评估转移性钙化抗性前列腺癌患者在镭-223基础上加用 Pembrolizumab 的随机 II 期研究。

IF 8.1 1区 医学 Q1 IMMUNOLOGY
Atish D Choudhury, Lucia Kwak, Alexander Cheung, Kathryn M Allaire, Jaqueline Marquez, David D Yang, Abhishek Tripathi, Jacqueline M Kilar, Meredith Flynn, Brianna Maynard, Rebecca Reichel, Amanda F Pace, Brandon K Chen, Eliezer M Van Allen, Kerry Kilbridge, Xiao X Wei, Bradley A McGregor, Mark M Pomerantz, Rupal S Bhatt, Christopher J Sweeney, Glenn J Bubley, Heather A Jacene, Mary-Ellen Taplin, Franklin W Huang, Lauren C Harshman, Lawrence Fong
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引用次数: 0

摘要

检查点免疫疗法 pembrolizumab 可诱导少数转移性去势抵抗性前列腺癌(mCRPC)患者产生反应。镭-223(R223)可能会增加骨转移灶的免疫原性并提高pembrolizumab(P)的活性。在一项随机II期研究中,我们评估了R223+P与R223相比对mCRPC患者肿瘤免疫浸润、安全性和临床结果的影响。研究的主要终点是 8 周骨转移活检中 CD4+ 和 CD8+ T 细胞浸润与基线的差异;次要终点是安全性、放射学无进展生存期 (rPFS) 和总生存期 (OS)。在42例接受治疗的患者(29例R223+P,13例R223)中,18例R223+P和8例R223患者有可评估的配对肿瘤活检。R223+P的CD4+ T细胞中位折叠变化为-0.7(范围:-9.3至4.7),R223的CD4+ T细胞中位折叠变化为0.1(-11.1至3.7)(P = 0.66);R223+P的CD8+ T细胞中位折叠变化为-0.6(-7.4至5.3),R223的CD8+ T细胞中位折叠变化为-1.3(-3.1至4.8)(P = 0.66)。R223+P的中位rPFS和OS分别为6.1个月(95%置信区间:2.7-11.0)和16.9个月[12.7个月未达标(NR)],R223的中位rPFS和OS分别为5.7个月(2.6-NR)和16.0个月(9.0-NR)。虽然 R223+P 的耐受性良好,没有出现意外毒性,但联合用药并未提高疗效。高维流式细胞术显示,R223 对免疫调节的作用微乎其微,而 R223+P 则诱导循环 CD4+ T 细胞表达 CTLA-4。临床应答者在基线时拥有较低的 Ki67+ T 细胞和髓系细胞循环频率,到第 9 周时拥有较高的 TIM-3+ T 细胞和髓系细胞循环频率。虽然R223+P没有诱导T细胞浸润到肿瘤微环境中,但诱导的外周T细胞免疫反应耗竭可能会抑制该组合的临床活性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Randomized Phase II Study Evaluating the Addition of Pembrolizumab to Radium-223 in Metastatic Castration-resistant Prostate Cancer.

The checkpoint immunotherapeutic pembrolizumab induces responses in a small minority of patients with metastatic castration-resistant prostate cancer (mCRPC). Radium-223 (R223) may increase immunogenicity of bone metastases and increase pembrolizumab (P) activity. In a randomized phase II study, we assessed the effect of R223+P compared with R223 on tumor immune infiltration, safety, and clinical outcomes in patients with mCRPC. The primary endpoint was differences in CD4+ and CD8+ T-cell infiltrate in 8-week versus baseline bone metastasis biopsies; secondary endpoints were safety, radiographic progression-free survival (rPFS), and overall survival (OS). Of the 42 treated patients (29 R223+P, 13 R223), 18 R223+P and 8 R223 patients had evaluable paired tumor biopsies. Median fold-change of CD4+ T cells was -0.7 (range: -9.3 to 4.7) with R223+P and 0.1 (-11.1 to 3.7) with R223 (P = 0.66); for CD8+ T cells, median fold-change was -0.6 (-7.4 to 5.3) with R223+P and -1.3 (-3.1 to 4.8) with R223 (P = 0.66). Median rPFS and OS was 6.1 (95% confidence interval: 2.7-11.0) and 16.9 months [12.7-not reached (NR)], respectively, with R223+P and 5.7 (2.6-NR) and 16.0 (9.0-NR), respectively, with R223. Although R223+P was well tolerated with no unexpected toxicity, the combination did not improve efficacy. High-dimensional flow cytometry demonstrated minimal immune modulation with R223, whereas R223+P induced CTLA-4 expression on circulating CD4+ T cells. Clinical responders possessed lower circulating frequencies of Ki67+ T and myeloid cells at baseline and higher circulating frequencies of TIM-3+ T and myeloid cells by week 9. Although R223+P did not induce T-cell infiltration into the tumor microenvironment, exhaustion of induced peripheral T-cell immune responses may dampen the combination's clinical activity.

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来源期刊
Cancer immunology research
Cancer immunology research ONCOLOGY-IMMUNOLOGY
CiteScore
15.60
自引率
1.00%
发文量
260
期刊介绍: Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes. Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.
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