PO.CL05.05 · 临床研究
接受177Lu-PSMA-617和pembrolizumab治疗的去势抵抗性前列腺癌患者的多组学单细胞评估显示放射性配体治疗的时机会改变免疫反应
Multi-omic single-cell assessment of castration-resistant prostate cancer patients receiving 177 Lu-PSMA-617 and pembrolizumab shows timing of radioligand therapy alters immune response
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：前列腺癌是男性癌症相关死亡的主要原因之一，对检查点抑制难治。1-3镥-177标记的PSMA-617(177Lu-PSMA，Pluvicto)是一种FDA批准用于CRPC的放射性配体疗法。我们已证明单次剂量的177Lu-PSMA具有免疫调节作用，并可在一项1期临床试验(NCT03805594)中与PD-1阻断剂pembrolizumab安全联用。4然而，这些治疗应如何联用的方案尚不明确。
方法：在我们的1期临床试验中，mCRPC患者接受单次剂量的177Lu-PSMA，分别于pembrolizumab之前(方案1，n=30)、与之同时(方案2，n=6)或之后(方案3，n=6)给药。连续采集外周血单个核细胞(PBMC)，并采用多组学单细胞RNA测序(scRNA-seq)进行分析，以剖析这三种方案下的免疫反应。
结果：我们发现，单次剂量的177Lu-PSMA单药治疗导致CD4+效应T细胞以及Treg的扩增，提示其具有直接的免疫调节活性。这伴随NK细胞和B细胞的减少。当177Lu-PSMA与pembrolizumab联用时，在所有三种给药方案中，我们观察到非Treg T细胞亚群(CD4⁺和CD8⁺ T细胞)、树突状细胞(DC)、NK细胞和B细胞的动态变化。方案1和方案2表现出稳定的T细胞水平并伴随DC的逐渐增加，而方案3的特征是T细胞频率低以及相对于基线DC的进行性下降。
结论：我们的研究证明了治疗顺序对于充分发挥单次剂量177Lu-PSMA的放射性配体治疗(RLT)免疫调节潜力、并优化其与PD-1阻断在mCRPC中的协同作用至关重要。以177Lu-PSMA起始或同时开始177Lu-PSMA与pembrolizumab均导致DC增加，而先以pembrolizumab起始则导致T细胞和DC频率降低，提示该方案可能对免疫结局不利。
查看英文原文 English abstract
Background: Prostate cancer, a leading cause of cancer-related death in men, is refractory to checkpoint inhibition. 1-3 Lutetium-177-labeled PSMA-617 ( 177 Lu-PSMA, Pluvicto) is an FDA-approved radioligand therapy in CRPC. We have shown that a single dose of 177 Lu-PSMA is immunomodulatory, and can be safely combined with the PD-1 blockade, pembrolizumab, in a phase 1 clinical trial (NCT03805594). 4 However, the schedule by which these treatments should be combined is unknown.
Methods: In our phase 1 clinical trial, patients with mCRPC received a single dose of 177 Lu-PSMA either before (Schedule 1, n=30), concurrently with (Schedule 2, n=6), or after pembrolizumab (Schedule 3, n=6). Serial peripheral blood mononuclear cells (PBMCs) were collected and analyzed using multi-omic single-cell RNA sequencing (scRNA-seq) to dissect the immune responses with these 3 schedules.
Results: We found that a single dose of 177 Lu-PSMA in monotherapy led to an expansion of CD4+ effector T cells as well as in Tregs indicative of direct immunomodulatory activity. This was accompanied by a reduction in NK and B cells. When 177 Lu-PSMA was combined with pembrolizumab, we saw dynamic changes in non-Treg T cell subsets (CD4⁺ and CD8⁺ T cells), dendritic cells (DCs), NK cells, and B cells across all three dosing schedules. Schedules 1 and 2 demonstrated stable T cell levels accompanied by a gradual increase in DCs, whereas Schedule 3 was characterized by low T cell frequencies and a progressive decline in DCs relative to baseline.
Conclusions: Our study demonstrates the critical importance of treatment sequencing to fully harness the immunomodulatory potential of RLT using a single dose of 177 Lu-PSMA and optimize synergy with PD-1 blockade in mCRPC. While initiating with either 177 Lu-PSMA or concurrently starting 177 Lu-PSMA with pembrolizumab resulted in an increase in DCs, starting with pembrolizumab first resulted in lower frequencies T cells and DCs suggesting that this schedule could be detrimental to immune outcomes.
利益披露 Disclosure
A. Muralidhar, None..
K. Law, None..
Z. Fan, None..
S. Shukla, None..
S. Kwek, None..
D. Y. Oh, None..
R. R. Aggarwal, None..
L. Fong, None.