肿瘤细胞治疗研究
英文原题：Targeting the intracellular immune checkpoint CISH with CRISPR-Cas9-edited T cells in patients with metastatic colorectal cancer: a first-in-human, single-centre, phase 1 trial.
Targeting the intracellular immune checkpoint CISH with CRISPR-Cas9-edited T cells in patients with metastatic colorectal cancer: a first-in-human, single-centre, phase 1 trial.
这些结果支持通过输注新抗原反应性 CISH 敲除 TIL 来抑制免疫检查点 CISH 的安全性和潜在抗肿瘤活性，这对化疗难治的晚期转移性癌症患者具有意义。
背景：过去十年，主要靶向PD-1/PD-L1免疫检查点轴的免疫治疗策略改变了许多实体瘤的治疗，但目前胃肠道肿瘤患者从中获益者仍较少。亟需使更多患者从免疫治疗中获益，同时解决现有免疫检查点抑制剂耐药问题。本研究旨在评估敲除细胞因子诱导的含SH2结构域蛋白（CISH）的安全性和抗肿瘤活性。CISH是新型细胞内免疫检查点靶点，也是SOCS家族E3连接酶的创始成员；研究采用CRISPR-Cas9基因编辑的TIL（肿瘤浸润淋巴细胞），治疗转移性胃肠道上皮癌患者。方法：这是一项首次人体、单中心、1期试验。纳入18至70岁、患转移性胃肠道上皮癌且至少接受一种一线标准治疗后疾病进展、存在可测量病灶（至少一个病灶可切除用于制备TIL，且另有至少一个符合RECIST标准的可测量病灶用于评估疗效），ECOG体能状态评分为0或1的患者。取肿瘤活检组织中的TIL，根据新抗原反应性进行扩增，并通过CRISPR-Cas9敲除CISH。12例患者在接受非清髓性淋巴细胞清除化疗后静脉输注细胞；化疗方案为研究第−6和−5天给予环磷酰胺（每次60 mg/kg），第−7至−3天给予氟达拉滨（每次25 mg/m²），随后给予大剂量IL-2（阿地白介素；每次720,000 IU/kg）。主要终点为输注CISH基因敲除的新抗原反应性TIL的安全性；关键次要终点为通过影像学客观缓解、无进展生存期和总生存期衡量的抗肿瘤活性。试验注册于ClinicalTrials.gov（NCT04426669），现已完成。结果：2020年5月12日至2022年9月16日期间，共有22名受试者入组（其中1名患者因首次未能扩增出TIL而重复入组）；10名女性、11名男性（均为自我认定），1人为亚裔，其余为白人（均为自我认定）。19例（86%）患者成功制备出CISH敲除TIL产品，其中12例（63%）接受了自体CISH敲除TIL输注。研究中位随访时间为129天（四分位距15–283）。12例患者（100%）均发生治疗相关严重不良事件。最常见的3–4级不良事件包括血液学事件（12例，100%，归因于预处理淋巴细胞清除化疗或IL-2预期作用）、疲乏（4例，33%）和厌食（3例，25%）。研究期间所有死亡均归因于所研究的基础疾病（转移性胃肠癌）及其相关并发症（10例），或感染（1例发生5级败血症）。未发生3级及以上细胞因子释放综合征或神经毒性事件。12例中有6例（50%）在第28天达到疾病稳定，4例（33%）至第56天仍维持疾病稳定。1名抗PD-1/CTLA-4治疗耐药、患微卫星高度不稳定型结直肠癌的年轻成人患者获得完全缓解，且缓解持续超过21个月。解读：这些结果支持输注新抗原反应性CISH敲除TIL具有安全性和潜在抗肿瘤活性，对免疫检查点抑制剂治疗耐药的晚期转移性癌症患者具有启示意义，并首次证明可通过治疗产生疗效的方式靶向新型细胞内检查点。经费来源：Intima Bioscience。
BACKGROUND: Over the past decade, immunotherapeutic strategies-mainly targeting the PD-1-PD-L1 immune checkpoint axis-have altered cancer treatment for many solid tumours, but few patients with gastrointestinal forms of cancer have benefited to date. There remains an urgent need to extend immunotherapy efficacy to more patients while addressing resistance to current immune checkpoint inhibitors. The aim of this study was to determine the safety and anti-tumour activity of knockout of CISH, which encodes cytokine-inducible SH2-containing protein, a novel intracellular immune checkpoint target and a founding member of the SOCS family of E3-ligases, using tumour infiltrating lymphocyte (TILs) genetically edited with CRISPR-Cas9 in patients with metastatic gastrointestinal epithelial cancers. METHODS: For this first-in-human, single-centre, phase 1 trial, patients aged 18-70 years with a diagnosis of metastatic gastrointestinal epithelial cancer with progressive disease following at least one first line standard therapy, measurable disease with at least one lesion identified as resectable for TIL generation and at least one other lesion meeting RECIST criteria as measurable to serve as an indicator of disease response, and an ECOG performance status of 0 or 1 were screened and enrolled if meeting these and all other eligibility criteria. TILs procured from tumour biopsies were expanded on the basis of neoantigen reactivity, subjected to CRISPR-Cas9-mediated CISH knockout, and infused intravenously into 12 patients after non-myeloablative lymphocyte depleting chemotherapy (cyclophosphamide 60 mg/kg per dose on study days -6 and -5, and fludarabine 25 mg/m 2 per dose on days -7 to -3) followed by high-dose IL-2 (aldesleukin; 720 000 IU/kg per dose). The primary endpoint was safety of administration of neoantigen-reactive TILs with knockout of the CISH gene, and a key secondary endpoint was anti-tumour activity measured as objective radiographic response and progression-free and overall survival. This study is registered with ClinicalTrials.gov, NCT04426669, and is complete. FINDINGS: Between May 12, 2020, and Sept 16, 2022, 22 participants were enrolled in the trial (one patient was enrolled twice owing to lack of TIL outgrowth on the first attempt); ten patients were female, and 11 were male (self-defined). One patient was Asian, the remainder were White (self-defined). We successfully manufactured CISH knockout TIL products for 19 (86%) of the patients, of whom 12 (63%) received autologous CISH knockout TIL infusion. The median follow-up time for the study was 129 days (IQR 15-283). All 12 (100%) patients had treatment-related severe adverse events. The most common grade 3-4 adverse events included haematological events (12 patients [100%]) attributable to the preparative lymphodepleting chemotherapy regimen or expected effects of IL-2, fatigue (four patients [33%]), and anorexia (three patients [25%]). Deaths of any cause for patients on study were attributed to the underlying disease under study (metastatic gastrointestinal cancer) and related complications (10 patients) or infection (grade 5 septicaemia in one patient). There were no severe ( grade 3) cytokine release or neurotoxicity events. Six (50%) of 12 patients had stable disease by day 28, and four (33%) had stable disease ongoing at 56 days. One young adult patient with microsatellite-instability-high colorectal cancer refractory to anti-PD1/CTLA-4 therapies had a complete and ongoing response (>21 months). INTERPRETATION: These results support the safety and potential antitumour activity of inhibiting the immune checkpoint CISH through the administration of neoantigen-reactive CISH-knockout TILs, with implications for patients with advanced metastatic cancers refractory to checkpoint inhibitor immunotherapies, and provide the first evidence that a novel intracellular checkpoint can be targeted with therapeutic effect. FUNDING: Intima Bioscience.
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