Safety, Antitumor Activity, and T-cell Responses in a Dose-Ranging Phase I Trial of the Oncolytic Peptide LTX-315 in Patients with Solid Tumors
Safety, Antitumor Activity, and T-cell Responses in a Dose-Ranging Phase I Trial of the Oncolytic Peptide LTX-315 in Patients with Solid Tumors
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DOI：
10.1158/1078-0432.ccr-20-3435
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发表时间：
2021-05-15
影响因子：
11.5
通讯作者：
Rekdal, Oystein
中科院分区：
文献类型：
--
作者：
Spicer, James;Marabelle, Aurelien;Rekdal, Oystein
目的：LTX-315是一种一流的9聚体膜溶解肽，在临床前模型中显示出强效的免疫调节特性。我们进行了一项I期剂量递增研究肿瘤内LTX-315给药晚期实体瘤patients with advanced solid tumors.Patients and Methods：39例患者入组，接受LTX-315注射到可访问的肿瘤。主要目的是评估这种方法的安全性和耐受性，抗肿瘤和免疫调节活性作为次要目的。肿瘤活检标本收集在基线和治疗后的免疫学parameters.Results分析：最常见的治疗相关的1-2级不良事件是血管疾病，包括短暂性低血压（18例，46%），潮红（11例，28%），和注射部位的反应，在38%的患者。最常见的3级LTX-315相关毒性为超敏反应或过敏反应（4例患者，10%）。对系列活检的免疫终点分析表明，LTX-315诱导坏死和CD 8（+）T细胞浸润到肿瘤微环境中。外周血中T细胞受体库的测序鉴定了治疗后T细胞克隆的显著扩增，其中49%存在于治疗后可用的肿瘤活检中，表明它们与肿瘤相关。29%的患者注射肿瘤体积显著缩小（>= 30%），86%（12/14例活检）的患者治疗后病灶内CD 8（+）T细胞增加。LTX-315治疗后未观察到免疫相关应答标准的部分应答，但证实了远端效应的证据。结论：LTX-315具有可接受的安全性，具有临床活性，诱导肿瘤微环境的变化，有助于免疫介导的抗癌活性。
Purpose: LTX-315 is a first-in-class, 9-mer membranolytic peptide that has shown potent immunomodulatory properties in preclinical models. We conducted a phase I dose-escalating study of intratumoral LTX-315 administration in patients with advanced solid tumors.Patients and Methods: Thirty-nine patients were enrolled, receiving LTX-315 injections into accessible tumors. The primary objective was to assess the safety and tolerability of this approach, with antitumor and immunomodulatory activity as secondary objectives. Tumor biopsies were collected at baseline and posttreatment for analysis of immunologic parameters.Results: The most common treatment-related grade 1-2 adverse events were vascular disorders including transient hypotension (18 patients, 46%), flushing (11 patients, 28%), and injection site reactions in 38% of patients. The most common grade 3 LTX-315-related toxicities were hypersensitivity or anaphylaxis (4 patients, 10%). Analysis of immune endpoints in serial biopsies indicated that LTX-315 induces necrosis and CD8(+) T-cell infiltration into the tumor microenvironment. Sequencing of the T-cell receptor repertoire in peripheral blood identified significant expansion of T-cell clones after treatment, of which 49% were present in available tumor biopsies after treatment, suggesting that they were tumor associated. Substantial volume reduction (>= 30%) of injected tumors occurred in 29% of the patients, and 86% (12/14 biopsies) had an increase in intralesional CD8(+) T cells posttreatment. No partial responses by immune-related response criteria were seen, but evidence of abscopal effect was demonstrated following treatment with LTX-315.Conclusions: LTX-315 has an acceptable safety profile, is clinically active, induces changes in the tumor microenvironment and contributes to immune-mediated anticancer activity.