Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Urology, University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Res Commun. 2024 Sep 1;4(9):2444-2453. doi: 10.1158/2767-9764.CRC-24-0237.
We performed a pilot study of daratumumab (an mAb directed against CD38) in muscle-invasive bladder cancer (MIBC) and treatment-refractory metastatic renal cell carcinoma (mRCC).
Patients with MIBC underwent baseline transurethral resection of the bladder tumor followed by four weekly doses of daratumumab prior to cystectomy. Patients with mRCC underwent baseline and sequential biopsies after eight weekly doses. The primary endpoint was safety. The secondary endpoints were pathologic complete response rate for the MIBC cohort and objective response rate and progression-free survival for the mRCC cohort. Exploratory analyses included immune monitoring and overall survival. A Bayesian sequential monitoring design for toxicity was used for excessive toxicity.
In both the MIBC (n = 8) and mRCC (n = 8) cohorts, no toxicity events were encountered. In the MIBC cohort, one patient experienced pathologic complete response rate. In the mRCC cohort, no objective responses were reported, and the median progression-free survival was 1.5 months (95% confidence interval, 1.1-1.8 months). Immune monitoring found significant reductions in NK cells in circulation in both cohorts after treatment. In the tissue analysis, IHC found evidence of diminished CD38 presence in mRCC with treatment, whereas the baseline levels in MIBC were low.
Treatment with daratumumab was safe. No signal of efficacy was detected in mRCC, and conclusions on the activity in MIBC were limited. Evidence of daratumumab targeting CD38 was detected in circulating immune cells and within the tumor microenvironment of mRCC and MIBC.
In this prospective clinical trial of daratumumab, treatment in patients with MIBC and mRCC was safe. Limited efficacy was observed. Treatment with daratumumab resulted in CD38-expressing immune cell subsets to be targeted both in circulation and within the tumor microenvironment.
我们对肌层浸润性膀胱癌（MIBC）和治疗抵抗转移性肾细胞癌（mRCC）患者进行了达妥木单抗（一种针对 CD38 的 mAb）的初步研究。
MIBC 患者接受基线经尿道膀胱肿瘤切除术，然后在膀胱切除术前接受每周 4 次达妥木单抗治疗。mRCC 患者在接受每周 8 次治疗后进行基线和序贯活检。主要终点是安全性。次要终点为 MIBC 队列的病理完全缓解率和 mRCC 队列的客观缓解率和无进展生存期。探索性分析包括免疫监测和总生存期。贝叶斯序贯毒性监测设计用于毒性过度。
在 MIBC（n=8）和 mRCC（n=8）队列中，均未发生毒性事件。在 MIBC 队列中，1 例患者出现病理完全缓解率。在 mRCC 队列中，未报告客观缓解，中位无进展生存期为 1.5 个月（95%置信区间，1.1-1.8 个月）。免疫监测发现，治疗后两个队列的循环 NK 细胞数量均显著减少。在组织分析中，IHC 发现 mRCC 中治疗后 CD38 存在减少的证据，而 MIBC 中的基线水平较低。
达妥木单抗治疗安全。mRCC 未发现疗效信号，对 MIBC 活性的结论有限。在 mRCC 和 MIBC 的循环免疫细胞和肿瘤微环境中均检测到达妥木单抗靶向 CD38 的证据。
在这项达妥木单抗的前瞻性临床试验中，MIBC 和 mRCC 患者的治疗安全。观察到有限的疗效。达妥木单抗治疗导致 CD38 表达的免疫细胞亚群在循环和肿瘤微环境中均成为靶点。
