Hong David S, Butler Marcus O, Pachynski Russell K, Sullivan Ryan, Kebriaei Partow, Boross-Harmer Sarah, Ghobadi Armin, Frigault Matthew J, Dumbrava Ecaterina E, Sauer Amy, Brophy Francine, Navenot Jean-Marc, Fayngerts Svetlana, Wolchinsky Zohar, Broad Robyn, Batrakou Dzmitry G, Wang Ruoxi, Solis Luisa M, Duose Dzifa Yawa, Sanderson Joseph P, Gerry Andrew B, Marks Diane, Bai Jane, Norry Elliot, Fracasso Paula M
Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Princess Margaret Hospital Cancer Centre, University of Toronto, Toronto, ON, Canada.
Front Oncol. 2022 Mar 18;12:818679. doi: 10.3389/fonc.2022.818679. eCollection 2022.
ADP-A2M10 specific peptide enhanced affinity receptor (SPEAR) T-cells are genetically engineered autologous T-cells that express a high-affinity melanoma-associated antigen (MAGE)-A10-specific T-cell receptor (TCR) targeting MAGE-A10-positive tumors in the context of human leukocyte antigen (HLA)-A*02. ADP-0022-004 is a phase 1, dose-escalation trial to evaluate the safety and anti-tumor activity of ADP-A2M10 in three malignancies (https://clinicaltrials.gov: NCT02989064).
Eligible patients were HLA-A*02 positive with advanced head and neck squamous cell carcinoma (HNSCC), melanoma, or urothelial carcinoma (UC) expressing MAGE-A10. Patients underwent apheresis; T-cells were isolated, transduced with a lentiviral vector containing the MAGE-A10 TCR, and expanded. Patients underwent lymphodepletion with fludarabine and cyclophosphamide prior to receiving ADP-A2M10. ADP-A2M10 was administered in two dose groups receiving 0.1×10 and >1.2 to 6×10 transduced cells, respectively, and an expansion group receiving 1.2 to 15×10 transduced cells.
Ten patients (eight male and two female) with HNSCC (four), melanoma (three), and UC (three) were treated. Three patients were treated in each of the two dose groups, and four patients were treated in the expansion group. The most frequently reported adverse events grade ≥3 were leukopenia (10), lymphopenia (10), neutropenia (10), anemia (nine), and thrombocytopenia (five). Two patients reported cytokine release syndrome (one each with grade 1 and grade 3), with resolution. Best response included stable disease in four patients, progressive disease in five patients, and not evaluable in one patient. ADP-A2M10 cells were detectable in peripheral blood from patients in each dose group and the expansion group and in tumor tissues from patients in the higher dose group and the expansion group. Peak persistence was greater in patients from the higher dose group and the expansion group compared with the lower dose group.
ADP-A2M10 has shown an acceptable safety profile with no evidence of toxicity related to off-target binding or alloreactivity in these malignancies. Persistence of ADP-A2M10 in the peripheral blood and trafficking of ADP-A2M10 into the tumor was demonstrated. Because MAGE-A10 expression frequently overlaps with MAGE-A4 expression in tumors and responses were observed in the MAGE-A4 trial (NCT03132922), this clinical program closed, and trials with SPEAR T-cells targeting the MAGE-A4 antigen are ongoing.
ADP - A2M10特异性肽增强亲和力受体（SPEAR）T细胞是经过基因工程改造的自体T细胞，在人类白细胞抗原（HLA）- A*02的背景下表达针对MAGE - A10阳性肿瘤的高亲和力黑色素瘤相关抗原（MAGE）- A10特异性T细胞受体（TCR）。ADP - 0022 - 004是一项1期剂量递增试验，旨在评估ADP - A2M10在三种恶性肿瘤中的安全性和抗肿瘤活性（https://clinicaltrials.gov：NCT02989064）。
符合条件的患者为HLA - A*02阳性，患有晚期头颈部鳞状细胞癌（HNSCC）、黑色素瘤或表达MAGE - A10的尿路上皮癌（UC）。患者接受单采术；分离T细胞，用含有MAGE - A10 TCR的慢病毒载体进行转导并扩增。患者在接受ADP - A2M10之前用氟达拉滨和环磷酰胺进行淋巴细胞清除。ADP - A2M10以两个剂量组给药，分别接受0.1×10和>1.2至6×10个转导细胞，以及一个接受1.2至15×10个转导细胞的扩增组。
治疗了10例患者（8例男性和2例女性），其中HNSCC患者4例、黑色素瘤患者3例、UC患者3例。两个剂量组各治疗3例患者，扩增组治疗4例患者。最常报告的≥3级不良事件为白细胞减少（10例）、淋巴细胞减少（10例）、中性粒细胞减少（10例）、贫血（9例）和血小板减少（5例）。两名患者报告了细胞因子释放综合征（1例1级，1例3级），均已缓解。最佳反应包括4例患者病情稳定，5例患者疾病进展，1例患者不可评估。在每个剂量组和扩增组患者的外周血以及高剂量组和扩增组患者的肿瘤组织中均可检测到ADP - A2M10细胞。与低剂量组相比，高剂量组和扩增组患者的峰值持续时间更长。
ADP - A2M10已显示出可接受的安全性，在这些恶性肿瘤中没有证据表明存在与脱靶结合或同种异体反应相关的毒性。证明了ADP - A2M10在外周血中的持久性以及ADP - A2M10向肿瘤的归巢。由于肿瘤中MAGE - A10表达常与MAGE - A4表达重叠，且在MAGE - A4试验（NCT03132922）中观察到了反应，该临床项目已结束，目前正在进行针对MAGE - A4抗原的SPEAR T细胞试验。
