COM701+nivolumab+/-BMS-986207治疗铂耐药卵巢癌患者后的免疫调节和基线生物标志物与临床获益的相关性

Gady Cojocaru, Zoya Alteber, Assaf Wool, Adi Shuchami, Inbal Barbiro, Roy Granit, Yu Liang, Zurit Levine, Pierre Ferre, Eran Ophir
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引用次数: 0

摘要

COM701是一种1tin类t细胞检查点抑制剂,与PVRIG结合,阻断其与肿瘤和抗原呈递细胞上表达的PVRL2的相互作用。我们已经报道了COM701+nivolumab+/-BMS-986207(抗tigit)在铂耐药卵巢癌(PROC)患者中的初始抗肿瘤活性。检查点抑制剂在PROC患者中活性有限,特别是在PD-L1和T细胞浸润减少的患者中在这里,我们对COM701+nivolumab+/-BMS-986207治疗的PROC患者进行了初步的转化评估。方法收集COM701+nivolumab+/-BMS-986207 Q4W (NCT03667716和NCT04570839)治疗患者的预处理活检(n=28)和治疗中活检(n=21),并进行抗pd - l1、抗cd8、抗pvrl2和抗pvrig的免疫组化染色。选择的活检组织进行ImmunoID NeXT检测。对两项研究的患者免疫组化数据进行汇总分析。结果PR或SD<180天的患者(按RECIST)被定义为与NCB患者(PD或SD<180)相比具有临床获益(CB)。临床反应与PD-L1、CD8和PVRIG基线表达无关:3/7的CB患者基线PD-L1 CPS<CB和NCB患者的中位CD8和PVRIG前期水平相似(图1A)。相比之下,较高的基线PVRL2 h评分与疗效相关,CB患者中位PVRL2评分为290,而NCB患者中位PVRL2评分为240 (p=0.05,图1B)。检查肿瘤结构基因组变异(通过外显子组- dna - eq)显示,一名应答患者(PR)具有基因组PVRL2扩增,基线PVRL2 h -评分为300(图2A)。TCGA分析显示,卵巢和胃肿瘤的PVRL2扩增率约为3-5%,这与mRNA的高表达相关(图2B)。研究免疫调节,CD8在8/13名配对活检患者中显示增加,其中CB患者的CD8增加明显,并且三重阻断与双重阻断治疗的患者CD8增加趋势更强(图3)。3名CB患者的配对TCR测序显示TCRb克隆数量增加。其中最主要的治疗克隆出现在治疗前,并在治疗后的TME中扩增(图4)。PR患者的免疫组化和mRNA(反卷积评分)显示CD8增加,同时t细胞克隆数量和克隆性增加,M1巨噬细胞增加。这些结果表明,无论肿瘤基线炎症状态如何,COM701治疗组合在临床反应和免疫调节方面都是有效的。此外,PVRIG配体、PVRL2的表达与临床获益之间的初步相关性可能表明,基线PVRL2有潜力作为一种生物标志物,丰富有反应的患者。参考文献摘要#159P;ESMO-IO 2022摘要#158P;ESMO-IO;[J] .中华临床医学杂志,2011;39(33):3671-3681
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29 Immune modulation and baseline biomarker correlation with clinical benefit following treatment with COM701+nivolumab+/-BMS-986207 in patients with platinum resistant ovarian cancer

Background

COM701 is a 1stin-class, T-cell checkpoint-inhibitor that binds to PVRIG, blocking its interaction with PVRL2 expressed on tumor and antigen-presenting cells. We have reported initial anti-tumor activity of COM701+nivolumab+/-BMS-986207 (anti-TIGIT) in patients with platinum-resistant ovarian cancer (PROC).1 2 Checkpoint inhibitors have limited activity in PROC patients, particularly in patients with reduced PD-L1 and T cell infiltration.3 Here, we present preliminary translational assessment of PROC patients treated with COM701+nivolumab+/-BMS-986207.

Methods

Pretreatment (n=28) and on-treatment (n=21) biopsies were collected from patients treated with COM701+nivolumab+/-BMS-986207 Q4W (NCT03667716 and NCT04570839) and subjected to IHC stain with anti-PD-L1, anti-CD8, anti-PVRL2 and anti-PVRIG. Selected biopsies were subjected to ImmunoID NeXT assay. Patient IHC data from both studies were pooled for analysis.

Results

Patients with PR or SD>180 days (per RECIST) were defined as having clinical benefit (CB) versus NCB patients (PD or SD<180). Clinical responses were independent of PD-L1, CD8 and PVRIG baseline expression: 3/7 CB patients had baseline PD-L1 CPS<1; median CD8 and PVRIG pre-levels were similar for both CB and NCB patients (figure 1A). In contrast, higher baseline PVRL2 H-score was correlated with response with median PVRL2 score of 290 in CB versus 240 NCB patients (p=0.05, figure 1B). Examining tumor structural genomic-variants (by exome-DNAseq) revealed one responding patient (PR) with a genomic PVRL2-amplification and baseline PVRL2 H-score of 300 (figure 2A). TCGA analysis revealed that ovarian and gastric-tumors have an amplification of PVRL2 rate of ~3–5% which is correlated with higher mRNA expression (figure 2B). Investigating immune modulation, CD8 increase was shown in 8/13 patients with paired biopsies, with a prominent increase in CB patients and trend for stronger CD8 increase in patients treated with triple versus dual blockade (figure 3). Paired TCR sequencing of three CB patients demonstrated an increase in the number of TCRb clones, where the most dominant on-treatment clones were present pretreatment and expanded in the TME following treatment (figure 4). CD8 increase demonstrated by IHC and mRNA (deconvolution-score) in a patient with PR, was accompanied by an increase in T-cell clone numbers and clonality and increase in M1 macrophages, while M2 macrophages mRNA-signature decreased (figure 5).

Conclusions

These results demonstrate the efficacy of COM701 treatment combinations in terms of clinical responses and immune modulation, regardless of the tumor baseline inflammatory status. In addition, the preliminary correlation between the expression of the PVRIG ligand, PVRL2, and clinical benefit may suggest the potential of baseline PVRL2 as a biomarker to enrich for responding patients.

References

Abstract #159P; ESMO-IO 2022 Abstract #158P; ESMO-IO; 2022 J Clin Oncol. 2021 Nov 20;39(33):3671–3681
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