编者按：2024年美国临床肿瘤学会（ASCO）年会即将于当地时间5月31日至6月4日在芝加哥隆重召开。ASCO年会作为世界上规模最大、学术水平最高、最具权威的临床肿瘤学会议之一，每年都汇聚了全球顶尖肿瘤学专家，共同分享和探讨国际临床肿瘤学领域的最新研究成果和治疗技术。北京时间2024年5月24日上午ASCO公布了超过5000份摘要内容，本文对消化道肿瘤领域免疫治疗专场部分口头摘要以及快速口头摘要内容进行介绍，以飨读者。

GUCY2C CAR-T疗法IM96应用于转移性结直肠癌患者中的Ⅰ期研究

摘要号：2518

背景

转移性结直肠癌（mCRC）的临床治疗效果一直受到限制，尤其在肝转移的情况下。近年来，研究人员发现了一种新的治疗策略，即通过靶向Guanylyl cyclase 2C（GUCY2C）来开发嵌合抗原受体T细胞（CAR-T）疗法。GUCY2C在所有阶段的结直肠癌（CRC）中均呈异位表达，且主要局限于肠道。针对这一特性，研究者们成功研发出了一款名为IM96的GUCY2C靶向CAR-T疗法，并开展了一项Ⅰ期临床试验（NCT05287165），旨在评估其安全性和有效性。

方法

这项开放标签的“3+3”剂量递增研究招募了GUCY2C阳性的mCRC患者，这些患者之前至少接受过3种治疗方案但效果不佳。在接受IM96治疗前，患者需先接受氟达拉滨和环磷酰胺预处理。随后，给予患者单次IM96输注，剂量分别为3×108（DL1）、6×108（DL2）、12×108（DL3）或20×108（DL4）CAR-T细胞。在DL3剂量下，研究还进行了剂量扩展研究。本研究的主要终点是评估IM96的安全性和毒性，次要终点则包括评估其疗效和药代动力学特性。

结果

截至2023年12月，共有20例患者入组并接受了IM96的输注。所有患者的随访时间为7~19个月。患者的中位年龄为52.5岁，其中男性患者11例，肝转移患者有11例（55%）。所有患者均表现为错配修复正常（pMMR）状态，其中12例（60.0%）患者存在KRAS突变，1例（5.0%）患者存在NRAS突变，3例（15.0%）患者存在BRAF突变。19例患者接受了桥接治疗。
在安全性方面，仅有1例（5.0%）患者出现了神经毒性和≥3级的细胞因子释放综合征（CRS）。16例（80.0%）患者出现了1~2级CRS，并伴随白细胞介素-6的显著升高。此外，14例（70.0%）患者出现了1~3级皮疹，11例（55.0%）患者出现了3级腹泻，而7例（35.0%）患者出现了1~3级口腔粘膜炎，这些症状主要出现在DL2、DL3和DL4剂量组。研究期间，未观察到剂量限制性毒性或最大耐受剂量。
在疗效评估方面，对于19例可评估的患者，疾病控制率（DCR）达到了73.7%。其中，部分患者出现了显著的肿瘤缩小和症状改善。此外，研究者还观察到IM96在患者体内具有良好的药代动力学特性，表明其能够有效作用于靶点并发挥治疗作用。

结论

本研究表明，IM96在pMMR mCRC患者中具有持久疗效和可接受的安全性，特别是在肝转移患者中显示出较高的治疗潜力。

临床试验信息：NCT05287165

抗CLDN18.2/CD3双特异性抗体IBI389在实体瘤、胃或胃食管肿瘤患者中的安全性和初步疗效结果：一项Ⅰ期剂量递增和扩展研究

背景

CLDN18.2在多种实体肿瘤中表达，尤其在胃癌中，显示出其作为抗肿瘤治疗的新型靶点的潜力。IBI389是一种抗CLDN18.2/CD3双特异性抗体，通过连接T细胞受体复合物中的CD3分子和肿瘤细胞膜上的CLDN18.2抗原，诱导免疫突触的形成。本研究报告了IBI389在晚期实体瘤患者中的安全性和有效性的初步研究结果。

