Wouters Jasper, Hunger Robert E, Garrod Terence, Dubuis Benoit, Hunziker Thomas, van den Oord Joost J, Lahav-le Coutre Ronit
Translational Cell and Tissue Research, Department of Imaging and Pathology, University of Leuven (KU Leuven), Leuven, Belgium;
Department of Dermatology, Inselspital, Bern, Switzerland;
Oncologist. 2015 Oct;20(10):1121-2. doi: 10.1634/theoncologist.2015-0139. Epub 2015 Sep 1.
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.
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.
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.
The intralesional applications of BQ788 were well tolerated and showed signs of directly and indirectly reducing the viability of melanoma cells.
这项首次在人体进行的概念验证研究旨在检验通过瘤内注射内皮素受体B（EDNRB）拮抗剂BQ788获得的安全性和临床前结果是否能在人类黑色素瘤患者中得到重复。
三名患者接受了一次3毫克的瘤内BQ788注射。3至7天后，对病灶进行测量并切除以进行分析。患者4的给药剂量增加到累积剂量8毫克（4×2.0毫克，第0至3天；第4天切除病灶），患者5的给药剂量增加到10毫克（3×3.3毫克，第0、3和10天；14天后切除病灶）。对照病灶同时用磷酸盐缓冲盐水（PBS）治疗。所有样本在不知道临床结果的情况下进行处理和分析。
由于患者数量（n = 5）和给药方式的变异性，无法进行统计评估。无论给药剂量如何，均未观察到不良事件。所有观察结果均与临床前研究结果一致。因此，在BQ788治疗组和PBS治疗组的样本之间未检测到肿瘤坏死程度的差异。此外，EDNRB和Ki67在患者2和5中表达降低，在患者1中表达降低程度较小。同样，在患者2和5中发现EDNRB mRNA表达降低，在患者2、3和5中发现BCL2A1和/或PARP3表达降低。重要的是，对患者2和4的BQ788治疗的肿瘤进行半定量评分的免疫组织化学显示，CD31和CD3分别显示更多的血管和淋巴细胞。此外，在所有患者中，我们观察到EDNRB和HIF1A表达水平呈负相关。最后，在患者5（唯一接受治疗超过1周的患者）中，通过大小测量显示病灶生长受到抑制。
瘤内注射BQ788耐受性良好，并显示出直接和间接降低黑色素瘤细胞活力的迹象。
