肿瘤细胞治疗研究
英文原题：A Vaccine (Neoantigen-Targeted ppDC) for the Treatment of H3 G34-mutant Diffuse Hemispheric Glioma
这是一项 I 期注册临床试验，评估树突状细胞治疗胶质瘤的安全性、可行性及初步疗效。当前状态：进行中（不再招募）。计划入组 6 例。试验地点：美国 · 洛杉矶（共 1 个中心）。登记号：NCT06342908。
不限性别 · ≥ 18 Years 且 ≤ 50 Years
入选标准 • 年龄18至50岁，病理确诊弥漫性半球胶质瘤（DHG），或病理复核结果与DHG相符。 • 有生育能力女性在首次给药前72小时内尿或血妊娠试验阴性，并同意在整个研究期间及末次给药后120天内采取充分避孕措施。 • 受试者（如适用，由法定授权代表代为）提供知情同意；未成年人须提供书面知情同意/赞同。 • 入组前既往手术切除至少间隔28天；立体定向活检至少间隔14天。 • 登记后有临床病理结果、商业靶向外显子组测序结果，或足量存档肿瘤组织可确诊DHG。优先提供25至50 mg速冻组织块；经申办方研究者同意，也可提供福尔马林固定石蜡包埋（FFPE）组织块或10张未染色FFPE切片（厚5 μm）。 • Karnofsky体能状态（KPS）≥70。 • 研究治疗开始前14天内检查：ANC≥1500/μL；血小板≥100,000/μL；血红蛋白≥9.0 g/dL或≥5.6 mmol/L。不得依赖促红细胞生成素，且过去2周内未输注浓缩红细胞。 • 肾功能：研究治疗开始前14天内肌酐≤1.5×ULN；若肌酐>机构ULN的1.5倍，则肌酐清除率≥30 mL/min。GFR也可替代肌酐或CrCl评估；CrCl按机构标准计算。 • 研究治疗开始前14天内总胆红素≤1.5×ULN；总胆红素>1.5×ULN者，直接胆红素须≤ULN。 • 研究治疗开始前14天内AST（SGOT）和ALT（SGPT）≤2.5×ULN；有肝转移者≤5×ULN。 • 研究治疗开始前14天内INR或PT、APTT≤1.5×ULN；正在接受抗凝治疗者除外，但PT或APTT须处于预期抗凝治疗范围内。 排除标准 • 年龄>50岁或<18岁。 • 目标肿瘤既往接受过超过1次彼此独立的复发治疗。 • 有生育能力女性入组前72小时内尿妊娠试验阳性；尿检阳性或无法确认阴性时须进行血清妊娠试验。 • 入组前2周内接受全身抗癌治疗（包括试验药物）。既往治疗引起的不良事件须恢复至≤1级或基线；≤2级神经病变者可能符合条件。 • 研究药物首次给药前30天内接种活疫苗。活疫苗包括麻疹、腮腺炎、风疹、水痘/带状疱疹、黄热病、狂犬病、卡介苗及伤寒疫苗等。注射用季节性流感疫苗通常为灭活疫苗，允许接种；鼻喷流感疫苗（如FluMist）为减毒活疫苗，不允许接种。 • 首次研究给药前4周内正在参加或曾参加试验药物研究，或使用试验器械。已进入其他试验随访阶段者，如距前一试验药物末次给药已满4周，可参加。 • 已确诊免疫缺陷，或首次研究给药前7天内接受慢性全身性皮质类固醇治疗（泼尼松等效剂量>1 mg/kg/日）或任何其他免疫抑制治疗。 • 已知有其他正在进展或过去3年内需积极治疗的恶性肿瘤。已根治性治疗的皮肤基底细胞癌、皮肤鳞状细胞癌或原位癌（如乳腺原位癌、宫颈原位癌）除外。 • 过去2年内有需全身治疗的活动性自身免疫病（使用改善病情药物、皮质类固醇或免疫抑制剂）。替代治疗（如甲状腺素、胰岛素，或肾上腺/垂体功能不全的生理性类固醇替代）不视为全身治疗。 • 有需类固醇治疗的非感染性肺炎病史，或当前有肺炎。 • 活动性感染且需全身治疗。 • 已知乙肝病史（HBsAg阳性）或活动性HCV感染（检出HCV RNA）。注：除非当地卫生主管部门要求，否则无需进行乙肝或丙肝检测。 • 已知活动性结核病史。 • 研究者认为可能混淆研究结果、妨碍完成全程研究，或不符合受试者最佳利益的任何病史、现病、治疗或实验室异常。 • 已知精神疾病或物质滥用障碍，可能影响配合研究要求。 • 肾功能障碍，无法接受钆对比剂。 • 妊娠、哺乳，或预计从筛选至试验治疗末次给药后120天内受孕。
Inclusion Criteria: * Participants between the ages of 18 and 50 years with pathologically-confirmed diagnosis of (or pathology re-review consistent with) DHG will be enrolled in this study * A female participant who has childbearing potential must have negative urine or serum pregnancy test 72 hours prior to the first dose and be willing to use adequate method of contraception for course of study and 120 days after last dose * The participant (or legally acceptable representative if applicable) provides informed consent (and written assent from minors) for the trial * An interval of the following durations prior to enrollment: * At least 28 days from prior surgical resection * At least 14 days from prior stereotactic biopsy * Have clinical pathology results, commercial targeted exome sequencing results, or sufficient archival tumor tissue to confirm DHG following registration. The following amount of tissue is preferred: 25-50 mg flash frozen tissue block. Formalin-fixed, paraffin embedded (FFPE) tissue block or 10 FFPE unstained slides (5µm thick) is acceptable at the discretion of the Sponsor-Investigator * Have a Karnofsky performance status (KPS) ≥ 70 * Absolute neutrophil count (ANC) ≥ 1500/uL (specimens must be collected within 14 days prior to the start of study treatment) * Platelets ≥ 100 000/µL (specimens must be collected within 14 days prior to the start of study treatment) * Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L (specimens must be collected within 14 days prior to the start of study treatment) * Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 week * Creatinine or measured or calculated b creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤ 1.5 × ULN or ≥ 30 mL/min for participant with creatinine levels \> 1.5 × institutional ULN (specimens must be collected within 14 days prior to the start of study treatment) * Creatinine clearance (CrCl) should be calculated per institutional standard. * Total bilirubin ≤ 1.5 ×ULN or direct bilirubin ≤ ULN for participants with total bilirubin levels \>1.5 × ULN (specimens must be collected