The intravesical instillation of the paclitaxel-hyaluronan conjugate ONCOFID-P-B™ in patients with bacillus Calmette-Guérin (BCG)-unresponsive bladder carcinoma in situ (CIS; NCT04798703 phase I study), induced 75 and 40% of complete response (CR) after 12 weeks of intensive phase and 12 months of maintenance phase, respectively. The aim of this study was to provide a detailed description of the tumor microenvironment (TME) of ONCOFID-P-B™-treated BCG-unresponsive bladder CIS patients enrolled in the NCT04798703 phase I study, in order to identify predictive biomarkers of response. The composition and spatial interactions of tumor-infiltrating immune cells and the expression of the most relevant hyaluronic acid (HA) receptors on cancer cells, were analyzed in biopsies from the 20 patients enrolled in the NCT04798703 phase I study collected before starting ONCOFID-P-B™ therapy (baseline), and after the intensive and the maintenance phases. Clinical data were correlated with cell densities, cell distribution and cell interactions. Associations between immune populations or HA receptors expression and outcome were analyzed using univariate Cox regression and log-rank analysis. In baseline biopsies, patients achieving CR after the intensive phase had a lower density of intra-tumoral CD8+ cytotoxic T lymphocytes (CTL), but also fewer interactions between CTL and macrophages or T-regulatory cells, as compared to non-responders (NR). NR expressed higher levels of the HA receptors CD44v6, ICAM-1 and RHAMM. The intra-tumoral macrophage density was positively correlated with the expression of the pro-metastatic and aggressive variant CD44v6, and the combined score of intra-tumoral macrophage density and CD44v6 expression had an AUC of 0.85 (95% CI 0.68–1.00) for patient response prediction. The clinical response to ONCOFID-P-B™ in bladder CIS likely relies on several components of the TME, and the combined evaluation of intra-tumoral macrophages density and CD44v6 expression is a potentially new predictive biomarker for patient response. Overall, our data allow to advance a potential rationale for combinatorial treatments targeting the immune infiltrate such as immune checkpoint inhibitors, to make bladder CIS more responsive to ONCOFID-P-B™ treatment.

中文翻译：

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紫杉醇-透明质酸缀合物 (ONCOFID-PB™) 用于治疗卡介苗无反应的膀胱原位癌患者：肿瘤微环境的动态评估

对卡介苗 (BCG) 无反应性膀胱原位癌患者（CIS；NCT04798703 I 期研究）进行膀胱内灌注紫杉醇-透明质酸缀合物 ONCOFID-PB™，术后分别诱导 75% 和 40% 的完全缓解 (CR)分别为 12 周的强化阶段和 12 个月的维持阶段。本研究的目的是详细描述参加 NCT04798703 I 期研究的经 ONCOFID-PB™ 治疗的 BCG 无反应膀胱 CIS 患者的肿瘤微环境 (TME)，以确定反应的预测生物标志物。在开始 ONCOFID-PB™ 之前收集参加 NCT04798703 I 期研究的 20 名患者的活检样本，分析肿瘤浸润免疫细胞的组成和空间相互作用以及癌细胞上最相关的透明质酸 (HA) 受体的表达治疗（基线）以及强化和维持阶段之后。临床数据与细胞密度、细胞分布和细胞相互作用相关。使用单变量 Cox 回归和对数秩分析来分析免疫群体或 HA 受体表达与结果之间的关联。在基线活检中，与无反应者 (NR) 相比，强化期后达到 CR 的患者肿瘤内 CD8+ 细胞毒性 T 淋巴细胞 (CTL) 密度较低，但 CTL 与巨噬细胞或 T 调节细胞之间的相互作用也较少。 NR 表达较高水平的 HA 受体 CD44v6、ICAM-1 和 RHAMM。肿瘤内巨噬细胞密度与促转移和侵袭性变体 CD44v6 的表达呈正相关，患者肿瘤内巨噬细胞密度和 CD44v6 表达的综合评分 AUC 为 0.85 (95% CI 0.68–1.00)响应预测。膀胱 CIS 对 ONCOFID-PB™ 的临床反应可能依赖于 TME 的多个组成部分，肿瘤内巨噬细胞密度和 CD44v6 表达的综合评估是患者反应的潜在新预测生物标志物。总体而言，我们的数据为针对免疫浸润的组合治疗（例如免疫检查点抑制剂）提出了潜在的理论依据，以使膀胱 CIS 对 ONCOFID-PB™ 治疗更加敏感。