提示, 接受 BQ788 治疗的患者 2 和 4 分别出现血管和淋巴细胞增加, 这一点非常重要。同时, 我们在所有患者中均观察到 EDNRB 和 HIF1A 表达水平呈负相关。最后, 我们通过测量病灶发现患者 5 (唯一 1 例治疗超过 1 周的患者) 病灶生长受到抑制。
结论. 病灶内注射 BQ788 耐受良好, 且直接和间接迹象均提示治疗减少了黑色素瘤细胞的存活力。The Oncologist 2015;20:1121–1122
Trial registration: ClinicalTrials.gov NCT02442466.
©AlphaMed Press; the data published online to support this summary is the property of the authors.