Webb Lindsay, Lofgren Michael, Patterson Troy, Watt Amy, Lajoie Jason, Zieba Adam, Fleury Michelle, Liu Erica, Ding Jian, Tighe Robert
TCR2 Therapeutics, Inc., Cambridge, MA, United States.
Adaptimmune, Cambridge, MA, United States.
Front Immunol. 2025 May 30;16:1609658. doi: 10.3389/fimmu.2025.1609658. eCollection 2025.
Although T-cell immunotherapies have been effective in the treatment of hematological malignancies, solid tumors have proven challenging due to the immunosuppressive microenvironment and lack of viable target antigens. The immune checkpoint ligand CD70, overexpressed in several solid tumors, yet with limited expression in healthy tissue, has emerged as a promising immunotherapeutic target.
This study describes the generation and preclinical characterization of ADP-520, a high-affinity, fratricide-resistant, CD70-targeted T-cell receptor fusion construct (TRuC) T-cell therapy enhanced with constitutively expressed mbIL-15, a membrane-bound fusion protein comprising interleukin-15 (IL-15) linked to full-length IL-15 receptor-alpha. The phenotypic distribution, expansion and persistence of ADP-520 TRuC T cells were measured under autonomous and antigen-dependent conditions, with the contributions of TCR and IL-15 signaling pathways ascertained using inhibition assays. Chronic antigen stimulation was used to evaluate exhaustion-resistance, while anti-tumor potency was explored both and .
ADP-520 was found to have potent and antigen-specific activity against hematological and solid CD70-expressing tumors, without apparent fratricide or killing of bystander T cells despite CD70 expression by activated lymphocytes. Engineered co-expression of mbIL-15 augmented antigen-dependent expansion through pro-survival effects and enrichment of an early memory T-cell phenotype, thus enhancing tumor-autonomous, exogenous cytokine-free persistence and bolstering exhaustion resistance during chronic stimulation. mbIL-15 co-expression also enhanced intratumoral T-cell infiltration for potent and persistent antitumor efficacy.
These findings characterize ADP-520 as a first-in-class, CD70-targeted, fratricide-resistant autologous TRuC T-cell therapy leveraging native TCR signaling combined with constitutive IL-15 signaling to impart T cells with enhanced persistence, tumor penetration, and antitumor efficacy. This makes ADP-520 a promising cell immunotherapy candidate for clinical development, with the potential to overcome hurdles intrinsic to the treatment of solid tumors.
尽管T细胞免疫疗法在血液系统恶性肿瘤的治疗中已取得成效，但实体瘤因其免疫抑制微环境和缺乏可行的靶抗原而颇具挑战性。免疫检查点配体CD70在多种实体瘤中过度表达，而在健康组织中表达有限，已成为一个有前景的免疫治疗靶点。
本研究描述了ADP - 520的产生及临床前特征，ADP - 520是一种高亲和力、抗自相残杀、靶向CD70的T细胞受体融合构建体（TRuC）T细胞疗法，通过组成性表达mbIL - 15增强，mbIL - 15是一种膜结合融合蛋白，由与全长IL - 15受体α连接的白细胞介素 - 15（IL - 15）组成。在自主和抗原依赖性条件下测量ADP - 520 TRuC T细胞的表型分布、扩增和持久性，并使用抑制试验确定TCR和IL - 15信号通路的作用。采用慢性抗原刺激来评估抗耗竭能力，同时在体内和体外探索抗肿瘤效力。
发现ADP - 520对表达CD70的血液系统和实体瘤具有强效且抗原特异性的活性，尽管活化淋巴细胞表达CD70，但未出现明显的自相残杀或旁观者T细胞杀伤现象。mbIL - 15的工程化共表达通过促生存作用和早期记忆T细胞表型的富集增强了抗原依赖性扩增，从而增强了肿瘤自主性、无外源性细胞因子的持久性，并在慢性刺激期间增强了抗耗竭能力。mbIL - 15共表达还增强了肿瘤内T细胞浸润，以实现强效且持久的抗肿瘤疗效。
这些发现将ADP - 520表征为一流的、靶向CD70、抗自相残杀的自体TRuC T细胞疗法，利用天然TCR信号传导与组成性IL - 15信号传导相结合，赋予T细胞增强的持久性、肿瘤穿透能力和抗肿瘤疗效。这使得ADP - 520成为临床开发中有前景的细胞免疫治疗候选药物，有可能克服实体瘤治疗固有的障碍。