within 14 days prior to the start of study treatment) * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) ≤ 2.5 × ULN (≤ 5 × ULN for participants with liver metastases) (specimens must be collected within 14 days prior to the start of study treatment) * International normalized ratio (INR) OR prothrombin time (PT) activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants (specimens must be collected within 14 days prior to the start of study treatment) Exclusion Criteria: * Age \> 50 years or \< 18 years * Have had more than 1 separately-treated recurrences of the index tumor * A woman of child-bearing potential who has a positive urine pregnancy test within 72 hours prior to enrollment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required * Has received prior systemic anti-cancer therapy including investigational agents within 2 weeks prior to enrollment. Note: Participants must have recovered from all adverse events (AEs) due to previous therapies to ≤ grade 1 or baseline. Participants with ≤ grade 2 neuropathy may be eligible * Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed * Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent * Has a diagnosis of immunodeficiency or is receiving chronic systemic corticosteroid therapy (dosing exceeding 1 mg/kg/day of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug * Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded * Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment * Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis * Has an active infection requiring systemic therapy * Has a known history of hepatitis B (defined as hepatitis B surface antigen \[HBsAg\] reactive) or known active hepatitis C virus (defined as hepatitis C virus \[HCV\] ribonucleic acid \[RNA\] is detected) infection. Note: no testing for hepatitis B and hepatitis C is required unless mandated by local health authority * Has a known history of active tuberculosis (Bacillus tuberculosis) * Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator * Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial * Kidney dysfunction precluding administration of gadolinium-based contrast * Is pregnant or breastfeeding, or expecting to conceive within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment
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：Incidence of regimen-limiting toxicities · Will be graded in severity according to Common Terminology Criteria for Adverse Events version 5.0 (CTCAE, v 5.0) guidelines, monitoring for 30 days following each dose for adverse event recording, and for 120 days following each dose for serious adverse event recording. · Up to 120 days after last dose
次要终点：Significant increase in gamma-interferon (IFN) gene expression signature；Significant clonal T cell expansion；Targets of clonal cytotoxic T cell expansion；Pro-inflammatory phenotypic changes in immune cell populations；Changes in immune cell subset expansion and contraction in T cell and myeloid-derived cell populations；Changes of immune cell markers profile in T cell and myeloid-derived cell populations
首次注射前10天进行白细胞单采。随后每2周一次在双臂皮内注射ppDC并肌肉注射Poly-ICLC，共3剂；之后每6个月给药一次，最多追加3剂。研究期间进行MRI及采血；筛选时和研究期间采集粪便样本。
这项I期研究评估新抗原靶向ppDC疫苗治疗H3 G34突变型弥漫性半球胶质瘤患者的安全性、副作用及最佳剂量。利用患者自身白细胞制备并经肽负载的树突状细胞疫苗，可能帮助机体建立有效免疫反应以杀伤肿瘤细胞。本研究将评估该疫苗的安全性、耐受性及潜在疗效。
This phase I trial tests the safety and side effects, and best dose of a vaccine (neoantigen-target ppDC) in treating patients with H3 G34-mutant diffuse hemispheric glioma. Vaccines made from the patient's own white blood cells and peptide-pulsed dendritic cells may help the body build an effective immune response to kill tumor cells. Giving neoantigen-targeted ppDC may be safe, tolerable and/or effective in treating patients with diffuse hemispheric glioma with a H3 G34 mutation.
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