Borgers Jessica S W, Lenkala Divya, Kohler Victoria, Jackson Emily K, Linssen Matthijs D, Hymson Sebastian, McCarthy Brian, O'Reilly Cosgrove Elizabeth, Balogh Kristen N, Esaulova Ekaterina, Starr Kimberly, Ware Yvonne, Klobuch Sebastian, Sciuto Tracey, Chen Xi, Mahimkar Gauri, Sheen Joong Hyuk F, Ramesh Suchitra, Wilgenhof Sofie, van Thienen Johannes V, Scheiner Karina C, Jedema Inge, Rooney Michael, Dong Jesse Z, Srouji John R, Juneja Vikram R, Arieta Christina M, Nuijen Bastiaan, Gottstein Claudia, Finney Olivia C, Manson Kelledy, Nijenhuis Cynthia M, Gaynor Richard B, DeMario Mark, Haanen John B, van Buuren Marit M
Department of Medical Oncology, Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands.
BioNTech US, Cambridge, MA, USA.
Nat Med. 2025 Mar;31(3):881-893. doi: 10.1038/s41591-024-03418-4. Epub 2025 Jan 3.
New treatment approaches are warranted for patients with advanced melanoma refractory to immune checkpoint blockade (ICB) or BRAF-targeted therapy. We designed BNT221, a personalized, neoantigen-specific autologous T cell product derived from peripheral blood, and tested this in a 3 + 3 dose-finding study with two dose levels (DLs) in patients with locally advanced or metastatic melanoma, disease progression after ICB, measurable disease (Response Evaluation Criteria in Solid Tumors version 1.1) and, where appropriate, BRAF-targeted therapy. Primary and secondary objectives were evaluation of safety, highest tolerated dose and anti-tumor activity. We report here the non-pre-specified, final results of the completed monotherapy arm consisting of nine patients: three at DL1 (1 × 10-1 × 10 cells) and six at DL2 (2 × 10-1 × 10 cells). Drug products (DPs) were generated for all enrolled patients. BNT221 was well tolerated across both DLs, with no dose-limiting toxicities of grade 3 or higher attributed to the T cell product observed. Specifically, no cytokine release, immune effector cell-associated neurotoxicity or macrophage activation syndromes were reported. A dose of 5.0 × 10-1.0 × 10 cells was identified for further study conduct. Six patients showed stable disease as best overall response, and tumor reductions (≤20%) were reported for four of these patients. In exploratory analyses, multiple mutant-specific CD4 and CD8 T cell responses were generated in each DP. These were cytotoxic, polyfunctional and expressed T cell receptors with broad functional avidities. Neoantigen-specific clonotypes were detected after treatment in blood and tumor. Our results provide key insights into this neoantigen-specific adoptive T cell therapy and demonstrate proof of concept for this new therapeutic approach. ClinicalTrials.gov registration: NCT04625205 .
对于对免疫检查点阻断（ICB）或BRAF靶向治疗难治的晚期黑色素瘤患者，有必要采用新的治疗方法。我们设计了BNT221，这是一种源自外周血的个性化、新抗原特异性自体T细胞产品，并在一项3+3剂量探索研究中对其进行了测试，该研究在局部晚期或转移性黑色素瘤、ICB治疗后疾病进展、可测量疾病（实体瘤疗效评价标准1.1版）且在适当情况下接受BRAF靶向治疗的患者中设置了两个剂量水平（DLs）。主要和次要目标是评估安全性、最高耐受剂量和抗肿瘤活性。我们在此报告已完成的单药治疗组的非预先指定的最终结果，该组包括9名患者：3名在DL1（1×10 - 1×10细胞），6名在DL2（2×10 - 1×10细胞）。为所有入组患者制备了药物产品（DPs）。BNT221在两个DLs中耐受性良好，未观察到归因于T细胞产品的3级或更高等级的剂量限制性毒性。具体而言，未报告细胞因子释放、免疫效应细胞相关神经毒性或巨噬细胞活化综合征。确定了5.0×10 - 1.0×10细胞的剂量用于进一步的研究。6名患者的最佳总体反应为疾病稳定，其中4名患者报告有肿瘤缩小（≤20%）。在探索性分析中，每个DP中产生了多种突变特异性CD4和CD8 T细胞反应。这些反应具有细胞毒性、多功能性，并表达具有广泛功能亲和力的T细胞受体。治疗后在血液和肿瘤中检测到新抗原特异性克隆型。我们的结果为这种新抗原特异性过继性T细胞疗法提供了关键见解，并证明了这种新治疗方法的概念验证。ClinicalTrials.gov注册号：NCT04625205 。