方法

该研究纳入不耐受标准治疗或标准治疗失败的晚期实体瘤患者。IBI389单药治疗的剂量递增采用了患者内剂量递增的加速滴定法和经典的“3+3”设计（从0.003 μg/kg到600 μg/kg）。在剂量递增阶段后，选择了特定的剂量水平，对晚期胃癌/胃食管交界处癌（G/GEJ C）和胰腺导管腺癌（PDAC）患者进行扩展研究。主要终点是安全性，次要终点是疗效，包括通过研究者根据RECIST v1.1标准进行评估的客观缓解率（ORR）和DCR。

结果

截至2024年1月9日，共入组114例患者（男性：67.5%，中位年龄：60.0岁，G/GEJ C：32.5%，PDAC：57.9%，IV期：81.6%）。在剂量递增过程中未观察到剂量限制性毒性（DLT），且最大耐受剂量（MTD）未达到。在所有患者中，112例（98.2%）发生了治疗相关的不良事件（TEAEs），其中76例（66.7%）发生了≥3级的TEAEs。111例（97.4%）患者发生了治疗相关的不良事件（TRAEs），其中63例（55.3%）发生了≥3级的TRAEs。最常见的≥3级TRAEs（≥4%）包括γ-谷氨酰转肽酶升高（21.9%）、淋巴细胞计数减少（13.2%）和恶心（4.4%）。65例（57.0%）患者发生了CRS相关的不良事件，其中1例（0.9%）患者发生了3级CRS，无4级或5级CRS。两组分别有44例（38.6%）和8例（7.0%）患者因TEAEs导致剂量中断和治疗中断。
在CLDN18.2表达≥10%（免疫组织化学2+/3+）的患者中观察到了IBI389的初步疗效。在先前接受过≥2线治疗的G/GEJ C患者中，接受IBI389治疗（剂量范围从10 μg/kg到600 μg/kg，n=26）的患者有8例获得部分缓解（PR），11例疾病稳定（SD）。ORR为30.8%（95%CI：14.3~51.8），DCR为73.1%（95%CI：52.2~88.4）。

结论

IBI389在晚期实体瘤患者中显示出可管理的安全性特征，并在CLDN18.2阳性的G/GEJ C患者中显示出初步疗效。
临床试验信息：NCT05164458

Claudin18.2靶向嵌合抗原受体T细胞治疗胃肠道癌症患者：CT041-CG4006的Ⅰ期试验最终结果

摘要号：2501

背景

CT041-CG4006试验（NCT03874897）探索了自体抗Claudin18.2（CLDN18.2）CAR-T细胞，即satricabtagene autoleucel（satri-cel）/CT041在胃肠道肿瘤中的应用，并且其中期结果已于2022年6月发布，本文报告了该试验的最终结果。

方法

该研究是一项单臂、开放标签、Ⅰ期临床试验，评估了CT041在CLDN18.2阳性晚期胃肠道（GI）肿瘤患者中的安全性和有效性。试验包括剂量递增（250×106、375×106、500×106或1000×106细胞）阶段，采用改良的“3+3”设计，以及CT041在四个队列中的剂量扩展（队列1：CT041治疗经过预处理的GI患者；队列2：CT041 联合抗 PD-1 治疗经过预处理的晚期GI患者；队列3：在GC患者一线治疗之后，使用 CT041 进行序贯治疗；队列4：CT041治疗抗 CLDN18.2 抗体治疗失败后的患者）。主要终点是安全性，次要终点是使用RECIST v1.1评估的有效性、药代动力学和免疫原性。

