Metts Jonathan, Rodriguez-Valentin Madeline, Hensel Jonathan, Alfaro Alex, Snyder Christopher W, Binitie Odion, Chebli Caroline, Monforte Hector, Pilon-Thomas Shari, Mullinax John
Cancer and Blood Disorders Institute, Johns Hopkins All Children's Hospital, St Petersburg, Florida, USA; Departments of Sarcoma, Immunology, and Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida, USA.
Departments of Sarcoma, Immunology, and Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida, USA.
Cytotherapy. 2025 Jan;27(1):29-35. doi: 10.1016/j.jcyt.2024.08.002. Epub 2024 Aug 16.
The expansion of tumor-infiltrating lymphocytes (TIL) for adoptive cellular therapy is under investigation in many solid tumors of adulthood. Marrow-infiltrating lymphocytes (MIL) have demonstrated antitumor reactivity preclinically. Successful expansion of TIL/MIL has not been reported across pediatric solid tumor histologies. The objective of this study was to demonstrate successful expansion of TIL from pediatric solid tumors for translation in an adoptive cell therapy (ACT) treatment strategy.
A prospective study of TIL/MIL expansion was performed on solid tumors of pediatric patients undergoing standard-of-care procedures. TIL/MIL expansions were performed in the presence of high-dose interleukin 2. To demonstrate a full-scale expansion to clinically-relevant cell doses for TIL therapy, initial TIL culture was followed by a rapid expansion protocol for select patients. Expanded specimens were analyzed for phenotype by flow cytometry and for anti-tumor reactivity by the interferon-gamma release assay.
Eighteen tumor samples were obtained. Initial TIL cultures were successfully generated from 14/18 samples (77.7%). A median of 5.52 × 107 (range: 2.5 × 106-3.23 × 108) cells were produced from initial cultures, with 46.9% expressing a CD3 phenotype (46.9%). Eight samples underwent rapid expansion, demonstrating a median 458-fold expansion and a CD3 phenotype of 98%. Initial MIL cultures were successfully generated from five samples, with a predominantly CD3 phenotype (45.2%). Sufficient tumor tissue was only available for seven TIL samples to be tested for reactivity; none demonstrated responsiveness to autologous tumor.
TIL and MIL expansion from pediatric solid tumors was successful, including the full-scale expansion process. This data supports translation to an ACT-TIL treatment strategy in the pediatric population and thus a Phase I trial of ACT-TIL in pediatric high-risk solid tumors is planned.
用于过继性细胞治疗的肿瘤浸润淋巴细胞（TIL）扩增正在多种成人实体瘤中进行研究。骨髓浸润淋巴细胞（MIL）在临床前已显示出抗肿瘤反应性。尚未有关于儿科实体瘤组织学中TIL/MIL成功扩增的报道。本研究的目的是证明从儿科实体瘤中成功扩增TIL，以便在过继性细胞治疗（ACT）策略中进行转化应用。
对接受标准治疗程序的儿科患者的实体瘤进行TIL/MIL扩增的前瞻性研究。TIL/MIL扩增在高剂量白细胞介素2存在的情况下进行。为了证明TIL治疗能全面扩增至临床相关细胞剂量，对部分患者在初始TIL培养后采用快速扩增方案。通过流式细胞术分析扩增样本的表型，并通过干扰素-γ释放试验分析其抗肿瘤反应性。
获取了18个肿瘤样本。14/18个样本（77.7%）成功培养出初始TIL。初始培养产生的细胞中位数为5.52×10⁷（范围：2.5×10⁶ - 3.23×10⁸），其中46.9%表达CD3表型（46.9%）。8个样本进行了快速扩增，显示中位数扩增458倍，CD3表型为98%。5个样本成功培养出初始MIL，主要为CD3表型（45.2%）。仅7个TIL样本有足够的肿瘤组织用于反应性测试；无一显示对自体肿瘤有反应。
从儿科实体瘤中成功扩增了TIL和MIL，包括全面扩增过程。该数据支持在儿科人群中转化为ACT-TIL治疗策略，因此计划开展儿科高危实体瘤ACT-TIL的I期试验。
