肿瘤细胞治疗研究
英文原题：Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12V Variant of Mutated RAS in HLA-A*11:01 Patients
这是一项 I/II 期注册临床试验，评估细胞治疗用于胰腺癌、胃癌、恶性肿瘤的安全性、可行性及初步疗效。当前状态：招募中。计划入组 110 例。试验地点：美国 · 贝塞斯达（共 1 个中心）。登记号：NCT03190941。
不限性别 · ≥ 18 Years 且 ≤ 72 Years
纳入标准： • 有可测量（按RECIST 1.1）、转移性或不可切除的恶性肿瘤，并经以下任一方法证实表达KRAS G12V突变：肿瘤组织RT-PCR、肿瘤DNA测序，或对切除组织进行的其他CLIA认证实验室检测。肿瘤表达NRAS或HRAS G12V突变者也可入组，因为这两种癌基因的N端前80个氨基酸与KRAS G12V完全同源，覆盖全部靶表位。 • 经美国国立卫生研究院输血医学部确认HLA-A*11:01阳性。 • 经美国国家癌症研究所病理实验室确认癌症诊断。 • 晚期癌症既往接受过标准全身治疗但无应答或复发，具体要求：转移性结直肠癌至少接受过两种含5-FU、亚叶酸、贝伐珠单抗、奥沙利铂和伊立替康（或类似药物）的全身化疗方案，或有禁忌；胰腺癌须接受过吉西他滨、5-FU和奥沙利铂（或类似药物），或有禁忌；非小细胞肺癌须按ALK、EGFR异常或PD-L1表达接受适当靶向治疗，其他患者须接受含铂化疗；卵巢癌或前列腺癌须接受获批的一线化疗。符合既往标准治疗要求者，或拒绝标准治疗者均可。 • 无症状脑转移灶≤3个且直径<1 cm者可入组。立体定向放射外科治疗后的病灶须临床稳定至少1个月；已手术切除的脑转移灶也可入组。 • 年龄18–72岁（含），ECOG体能状态0–1。 • 同意从入组起采取避孕措施；女性持续至最后一次联合化疗后12个月，男性持续至治疗后4个月。有生育能力女性同意治疗前进行妊娠检测。某些肿瘤可能分泌激素导致妊娠试验假阳性，可通过连续血液检测（如HCG）和/或超声进一步判定。 • HIV抗体阴性；乙肝表面抗原阴性且丙肝抗体阴性。丙肝抗体阳性者须经RT-PCR检测，且HCV RNA阴性。 • 血液学符合：无需非格司亭支持时ANC>1,000/mm³；白细胞≥2,500/mm³；血小板≥80,000/mm³；血红蛋白>8.0 g/dL（可输血达到该标准）。 • 生化指标符合：ALT/AST≤5×ULN；总胆红素≤2.0 mg/dL，Gilbert综合征者须<3.0 mg/dL。 • eGFR>60 mL/min（基于血清肌酐及实验室列线图）或正式测定的6–24小时肌酐清除率>60 mL/min。 • 入组时已完成所有既往全身治疗。入组前4周内可接受小型手术或有限范围放疗，但相关主要器官毒性须恢复至≤1级。 • 能理解研究并愿签署书面知情同意书及持久授权书；须同时参加方案03C0277。 排除标准： • 大范围肺部照射史。 • 有生育能力且妊娠或哺乳的女性。 • 同时接受全身性糖皮质激素治疗。 • 活动性全身感染且需抗感染治疗、凝血障碍，或其他活动性/失代偿的重大疾病。 • 原发性免疫缺陷（如重症联合免疫缺陷）。 • 同时存在机会性感染。该研究治疗依赖完整免疫系统；免疫功能下降者可能疗效较差且毒性风险较高。 • 对环磷酰胺、氟达拉滨或阿地白介素有严重速发型超敏反应史。 • 冠状动脉血运重建史或缺血症状史。 • 有临床病史并需心脏评估者：最近一次LVEF≤45%。 • 有临床病史并需肺部评估者：已知FEV1≤50%或DLCO<60%。 • 正在接受其他研究性药物。
* INCLUSION CRITERIA:
* Measurable (per RECIST V1.1 criteria, metastatic, or unresectable malignancy expressing G12V mutated KRAS as assessed by one of the following methods: RT-PCR on tumor tissue, tumor DNA sequencing, or any other CLIA-certified laboratory test on resected tissue. Patients shown to have tumors expressing G12V mutated NRAS and HRAS will also be eligible as these oncogenes share complete amino acid homology with G12V mutated KRAS for their first 80 N-terminal amino acids, completely encompassing the target epitope.
* Patients must be HLA-A\*11:01 positive as confirmed by the NIH Department of Transfusion Medicine.
* Confirmation of the diagnosis of cancer by the NCI Laboratory of Pathology.
* Patients must have:
* previously received standard systemic therapy for their advanced cancer and have been either non-responders or have recurred, specifically:
* Patients with metastatic colorectal cancer must have had at least two systemic chemotherapy regimens that include 5FU, leucovorin, bevacizumab, oxaliplatin, and irinotecan (or similar agents), or have contraindications to receiving those medications.
* Patients with pancreatic cancer must have received gemcitabine, 5FU, and oxaliplatin (or similar agents), or have contraindications to receiving those medications.
* Patients with non-small cell lung cancer (NSCLC) must have had appropriate targeted therapy as indicated by abnormalities in ALK, EGFR, or expression of PDL- 1. Other patients must have had platinum-based chemotherapy.
* Patients with ovarian cancer or prostate cancer must have had approved first-line chemotherapy.
OR
* declined standard treatment
* Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for one month after treatment for the patient to be eligible. Patients
with surgically resected brain metastases are eligible.