结果

从2019年3月26日至2024年1月26日，共有98例患者接受了CT041输注，包括GC（n=73）、胰腺癌（n=10）、胆道癌（n=4）、肠癌（n=8）和其他肿瘤（n=3）。共有89例患者接受了250×106剂量，6例患者接受了375×106剂量，3例患者接受了500×106剂量，中位随访时间为29.7个月。基于剂量递增结果，选择了250×106作为剂量扩展阶段的剂量。最常见报告的3级或更高级别的治疗相关不良事件是与淋巴清除相关的血液毒性。未报告剂量限制性毒性、与治疗相关的死亡或免疫效应细胞相关神经毒性综合征。96.9%的患者发生CRS，均为1~2级。8例（8.2%）患者发生胃粘膜损伤，包括7例1~2级和1例3级糜烂性胃炎，后者已恢复。对于所有患者（N=98），ORR和DCR分别达到37.8%和75.5%。
所有患者的中位PFS和中位总生存期（OS）分别为4.4个月（95%CI：4.0~6.0）和8.4个月（95%CI：7.0~10.0）。在接受CT041单药治疗的疗效可评估的GC患者中，可测量疾病患者（n=47）的ORR和DCR分别为57.4%和83.0%，所有疗效可评估的GC患者（n=55）的中位PFS和中位OS分别为5.8个月（95%CI：4.2~8.4）和9.7个月（95%CI：7.1~14.4）。

结论

Satri-cel/CT041在CLDN18.2阳性晚期GI肿瘤患者中的安全性表现良好，疗效鼓舞人心。
临床试验信息：NCT03874897

抗CCR8单克隆抗体LM-108联合抗PD-1抗体治疗胃癌患者的有效性和安全性：Ⅰ/Ⅱ期研究结果

摘要号：2504

背景

靶向肿瘤浸润性调节性T细胞（Tregs）是克服癌症免疫治疗抵抗的潜在方法之一。LM-108是一种新型的Fc优化型抗CCR8单克隆抗体，能选择性消耗肿瘤浸润性Tregs。本文报告了3项Ⅰ/Ⅱ期研究（NCT05199753；NCT05255484；NCT05518045）的汇总分析结果，以评估LM-108联合抗PD-1疗法在胃癌患者中的疗效和安全性。

方法

纳入分析的是接受LM-108联合抗PD-1抗体治疗的符合条件的胃癌患者。患者接受静脉注射LM-108，剂量水平为3 mg/kg Q2W、6 mg/kg Q3W或10 mg/kg Q3W，同时联合使用抗PD-1抗体（静脉注射帕博利珠单抗200 mg Q3W或400 mg Q6W或特瑞普利单抗240 mg Q3W）。主要终点是研究者根据RECIST v1.1评估的ORR。次要终点包括安全性、其他疗效指标和生物标志物分析。汇总分析的数据截止日期为2023年12月25日。

结果

共有来自中国、美国和澳大利亚的48例胃癌患者（中位年龄：60.5岁；男性：72.9%）接受了至少1剂LM-108联合帕博利珠单抗或特瑞普利单抗的治疗。大多数患者（n=47，97.9%）先前至少接受过1次抗癌治疗，其中43例（89.6%）患者接受过抗PD-1治疗。39例（81.3%）患者发生了TRAEs，其中最常见的事件（≥15%）包括丙氨酸转氨酶升高（25.0%）、天冬氨酸转氨酶升高（22.9%）、白细胞减少（22.9%）和贫血（16.7%）。18例（37.5%）患者发生了≥3级的TRAEs，最常见的事件（≥4%）包括贫血（8.3%）、脂肪酶升高（4.2%）、皮疹（4.2%）和淋巴细胞计数减少（4.2%）。
在所有方案中，36例可评估疗效的患者中，ORR为36.1%（95%CI：20.8%～53.8%），DCR为72.2%（95%CI：54.8%～85.8%）。中位PFS为6.53个月（95%CI：2.96个月～无法估计）。在11例一线治疗失败的患者中，ORR为63.6%（95%CI：30.8%～89.1%），DCR为81.8%（95%CI：48.2%～97.7%）。在这11例患者中，有8例患者CCR8表达水平高。在这8例患者中，ORR为87.5%，DCR为100%，观察到1例完全缓解（CR），6例PR和1例SD。

结论

LM-108联合抗PD-1抗体在抗PD-1治疗抵抗的胃癌患者中显示出有希望的抗肿瘤活性，且联合疗法耐受性良好。这些结果支持进一步评估LM-108在CCR8阳性胃癌中的疗效。

