肿瘤细胞治疗研究
英文原题：Observational Comparison of Overall Survival between Phase 1b Orca-T and Registry-Based Post-Transplant Cyclophosphamide Patients.
这些结果提示，与PTCy相比，Orca-T可能改善异基因造血干细胞移植后的生存。
Orca-T是一种细胞免疫疗法，包含纯化的供者造血祖干细胞、调节性T细胞（Tregs）和常规T细胞（Tcons）。在随机临床试验中，Orca-T和移植后环磷酰胺（PTCy）均显示出优于他克莫司联合甲氨蝶呤的移植物抗宿主病（GVHD）控制效果。Orca-T通过高纯度调节性T细胞实现免疫耐受，而PTCy方案则采用广泛的药理学免疫抑制。本研究的主要目标是评估Orca-T相较于PTCy的长期总生存期（OS）。在这项回顾性分析中，长期生存随访数据来自一项于2019年启动的多中心Orca-T 1b期研究。OS结局通过与接受基于PTCy的GVHD预防的患者队列进行比较来评估，该队列数据来自国际血液和骨髓移植研究中心/NMDP的注册数据库。为确保可比性，纳入标准与Orca-T 3期试验资格标准一致，具体为年龄≤65岁、诊断为完全缓解的中危或高危急性髓系白血病或急性淋巴细胞白血病、或骨髓增生异常综合征、清髓性预处理，以及8/8 HLA相合供者。分析纳入76例Orca-T患者和360例PTCy患者。在3年随访期内，Orca-T与显著更高的OS相关，优于PTCy（风险比[HR]=0.41；log-rank P=.003）。Orca-T在1年、2年和3年的OS分别为96%（95% CI：88%至99%）、86%（76%至92%）和83%（73%至90%）。PTCy队列在1年、2年和3年的OS分别为81%（77%至85%）、72%（67%至77%）和66%（60%至71%）。一项倾向性评分匹配分析（每组 n = 76）证实了主要发现（HR = 0.40；log-rank 检验 P = .010），校正受者年龄、性别、疾病、疾病风险指数、HCT-CI 和供者类型的多变量 Cox 模型亦证实了这一点（校正 HR = 0.38；95% CI 0.21 至 0.71；P = .002）。在排除骨髓移植物作为对照以及将两组均限制于重叠的 2019 至 2021 移植时代的敏感性分析中，该优势持续存在（所有设定下 HR 范围为 0.36 至 0.48）。Orca-T 的 3 年非复发死亡率较低（3.1% 对 10%；Gray's P = .0497），而复发无显著差异；在 PTCy 队列中，结局不因吗替麦考酚酯的使用而不同。Orca-T 的 OS 优势在年龄、疾病类型和其他临床亚组中均一致观察到。在本回顾性分析的局限性范围内，这些结果提示，与 PTCy 相比，Orca-T 可能改善异基因造血干细胞移植后的生存。
Orca-T is a cellular immunotherapy comprising purified donor hematopoietic progenitor stem cells, regulatory T cells (Tregs), and conventional T cells (Tcons). Both Orca-T and post-transplant cyclophosphamide (PTCy) have demonstrated superior graft-versus-host disease (GVHD) control compared to tacrolimus and methotrexate in randomized clinical trials. Orca-T achieves immune tolerance through high-purity regulatory T cells in contrast to broad pharmacological immunosuppression with PTCy regimens. The principal goal of this study was to evaluate the long-term overall survival (OS) of Orca-T compared to PTCy. In this retrospective analysis, long-term survival follow-up was collected from a multicenter Phase 1b study of Orca-T that was initiated in 2019. OS outcomes were evaluated against a cohort of patients receiving PTCy-based GVHD prophylaxis, using a registry dataset obtained from the Center for International Blood and Marrow Transplant Research/NMDP. To ensure comparability, inclusion criteria were aligned with Orca-T Ph3 eligibility, specifically age ≤65 yr, diagnosis of intermediate- or high-risk acute myeloid leukemia or acute lymphoblastic leukemia in complete remission or myelodysplastic syndrome, myeloablative conditioning, and an 8/8 HLA-matched donor. The analysis included 76 Orca-T patients and 360 PTCy patients. Orca-T was associated with significantly higher OS over a 3-yr follow-up period compared to PTCy (hazard ratio [HR] = 0.41; log-rank P = .003). OS at 1, 2, and 3 yr for Orca-T was 96% (95% CI: 88% to 99%), 86% (76% to 92%), and 83% (73% to 90%), respectively. For the PTCy cohort, OS at 1, 2, and 3 yr was 81% (77% to 85%), 72% (67% to 77%), and 66% (60% to 71%), respectively. A propensity score-matched analysis (n = 76/group) confirmed the primary findings (HR = 0.40; log-rank test P = .010), as did a multivariable Cox model adjusted for recipient age, sex, disease, disease risk index, HCT-CI, and donor type (adjusted HR = 0.38; 95% CI 0.21 to 0.71; P = .002). The advantage persisted in sensitivity analyses excluding bone marrow grafts from the comparator and restricting both arms to the overlapping 2019 to 2021 transplant era (HR range across all specifications, 0.36 to 0.48). Three-yr nonrelapse mortality was lower with Orca-T (3.1% versus 10%; Gray's P = .0497), while relapse did not differ significantly; within the PTCy cohort, outcomes did not differ by mycophenolate mofetil use. The OS advantage for Orca-T was consistently observed across age, disease type, and other clinical subgroups. Within the limitations of this retrospective analysis, these results suggest that survival following allogeneic hematopoietic stem cell transplantation may be improved with Orca-T relative to PTCy.
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