* Age greater than or equal to 18 years and less than or equal to 72 years.
* Clinical performance status of ECOG 0 or 1
* Patients must be willing to practice birth control from the time of enrollment on this study and 12 months after the last dose of combined chemotherapy for women and for 4 months after treatment for men.
* Women of child-bearing potential must be willing to undergo pregnancy testing prior to the start of treatment because of the potentially dangerous effects of the treatment on the fetus.
NOTE: Certain malignancies may secrete hormones that produce false positive pregnancy tests. Serial blood testing (e.g. HCG measurements) and/ or ultrasound may be performed for clarification.
* Serology
* Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive may have decreased immune-competence and thus may be less responsive to the experimental treatment and more susceptible to its toxicities.)
* Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.
* Hematology
* ANC greater than 1000/mm\^3 without the support of filgrastim
* WBC greater than or equal to 2500/mm\^3
* Platelet count greater than or equal to 80,000/mm\^3
* Hemoglobin \> 8.0 g/dL. Subjects may be transfused to reach this cut-off.
* Chemistry
* Serum ALT/AST less than or equal to 5.0 times ULN
* Total bilirubin less than or equal to 2.0 mg/dL, except in patients with Gilbert s Syndrome, who must have a total bilirubin less than 3.0 mg/dL.
* Patients must have either an eGFR \> 60 mL/m (based on serum creatinine and lab nomogram) or a formal 6-24h CrCl \> 60 mL/m.
* Patients must have completed any prior systemic therapy at the time of enrollment.
Note: Patients may have undergone minor surgical procedures or limited field radiotherapy within the four weeks prior to enrollment, as long as related major organ toxicities have recovered to less than or equal to grade 1.
* Ability of subject to understand and the willingness to sign a written informed consent document.
* Willing to sign a durable power of attorney.
* Subjects must be co-enrolled on protocol 03C0277.
EXCLUSION CRITERIA:
* Large volume pulmonary irradiation.
* Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
* Concurrent systemic steroid therapy.
* Active systemic infections requiring anti-infective treatment, coagulation disorders, or any other active or uncompensated major medical illnesses.
* Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
* Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune-competence may be less responsive to the experimental treatment and more susceptible to its toxicities.)
* History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or aldesleukin.
* History of coronary revascularization or ischemic symptoms
* For select patients with a clinical history prompting cardiac evaluation: last known LVEF less than or equal to 45%.
* For select patients with a clinical history prompting pulmonary evaluation: known FEV1 less than or equal to 50% or DLCO less than 60%.
* Patients who are receiving any other investigational agents.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：Response rate · Percentage of patients who have a clinical response (PR+CR) to treatment (objective tumor regression) · 6 weeks and 12 weeks following administration of the cell product, then every 3 months x3, then every 6 months x 2 years, then per PI discretion；Frequency and severity of treatment-related adverse events · Grade and type of toxicity per dose level; fraction of patients who experience a DLT at a given dose level, and number and grade of each type of DLT · From time of cell infusion to two weeks after cell infusion
采用非清髓性淋巴细胞清除预处理方案（环磷酰胺和氟达拉滨），随后给予递增剂量的抗KRAS G12V mTCR外周血淋巴细胞，并联合大剂量阿地白介素。
采用非清髓性淋巴细胞清除预处理方案（环磷酰胺和氟达拉滨），随后给予最大耐受剂量（MTD）的抗KRAS G12V mTCR外周血淋巴细胞，并联合大剂量阿地白介素。
背景：一种新型癌症治疗方法是采集患者白细胞，在实验室扩增并进行基因修饰，再回输患者体内；本研究使用抗KRAS G12V突变T细胞受体（mTCR）细胞进行基因转移。 目的：评估抗KRAS G12V mTCR细胞的安全性及其缩小肿瘤的能力。 对象：年龄≥18岁、肿瘤表达KRAS G12V的成人。 流程：受试者先住院，通过胸部导管接受为期5天的两种化疗药物；几天后经导管输注抗KRAS G12V mTCR细胞，之后最多3天接受激活细胞的药物。细胞输注次日皮下注射促进白细胞增多的药物。受试者住院恢复1–2周，接受实验室及血液检查，并至少服用抗生素6个月。前2年每隔数月进行1–2天的门诊复查，包括实验室检查、影像学和体格检查，部分访视可能进行白细胞单采或采血；之后按医生安排随访，数年内继续采集血样。
Background: A new cancer therapy involves taking white blood cells from a person, growing them in the lab, genetically modifying them, then giving them back to the person. This therapy is called gene transfer using anti-KRAS G12V mTCR cells. Objective: To see if anti-KRAS G12 V mTCR cells are safe and can shrink tumors. Eligibility: Adults at least 18 years old with cancer that has the KRAS G12V molecule on the surface of tumors. Design: In another protocol, participants will: Be screened Have cells harvested and grown Have leukapheresis In this protocol, participants will have the procedures below. Participants will be admitted to the hospital. Over 5 days, participants will get 2 chemotherapy medicines as an infusion via catheter in the upper chest. A few days later, participants will get the anti-KRAS G12V mTCR cells via catheter. For up to 3 days, participants will get a drug to make the cells active. A day after getting the cells, participants will get a drug to increase their white blood cell count. This will be a shot or injection under the skin. Participants will recover in the hospital for 1-2 weeks. They will have lab and blood tests. Participants will take an antibiotic for at least 6 months. Participants will have visits every few months for 2 years, and then as determined by their doctor. Visits will be 1-2 days. They will include lab tests, imaging studies, and physical exam. Some visits may include leukapheresis or blood drawn. Participants will have blood collected over several years.
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