临床试验信息：

NCT05199753；NCT05255484；NCT05518045

肿瘤源性免疫抑制因子GDF-15的中和对抗PD-1活性的研究：在复发/难治性非鳞状非小细胞肺癌、尿路上皮癌和肝细胞癌抗PD-L1患者中的效果

摘要号：2513

背景

本研究首次揭示了生长因子15（GDF-15）在非小细胞肺癌（NSCLC）、尿路上皮癌（UC）和肝细胞癌（HCC）中作为免疫抑制因子的作用。研究还提供了临床证据，表明通过visugromab阻断GDF-15可以恢复抗PD1活性，对接受抗PD1/PD-L1治疗但复发或耐药的最后线治疗患者有益。

方法

研究团队进行了一项大型转化研究计划，分析了癌症基因组图谱（TCGA）中的超过11000个肿瘤样本，并研究了配对血清/肿瘤样本中GDF-15对肿瘤微环境的影响。在GDFather ph2a首次人体visugromab试验中，接受晚期、抗PD-1/PD-L1复发或耐药的最后线实体瘤治疗的患者接受了GDF-15中和抗体visugromab（CTL-002）联合纳武利尤单抗的治疗。主要终点是总缓解率（ORR）。

结果

通过计算机模拟TCGA分析，研究发现GDF-15的mRNA表达与关键免疫相关特征之间存在负相关，表明GDF-15在包括非小细胞肺癌和尿路上皮癌在内的多种实体瘤中具有强大的免疫抑制作用。此外，在新诊断的早期尿路上皮癌患者样本中，GDF-15血清水平与CD8+ T细胞密度减少和免疫细胞增殖减少（CD45+ki67+）呈正相关。在ph2a试验中，visugromab联合纳武利尤单抗在预先接受大量治疗的患者中显示出良好的总体耐受性，不良反应较少。在NSCLC、UC和HCC患者中，观察到的ORR分别为13.5%、17.6%和18.8%，并且部分患者的缓解持续时间已超过12个月。

结论

本研究分析了GDF-15在非小细胞肺癌、尿路上皮癌和肝细胞癌肿瘤微环境中的免疫抑制作用，并将其识别为潜在的导致CPI抵抗的关键因素。在接受严格标准筛选的抗PD-1/PD-L1复发或耐药、晚期/最后线治疗的患者中，通过visugromab中和GDF-15联合纳武利尤单抗治疗，这些肿瘤类型的ORR达到了16.1%，并且缓解具有较长的持久性。

临床试验信息：NCT04725474

摘要原文

（一）Background:The clinical outcomes of metastatic colorectal cancer (mCRC) therapies are limited, especially for liver metastasis. Guanylyl cyclase 2C (GUCY2C) is ectopically expressed in all stages of CRC and intestinally restricted. GUCY2C-targeted CAR-T (IM96) was developed and phase I study was conducted to evaluate the safety and efficacy (NCT05287165).Methods:In this open-label, 3+3 dose-escalation study, IM96 was evaluated in GUCY2C-positive mCRC patients (pts) failed to ≥3 lines of therapies. Pts were pre-treated with fludarabine and cyclophosphamide, and received a single infusion of IM96 at the dose of 3×108 (DL1), 6×108 (DL2), 12×108 (DL3), or 20×108 (DL4) CAR-T cells. Dose-expansion study was performed at DL3. The primary objectives were safety and toxicity, and the secondary objectives were efficacy and pharmacokinetic profile.Results:As of December 2023, 20 pts were enrolled and infused with IM96. The follow-up time was 7-19 months for all pts. The median age was 52.5, and 11/20 cases were male. Liver metastasis was found in 11/20 cases (55%), proficient mismatch repair (pMMR) in 20/20 pts (100%), KRAS mutation in 12/20 pts (60.0%), NRAS mutation in 1/20 pts (5.0%), and BRAF mutation in 3/20 pts (15.0%). Bridging therapies were used in 19 pts. Only 1/20 pt (5.0%) showed neurotoxicity and ≥grade 3 cytokine release syndromes (CRS). Grade 1-2 CRS occurred in 16/20 pts (80.0%) with dramatic increase of interleukin-6. Grade 1-3 rash was observed in 14/20 pts (70.0%). Grade 3 diarrhea occurred in 11/20 pts (55.0%), and grade 1-3 oral mucositis appeared in 7/20 pts (35.0%), only in DL2, DL3 and DL4 groups. Dose-limiting toxicity and maximum tolerated dose were not achieved. Among 19 evaluable pts, the disease control rate (DCR) was 73.7%, and the objective response rate (ORR) was 26.3%. In DL3 group, pts showed an ORR of 40.0%, nevertheless of liver metastasis or not. The median progression-free survival time was 7 months, and the median duration of response was 10 months in DL3 group. No responding pts showed disease progression within 6 months. Tumor responses were correlated with significant decreases in carcinoembryonic antigen levels among all pts.Conclusions:This study demonstrated that IM96 has durable efficacy with acceptable safety profile in pMMR mCRC pts, in particularly, showing high therapeutic potential in liver metastasis pts. Clinical trial information: NCT05287165.

