肿瘤细胞治疗研究
英文原题：A Study to Evaluate the Safety and Efficacy of Mesothelin-Targeting Logic-gated CAR T, in Participants With Solid Tumors That Express MSLN and Have Lost HLA-A*02 Expression
这是一项 I/II 期注册临床试验，评估细胞治疗用于实体瘤、结直肠癌、非小细胞肺癌的安全性、可行性及初步疗效。当前状态：招募中。计划入组 474 例。试验地点：美国 · 吉尔伯特、拉霍亚、洛杉矶、斯坦福（共 12 个中心）。登记号：NCT06051695。
不限性别 · ≥ 18 Years
主要入选标准 1. 已按A2 Biotherapeutics, Inc.的BASECAMP-1研究完成适当入组；组织样本经二代测序（NGS）证实存在HLA-A*02杂合性缺失（尽可能取自原发部位）；已成功完成白细胞单采及外周血单个核细胞（PBMC）处理，并有足量冻存细胞用于Tmod CAR-T细胞治疗。 2. 组织学确诊复发、不可切除、局部晚期或转移性结直肠癌（CRC）、非小细胞肺癌（NSCLC）、胰腺癌（PANC）、卵巢癌（OVCA）、间皮瘤（MESO）或其他表达间皮素（MSLN）的实体瘤。须有可测量病灶，CT测量病灶≥1.0 cm。 3. 已按方案要求接受相应实体瘤的既往治疗。 4. 器官功能充分，具体按方案规定。 5. ECOG体能状态0至1。 6. 预期寿命≥3个月。 7. 愿意遵守研究评估时间表，包括长期安全性随访。 主要排除标准 1. 疾病适合局部治疗，或可接受具有根治/治疗目的（而非姑息目的）的标准治疗。 2. 既往接受异基因造血干细胞移植。 3. 既往接受实体器官移植。 4. 间皮瘤胸膜受累并延伸至腹膜。 5. 输注前3周内或3个半衰期内接受抗癌治疗。 6. 输注前28天内接受放射治疗。 7. 过去6个月内发生不稳定型心绞痛、心律失常、心肌梗死或其他显著心脏病。 8. 入组前3个月内新发有症状的肺栓塞（PE）或深静脉血栓（DVT）。若既往PE/DVT距入组>3个月且已充分治疗，允许使用治疗剂量抗凝药。 9. 有间质性肺病史（包括药物诱发的间质性肺病及放射性肺炎），且过去1年内需长期使用类固醇或其他免疫抑制剂治疗。 10. 需在家补充氧气。 11. 有生育能力且妊娠或哺乳的女性。 12. 有生育能力的男性或女性受试者不愿从签署知情同意书起至输注后6个月采取避孕措施。
Inclusion Criteria: Key Inclusion Criteria: 1. Appropriately enrolled in the BASECAMP-1 A2 Biotherapeutics, Inc. study, with tissue demonstrating LOH of HLA-A\*02 by NGS (whenever possible from the primary site), successful apheresis and PBMC processing, and with sufficient stored cells available for Tmod CAR T-cell therapy 2. Histologically confirmed recurrent unresectable, locally advanced, or metastatic CRC, NSCLC, PANC, OVCA, MESO, or other solid tumors with MSLN expression. Measurable disease is required with lesions of ≥1.0 cm by CT. 3. Received previous required therapy for the appropriate solid tumor disease as described in the protocol 4. Has adequate organ function as described in the protocol 5. ECOG performance status of 0 to 1 6. Life expectancy of ≥3 months 7. Willing to comply with study schedule of assessments including long term safety follow up Key Exclusion Criteria: 1. Has disease that is suitable for local therapy or able to receive standard of care therapy that is therapeutic and not palliative 2. Prior allogeneic stem cell transplant 3. Prior solid organ transplant 4. MESO with pleural involvement extending into the peritoneum 5. Cancer therapy within 3 weeks or 3 half lives of infusion 6. Radiotherapy within 28 days of infusion 7. Unstable angina, arrhythmia, myocardial infarction, or any other significant cardiac disease within the last 6 months 8. Any new symptomatic pulmonary embolism (PE) or a deep vein thrombosis (DVT) within 3 months of enrollment. Therapeutic dosing of anticoagulants is allowed for history of PE or DVT if greater than 3 months from time of enrollment, and adequately treated 9. History of interstitial lung disease including drug-induced interstitial lung disease and radiation pneumonitis that requires treatment with prolonged steroids or other immune suppressive agents within 1 year 10. Requires supplemental home oxygen 11. Females of childbearing potential who are pregnant or breastfeeding 12. Subjects, both male and female, of childbearing potential who are not willing to practice birth control from the time of consent through 6 months post infusion
以上为辅助阅读译文。是否适合入组须由主治医生判断，最终以登记平台与研究者确认为准。
主要终点：Phase 1: Rate of adverse events and dose limiting toxicities (DLTs) by dose level · Adverse Events and toxicity will be evaluated according to the Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events version (CTCAE) 5.0 (or current version). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) events will be graded according to the criteria described in the current protocol. · From the time of Informed consent until 24 months (2 years) post infusion；Phase 1: Recommended Phase 2 Dose (RP2D) · The RP2D will be identified utilizing a BOIN study design in addition to considering safety and biomarker analysis. · 21 days post infusion；Phase 2: The Overall Response Rate (ORR) for patients · The ORR will be evaluated per RECIST v1.1 and assessed by independent central review. · 24 months post infusion
次要终点：Persistence of Tmod product；Cytokine analysis
先接受预处理淋巴清除（PCLD）方案，随后于第0天静脉输注一次A2B694。
先接受预处理淋巴清除（PCLD）方案，随后于第0天静脉输注一次A2B543。
本研究旨在评估自体逻辑门控Tmod™ CAR-T细胞制品治疗实体瘤的效果，包括结直肠癌、胰腺癌、非小细胞肺癌、卵巢癌、间皮瘤及其他表达间皮素（MSLN）且HLA-A*02表达缺失的实体瘤。I期主要确定对患者安全的推荐剂量；II期评估该剂量能否杀伤实体瘤细胞并保护患者健康细胞。受试者将接受BASECAMP-1研究（NCT04981119）入组及白细胞单采、预处理淋巴清除方案，并按分配剂量接受Tmod CAR-T细胞。
The goal of this study is to test autologous logic-gated Tmod™ CAR T-cell products in subjects with solid tumors including colorectal cancer (CRC), pancreatic cancer (PANC), non-small cell lung cancer (NSCLC), ovarian cancer (OVCA), mesothelioma (MESO), and other solid tumors that express mesothelin (MSLN) and have lost HLA-A\*02 expression. The main questions this study aims to answer are: Phase 1: What is the recommended dose that is safe for patients Phase 2: Does the recommended dose kill solid tumor cells and protect the patient's healthy cells Participants will be required to perform study procedures and assessments, and will also receive the following study treatments: Enrollment and Apheresis in BASECAMP-1 (NCT04981119) Preconditioning Lymphodepletion (PCLD) Regimen Tmod CAR T cells at the assigned dose
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