Lepik Kirill V, Markelov Vladislav V
RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, 191144 St. Petersburg, Russia.
Cancers (Basel). 2025 Jan 20;17(2):317. doi: 10.3390/cancers17020317.
T-cell redirecting therapies, which include chimeric antigen receptor T-cells (CAR-Ts) and bispecific antibodies (BSAs), have revolutionized the treatment of relapsed\refractory large B-cell lymphoma (LBCL). Expanding clinical experience with these advanced therapies shows the potential for the optimization of their use with combination or consolidation strategies, which necessitates the prognostic stratification of patients. While traditional clinical prognostic factors identified in the era of chemotherapy are characterized by limited value, the tumor microenvironment (TME) is becoming a new prognostic cluster. We examine how the heterogeneity of LBCL, characterized by variations in tumor parameters and differences in TME immune cell composition, immune checkpoint expression, and cytokine milieu, correlates with both positive responses and resistance to treatment. While classical parameters such as histological subtype, cell of origin, and target antigen expression lack proven prognostic value for T-cell redirecting therapies, the density and functional state of tumor-infiltrating lymphocytes, tumor-associated macrophages, and immune checkpoint molecules are shown to be critical determinants of therapeutic success, particularly in CAR-T therapy. We identify several gaps in the current knowledge and suggest that the insights gained from CAR-T experience could be instrumental in refining BSA applications. This report also highlights limitations in the current knowledge, as TME data derive from a limited number of registrational trials with varying methodologies, complicating cross-study comparisons and often focusing on immediate response metrics rather than long-term outcomes. By dissecting the complex interactions within the TME, this review aims to identify new prognostic factors and targets, ultimately fostering more effective and tailored treatment strategies for LBCL patients.
T细胞重定向疗法，包括嵌合抗原受体T细胞（CAR-T）和双特异性抗体（BSA），已经彻底改变了复发/难治性大B细胞淋巴瘤（LBCL）的治疗方式。随着这些先进疗法临床经验的不断积累，显示出通过联合或巩固策略优化其使用的潜力，这就需要对患者进行预后分层。虽然化疗时代确定的传统临床预后因素价值有限，但肿瘤微环境（TME）正成为一个新的预后类别。我们研究了LBCL的异质性，其特征在于肿瘤参数的变化以及TME免疫细胞组成、免疫检查点表达和细胞因子环境的差异，如何与治疗的阳性反应和耐药性相关。虽然组织学亚型、起源细胞和靶抗原表达等经典参数对T细胞重定向疗法缺乏已证实的预后价值，但肿瘤浸润淋巴细胞、肿瘤相关巨噬细胞和免疫检查点分子的密度和功能状态被证明是治疗成功的关键决定因素，尤其是在CAR-T治疗中。我们确定了当前知识中的几个空白，并表明从CAR-T经验中获得的见解可能有助于完善BSA的应用。本报告还强调了当前知识的局限性，因为TME数据来自数量有限、方法各异的注册试验，这使得跨研究比较变得复杂，并且往往侧重于即时反应指标而非长期结果。通过剖析TME内的复杂相互作用，本综述旨在确定新的预后因素和靶点，最终为LBCL患者制定更有效、更具针对性的治疗策略。
