Cullinan Oncology, Inc., One Main Street, Cambridge, Massachusetts, USA.
Institute for Immunology, LMU Munich, Planegg-Martinsried, Germany.
Curr Opin Oncol. 2022 Sep 1;34(5):552-558. doi: 10.1097/CCO.0000000000000869. Epub 2022 Jul 28.
T-cell-engaging antibodies or T-cell engagers (TCEs) can connect a patient's cytotoxic T cells with cancer cells, leading to potent redirected lysis. Until very recently, only one TCE was approved, the CD19/CD3-bispecific blinatumomab. Many new TCEs in late-stage clinical development target various hematopoietic lineage markers like CD20, BCMA, or CD123. Although very compelling single-agent activity of TCEs was observed with various blood-borne cancers, therapy of solid tumor indications has thus far been less successful.
The approval in 2022 of the gp100 peptide-major histocompatibility complex (MHC)/CD3 bispecific TCE tebentafusp in uveal melanoma confirms that TCEs can also efficiently work against solid tumors. TCEs targeting peptide-MHC complexes will expand the target space for solid tumor therapy to intracellular targets. Likewise, early clinical trial data from TCEs targeting DLL3 in small cell lunger cancer showed promising antitumor activity. Various technologies for conditional activation of TCEs in the tumor microenvironment (TME) may expand the scope of conventional surface targets that suffer from a narrow therapeutic window. Finally, pharmacological enhancements for TCE therapies by engagement of certain costimulatory receptors and cytokines, or blockade of checkpoints, are showing promise.
Targeting peptide-MHC complexes, conditional TCE technologies, and concepts enhancing TCE-activated T cells are paving the way towards overcoming challenges associated with solid tumor therapy.
综述目的：T 细胞衔接抗体或 T 细胞衔接器（TCE）可将患者的细胞毒性 T 细胞与癌细胞连接起来，导致有效的重定向裂解。直到最近，只有一种 TCE 获批，即 CD19/CD3 双特异性blinatumomab。许多处于临床后期开发阶段的新型 TCE 针对各种造血谱系标志物，如 CD20、BCMA 或 CD123。尽管观察到各种血源性癌症的 TCE 具有非常令人信服的单一药物活性，但针对实体瘤适应症的治疗迄今为止并不成功。
最新发现：2022 年批准的 gp100 肽-主要组织相容性复合物（MHC）/CD3 双特异性 TCE tebentafusp 用于葡萄膜黑色素瘤，证实 TCE 也可以有效地对抗实体瘤。针对肽-MHC 复合物的 TCE 将扩大实体瘤治疗的靶标空间，涵盖细胞内靶标。同样，针对小细胞肺癌中 DLL3 的 TCE 的早期临床试验数据显示出有希望的抗肿瘤活性。用于在肿瘤微环境（TME）中条件激活 TCE 的各种技术可能会扩大传统表面靶标的范围，这些靶标因治疗窗口狭窄而受到限制。最后，通过某些共刺激受体和细胞因子的结合或阻断检查点来增强 TCE 疗法的药理学增强作用也显示出前景。
总结：靶向肽-MHC 复合物、条件性 TCE 技术以及增强 TCE 激活的 T 细胞的概念，为克服实体瘤治疗相关挑战铺平了道路。