（二）Background:CLDN18.2 expression has been observed in various solid tumors especially in gastric cancer, indicating its potential as a novel target for anti-tumor therapy. IBI389 is an anti-CLDN18.2/CD3 bispecific antibody that induces immune synapse formations by linking CD3 molecules in T-cell receptor complexes and CLDN18.2 antigens on the membrane of tumor cells. Herein, we report preliminary results from a phase I study to evaluate safety and efficacy of IBI389 in patients (pts) with advanced solid tumors.Methods:Eligible pts with advanced solid tumors who failed or were intolerant to standard treatments were enrolled. The dose escalation of IBI389 monotherapy used intra-patient dose escalation with accelerated titration and the classic 3+3 design (0.003 μg/kg to 600 μg/kg). Selected dose levels were expanded in pts with advanced gastric/gastroesophageal junction cancer (G/GEJ C) and pancreatic ductal adenocarcinoma (PDAC). The primary objective was safety. Secondary objective was efficacy assessed by investigator per RECIST v1.1 including objective response rate (ORR) and disease control rate (DCR).Results:As of January 9, 2024, a total of 114 pts were enrolled (males: 67.5%, median age: 60.0 years, G/GEJ C: 32.5%, PDAC: 57.9%, stage IV: 81.6%). No dose-limiting toxicity (DLT) was observed during dose escalation. The MTD was not reached. In all pts, treatment-emergent adverse events (TEAEs) occurred in 112 (98.2%) pts including 76 (66.7%) pts with grade ≥3 TEAEs. Treatment-related adverse events (TRAEs) occurred in 111 (97.4%) pts including 63 (55.3%) pts with grade ≥3 TRAEs. The most common grade ≥3 TRAEs (≥ 4%) were gamma-glutamyl transferase increased (21.9%), lymphocyte count decreased (13.2%) and nausea (4.4%). Cytokine release syndrome (CRS) related adverse events occurred in 65 (57.0%) pts including 1 (0.9%) pts with grade 3 CRS and no grade 4 or 5 CRS. TEAEs leading to dose interruption and treatment discontinuation occurred in 44 (38.6%) and 8 (7.0%) pts. Preliminary efficacy of IBI389 was observed in pts with CLDN18.2 expression ≥10% (immunohistochemistry 2+/3+). In G/GEJ C pts with previous treatments ≥2 lines receiving IBI389 at various dose levels ranging from 10μg/kg to 600 μg/kg (n=26), 8 pts had partial response (PR) and 11 pts had stable disease (SD). The ORR was 30.8% (95%CI: 14.3-51.8) and DCR was 73.1% (95%CI: 52.2-88.4).Conclusions:IBI389 showed manageable safety profiles in pts with advanced solid tumors and preliminary efficacy in CLDN18.2-positive pts with G/GEJ C. Clinical trial information: NCT05164458.
（三）Background:Autologous anti-claudin18.2 (CLDN18.2) CAR T cell, satricabtagene autoleucel (satri-cel)/CT041, was investigated in gastrointestinal cancers in clinical trials. The interim results of CT041-CG4006 trial (NCT03874897) were published in June 2022 [1]. Herein, we present the final results of this trial.Methods:This single-arm, open-label, phase 1 trial evaluated the safety and efficacy of CT041 in patients (pts) with CLDN18.2-positive advanced gastrointestinal (GI) cancers. The trial consisted of a dose-escalation (250×106, 375×106, 500×106 or 1000×106cells) using modified ‘3+3’ design and dose expansion of CT041 in 4 cohorts (Cohort 1: CT041 in pretreated pts with advanced GI cancers, Cohort 2: CT041 plus anti-PD-1 therapy in pretreated pts with advanced GI cancers, Cohort 3: CT041 sequential treatment following first-line therapy in gastric cancer (GC) and Cohort 4: CT041 in pts with prior failure to anti-CLDN18.2 antibody). The primary endpoint was safety; secondary endpoints were efficacy using RECIST v1.1, pharmacokinetics, and immunogenicity.Results:From 26 March 2019 to 26 January 2024, a total of 98 pts received CT041 infusion, including GC (n=73), pancreatic cancer (n=10), biliary tract cancer (n=4), intestinal cancer (n=8) and other tumors (n=3). A total of 89 pts were dosed with 250×106, 6 pts with 375×106, and 3 pts with 500×106 cells, with a median follow-up of 29.7 (range: 1.2, 35.5) months. 