A Therapeutic Vaccine for Fibrolamellar Hepatocellular Carcinoma

Fibrolamellar hepatocellular carcinoma (FLC) is a rare form of liver cancer affecting 33 children and young adults that is driven by a chimeric protein, DNAJ-PKAc. We conducted a phase 1 clinical trial of a therapeutic vaccine targeting DNAJ-PKAc 38 (FLC-Vac), in combination with nivolumab and ipilimumab, in children and adults with advanced FLC. Among 16 patients enrolled, 12 completed the vaccine priming phase and were evaluable for both immunological and clinical endpoints. Grade 3 treatment-related adverse events were reported by six patients (37.5%). DNAJ43 PKAc-specific T cell responses were detected in 9/12 patients after treatment. In the subset of patients who completed the initial priming phase the disease control rate (DCR) was 75% (9/12), with three partial responses (25%). All patients with clinical responses also had DNAJ-PKAc specific T cell responses, from which we identified multiple class II-restricted T cell receptors (TCRs) with specificity for DNAJ-PKAc. Correlates of response included both functional neoantigen reactivity and changes in TCR repertoire features over time. Immune escape in two patients corresponded with immune exhaustion rather than neoantigen escape or HLA loss. ]]>
Inclusion Criteria: Cohorts A and B: Must have histologically confirmed FLC (fibrolamellar hepatocellular cancer) that is metastatic or unresectable.Age > 12 years. Note: Subjects age > 12 years but <18 are eligible to enroll only after 6 adult patients have enrolled on the study.Patients < 18 years old must have a body weight ≥40 kg.Cohort C: Patients with histologically proven metastatic or unresectable DNAJB1-PRKACA fusion transcript positive solid tumor malignancies, non-FLC solid tumors. Patients must be Age ≥ 18 years.All Cohorts: Presence of DNAJB1-PRKACA fusion transcript, assessed by RNA-sequencing, DNA-sequencing, or in situ hybridization in the archival tissue. ECOG performance status of ≤2 (Karnofsky ≥60%) Patients must have adequate liver, kidney and marrow function defined by study-specified laboratory tests prior to initial study drug. Patients must have measurable disease per RECIST 1.1. Patients > 18 years old must have an accessible non-bone tumor lesion from which serial core biopsy specimens can be obtained. Must be willing to provide tissue and blood samples for mandatory translational research. Woman of childbearing potential must have a negative pregnancy test and follow contraceptive guidelines as defined per protocol. Men must use acceptable form of birth control while on study. Ability to understand and willingness to sign a written informed consent document. Exclusion Criteria: Cohorts A and C: Patients with a history of prior treatment with checkpoint inhibitors, such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-OX-40, anti-CD40, anti-CTLA-4, or anti-LAG-3 antibodies. NOTE: Prior therapy with interferon-alpha is allowed. Cohort B: Participants with a history of unacceptable, life-threatening toxicity related to prior immune therapy (e.g., anti-CTLA-4 or anti-PD-1/PD-L1 treatment, any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (e.g., hormone replacement after endocrinopathy).All Cohorts: Have had chemotherapy or other systemic therapy or radiotherapy, as follows:Have had chemotherapy, biological cancer therapy, or radiation 14 days prior to the first dose of study drug. Have had surgery within 28 days of dosing of investigational agent, excluding minor procedures (dental work, skin biopsy, etc.), celiac plexus block, and biliary stent placement. Have received other approved or investigational agents or device within 28 days of the first dose of study drug. Have not recovered from acute adverse events to grade ≤1 or baseline due to agents administered. Have received any non-oncology live vaccine therapy used for prevention of infectious diseases within 28 days of study treatment Known sensitivity to or history of allergic reactions to investigational drug (s). Hypersensitivity reaction to any monoclonal antibody. Has active autoimmune disease that has required systemic treatment in the past 2 years, or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Presence of any tissue or organ allograft, regardless of need for immunosuppression, including corneal allograft. Patients with a history of allogeneic hematopoietic stem cell transplant will be excluded. Has a diagnosis of immunodeficiency. Systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days of study drug administration. Symptomatic interstitial lung disease. Has a pulse oximetry of <92% on room air or is on supplemental home oxygen. Active or untreated brain metastases or leptomeningeal metastases. Uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, symptomatic congestive heart failure, unstable angina, cardiac arrhythmia, metastatic cancer, or psychiatric illness/social situations that would limit compliance with study requirements. Are pregnant or breastfeeding. Infection with HIV or hepatitis B or C. Have had evidence of active or acute diverticulitis, intra-abdominal abscess, or GI obstruction. Unwilling or unable to follow the study schedule for any reason. Any other sound medical, psychiatric, and/or social reason as determined by the Investigator. Any illicit drugs or other substance abuse. Clinically meaningful ascites. ]]>