250×106 was selected for the dose-expansion stage based on the dose-escalation results. The most commonly reported treatment-emergent adverse events of grade 3 or higher were hematologic toxicity related to lymphodepletion. No dose-limiting toxicities, treatment-related deaths, or immune effector cell-associated neurotoxicity syndrome were reported. Cytokine release syndrome occurred in 96.9% of pts, all classified as grade 1-2. Gastric mucosal injuries were identified in 8 (8.2%) pts, including 7 cases of grade 1-2 and 1 case of grade 3 gastritis erosive which recovered. For all pts (N=98), the ORR and DCR reached 37.8% and 75.5%, respectively. The median PFS and median OS were 4.4 (95% CI: 4.0, 6.0) months and 8.4 (95% CI: 7.0, 10.0) months for all pts. Among efficacy evaluable GC pts who received CT041 monotherapy, the ORR and DCR in those with measurable disease (n=47) reached 57.4% and 83.0%, respectively, and the median PFS and median OS in all efficacy evaluable GC pts (n=55) were 5.8 (95% CI: 4.2, 8.4) months and 9.7 (95% CI: 7.1, 14.4) months, respectively.Conclusions:Satri-cel/CT041 demonstrated a promising safety profile and highly encouraging efficacy in heavily pretreated patients with CLDN18.2-positive advanced GI cancers. Clinical trial information: NCT03874897.
（四）Background:Targeting tumor-infiltrating regulatory T cells (Tregs) is a potential approach to overcome immunotherapy resistance in the treatment of cancers. LM-108 is a novel Fc-optimized, anti-CCR8 monoclonal antibody that selectively depletes tumor-infiltrating Tregs. Here we report a pooled analysis of results from 3 phase 1/2 studies (NCT05199753; NCT05255484; NCT05518045) to evaluate the efficacy and safety of LM-108 in combination with anti-PD-1 therapy in patients with gastric cancer.Methods:Eligible patients with gastric cancer treated with LM-108 in combination with an anti-PD-1 antibody were included in the analysis. Patients received intravenous LM-108 at dose levels of 3 mg/kg Q2W, 6 mg/kg Q3W, or 10 mg/kg Q3W plus an anti-PD-1 antibody (intravenous pembrolizumab 200 mg Q3W or 400 mg Q6W or toripalimab 240 mg Q3W). The primary endpoint was investigator-assessed ORR per RECIST v1.1. The secondary endpoints included safety, other efficacy outcomes, and biomarkers analysis. Data cutoff date for the pooled analysis was December 25, 2023.Results:Forty-eight patients with gastric cancer (median age: 60.5 years; male: 72.9%) from China, USA, and Australia were treated ≥ 1 dose of LM-108 in combination with pembrolizumab or toripalimab. Most (n = 47, 97.9%) patients had received at least 1 prior anticancer treatment, and 43 (89.6%) had received prior anti-PD-1 therapy. Treatment-related adverse events (TRAEs) occurred in 39 (81.3%) patients, in which the most common events (≥15%) were alanine transaminase increased (25.0%), aspartate transaminase increased (22.9%), white blood cell decreased (22.9%), anemia (16.7%). Grade ≥ 3 TRAEs occurred in 18 (37.5%) patients, the most common events (≥ 4%) were anemia (8.3%), lipase increased (4.2%), rash (4.2%), and lymphocyte count decreased (4.2%). Among 36 efficacy-evaluable patients across all regimens, ORR was 36.1% (95% CI 20.8%–53.8%) and DCR was 72.2% (95% CI 54.8%–85.8%). The median PFS was 6.53 months (95% CI 2.96–NA). Among 11 patients whose disease had progressed on first-line treatment, ORR was 63.6% (95% CI 30.8%–89.1%) and DCR was 81.8% (95% CI 48.2%–97.7%). Of the 11 patients who progressed on first-line treatment, 8 had high CCR8 expression. Among these 8 patients, ORR was 87.5% and DCR was 100%, with 1 CR, 6 PR, and 1 SD observed.Conclusions:LM-108 in combination with an anti-PD-1 antibody showed promising antitumor activity in patients with gastric cancer that was resistance to anti-PD-1 therapy. The combination therapy was well tolerated. These results support further evaluation of LM-108 in CCR8 positive gastric cancer. Clinical trial information: NCT05199753; NCT05255484; NCT05518045.
（五）Background:Growth and Differentiation Factor 15 (GDF-15) plays a critical role as potent, local immunosuppressant during pregnancy. Here we report for the first time data identifying GDF-15 as immunosuppressant in non-sq NSCLC, urothelial (UC) and hepatocellular (HCC) cancer and provide clinical evidence that GDF-15 blockade with visugromab can restore anti-PD1 activity in last-line, anti-PD1-(L)1 r/r patients with these tumors.Methods:A large translational research program, analyzing > 11.000 tumors in The Cancer Genome Atlas (TCGA) and paired serum/tumor samples for GDF-15 impact on the tumor microenvironment was conducted. In the GDFather ph2a first-in-human visugromab trial, subjects with advanced-stage, anti-PD1/PD-L1 relapsed/refractory (r/r) last-line solid tumors received the GDF-15 neutralizing antibody visugromab (CTL-002) at 10 mg/kg Q2W in combination with nivolumab 240 mg Q2W om three defined expansion cohorts (NSCLC:n=5 2, UC :n=34, HCC: n=16). All patients were either (1) primary refractory to or (2) relapsed on continued checkpoint inhibitor (CPI) therapy after initial response, with all patients having received minimum of 12 weeks of continuous prior anti-PD-1/-L1 exposure. Primary endpoint was ORR.Results:In in-silico TCGA analyses, an inverse correlation between GDF-15 mRNA expression and key immune-related signatures revealed potent immunosuppression of several solid tumors including non-sq NSCLC and UC by GDF-15. In addition, in newly diagnosed, early-line UC patient samples, correlation of GDF-15 serum levels with reduced density of CD8+ T cells and immune cell proliferation (CD45+ki67+) was demonstrated. In the ph2a trial, visugromab + nivolumab showed excellent overall tolerability in heavily pre-treated patients, with just 6.9% of patients experiencing CTCAE Grade ≥ 3 treatment-related adverse events across these three indications. The observed ORR as per RECIST v1.1 criteria was 13.5% (5/37, 4PR, 1CR) in non-sq NSCLC, and 0% (0/15) in sq-NSCLC, in line with the translational research data. In UC, ORR was 17.6% (6/34, 5 PR, 1CR), and in HCC 18.8% (3/16, 2PR, 1CR); with 25 pts continuing on treatment, respectively. Duration of response (DoR) is surpassing 12 months for non-sq and UC lead cohort patients (N = 27 each) already, and 10/14 responses are ongoing.Conclusions:These analyses presented identify GDF-15 as novel, potent immunosuppressant in the tumor microenvironment of non-sq NSCLC, UC and HCC and identify it as potential key cause for CPI resistance. In heavily pretreated, by strict criteria anti-PD-1/-L1 r/r, late/last-line patients with NSCLC, UC and HCC, neutralization of GDF-15 by visugromab in combination with nivolumab resulted in an ORR of 16.1% (14/87; 11 PR and 3 CR) across these indications and long durability. Clinical trial information: NCT04725474.