纤维板层型肝细胞癌（fibrolamellar hepatocellular carcinoma, FLC）是一种罕见的肝癌亚型，好发于儿童及青年群体，年发病约33例，其发病由嵌合蛋白DNAJ-PKAc驱动。本研究针对DNAJ-PKAc开发了治疗性疫苗FLC-Vac（编号38），并联合纳武利尤单抗（nivolumab）与伊匹木单抗（ipilimumab）开展I期临床试验，纳入进展期FLC的儿童与成年患者。本试验共入组16例患者，其中12例完成疫苗致敏阶段，可同时评估免疫学与临床终点。6例患者（37.5%）报告了3级治疗相关不良事件。治疗后，9/12的患者可检测到针对DNAJ43 PKAc的T细胞应答。在完成初始致敏阶段的患者亚组中，疾病控制率（disease control rate, DCR）达75%（9/12），其中3例获得部分缓解（25%）。所有出现临床应答的患者均存在DNAJ-PKAc特异性T细胞应答，研究团队从中鉴定出多个针对DNAJ-PKAc的II类限制性T细胞受体（T cell receptor, TCR）。应答相关标志物包括功能性新抗原反应性以及随时间变化的T细胞受体库特征。2例患者出现免疫逃逸，其机制为免疫耗竭，而非新抗原逃逸或HLA（Human Leukocyte Antigen）丢失。

### 入组标准
#### A组与B组：
1. 经组织学确认的转移性或不可切除性纤维板层型肝细胞癌；
2. 年龄＞12岁。注：年龄＞12岁但＜18岁的受试者，仅在6例成年患者入组本研究后方可入组；
3. 年龄＜18岁的患者体重需≥40 kg。
#### C组：
1. 经组织学证实存在DNAJB1-PRKACA融合转录本阳性的实体瘤（非纤维板层型肝细胞癌）；
2. 年龄≥18岁。
#### 所有队列通用标准：
1. 存档组织经RNA测序（RNA-sequencing）、DNA测序（DNA-sequencing）或原位杂交检测确认存在DNAJB1-PKACA融合转录本；
2. 东部肿瘤协作组体能状态评分（Eastern Cooperative Oncology Group performance status, ECOG PS）≤2（卡氏评分≥60%）；
3. 首次使用研究药物前，需符合研究规定的实验室检测标准，确保肝、肾及骨髓功能充足；
4. 实体瘤疗效评价标准1.1版（Response Evaluation Criteria in Solid Tumors 1.1, RECIST 1.1）确认存在可测量病灶；
5. 年龄＞18岁的患者需存在可及的非骨源性肿瘤病灶，以便获取系列核心活检标本；
6. 自愿提供组织与血液样本，用于强制开展的转化性研究；
7. 育龄期女性需妊娠试验阴性，并遵循试验方案规定的避孕方案；男性受试者在研究期间需采取合格的避孕措施；
8. 能够理解并自愿签署书面知情同意书。

### 排除标准
#### A组与C组：
存在既往接受检查点抑制剂治疗的病史，包括抗PD-1、抗PD-L1、抗PD-L2、抗CD137、抗OX-40、抗CD40、抗CTLA-4或抗LAG-3抗体治疗。注：既往接受α干扰素治疗是允许的。
#### B组：
存在既往免疫治疗相关的不可接受的危及生命的毒性反应病史（如抗CTLA-4或抗PD-1/PD-L1治疗、其他靶向T细胞共刺激或免疫检查点通路的抗体或药物），但可通过标准干预措施避免复发的情况除外（如内分泌病后的激素替代治疗）。
#### 所有队列通用标准：
1. 首次使用研究药物前14天内接受过化疗、其他系统性癌症治疗或放疗；
2. 首次使用研究药物前28天内接受过手术操作（牙科治疗、皮肤活检、腹腔神经丛阻滞、胆道支架置入术等小操作除外）；
3. 首次使用研究药物前28天内接受过其他获批或在研药物/器械；
4. 因既往使用的药物导致的急性不良事件未恢复至≤1级或基线水平；
5. 研究治疗开始前28天内接受过用于预防传染病的非肿瘤学活疫苗治疗；
6. 对研究药物存在已知敏感性或过敏反应史；对任何单克隆抗体存在超敏反应；
7. 过去2年内需要系统性治疗的活动性自身免疫性疾病，或有临床严重自身免疫性疾病病史，或需要系统性糖皮质激素或免疫抑制剂治疗的综合征；
8. 存在任何组织或器官移植（无论是否需要免疫抑制治疗，包括角膜移植）；有同种异体造血干细胞移植病史的患者将被排除；
9. 确诊为免疫缺陷；
10. 研究药物给药前7天内接受过系统性糖皮质激素治疗（每日泼尼松等效剂量＞10 mg）或其他免疫抑制药物；
11. 有症状的间质性肺疾病；
12. 室内空气下脉搏血氧饱和度＜92%，或需要家庭供氧；
13. 存在活动性或未治疗的脑转移或软脑膜转移；
14. 存在未控制的内科合并症，包括但不限于：未控制的感染、症状性充血性心力衰竭、不稳定型心绞痛、心律失常、转移性癌症，或会影响研究依从性的精神疾病/社会状况；
15. 妊娠或哺乳期；
16. HIV、乙型肝炎或丙型肝炎感染；
17. 存在活动性或急性憩室炎、腹腔脓肿或胃肠道梗阻证据；
18. 因任何原因不愿意或无法遵循研究方案流程；
19. 研究者判定的其他任何合理的内科、精神科或社会原因；
20. 存在任何违禁药物或其他药物滥用情况；
21. 存在临床意义明确的腹水。