Department of Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
Department of Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida; Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
Int J Radiat Oncol Biol Phys. 2021 Dec 1;111(5):1145-1154. doi: 10.1016/j.ijrobp.2021.06.038. Epub 2021 Jul 6.
PURPOSE: Chimeric antigen receptor T-cell (CAR T) therapy is capable of eliciting durable responses in patients with relapsed/refractory (R/R) lymphomas. However, most treated patients relapse. Patterns of failure after CAR T have not been previously characterized, and may provide insights into the mechanisms of resistance guiding future treatment strategies. METHODS AND MATERIALS: This is a retrospective analysis of patients with R/R large B-cell lymphoma who were treated with anti-CD19 CAR T at a National Cancer Institute-designated Comprehensive Cancer Center between 2015 and 2019. Pre- and posttreatment positron emission/computed tomography scans were analyzed to assess the progression of existing (local failures) versus new, nonoverlapping lesions (de novo failures) and identify lesions at a high risk for progression. RESULTS: A total of 469 pretreatment lesions in 63 patients were identified. At a median follow-up of 12.6 months, 36 patients (57%) recurred. Most (n = 31; 86%) had a component of local failure, and 13 patients (36%) exhibited strictly local failures. Even when progressing, 84% of recurrent patients continued to have a subset of pretreatment lesions maintain positron emission/computed tomography resolution. Lesions at a high risk for local failure included those with a diameter ≥5 cm (odds ratio [OR], 2.34; 95% confidence interval [CI], 1.55-3.55; P < .001), maximum standardized uptake value ≥10 (OR, 2.08; 95% CI, 1.38-3.12; P < .001), or those that were extranodal (OR, 1.49; 95% CI, 1.10-2.04; P = .01). In the 69 patients eligible for survival analysis, those with any lesion ≥5 cm (n = 46; 67%) experienced inferior progression-free survival (hazard ratio, 2.41; 95% CI, 1.15-5.04; P = .02) and overall survival (hazard ratio, 3.36; 95% CI, 1.17-9.96; P = .02). CONCLUSIONS: Most patients who recur after CAR T experience a component of local progression. Furthermore, lesions with high-risk features, particularly large size, were associated with inferior treatment efficacy and patient survival. Taken together, these observations suggest that lesion-specific resistance may contribute to CAR T treatment failure. Locally directed therapies to high-risk lesions, such as radiation therapy, may be a viable strategy to prevent CAR T failures in select patients.
目的：嵌合抗原受体 T 细胞（CAR T）疗法能够在复发/难治性（R/R）淋巴瘤患者中引发持久的反应。然而，大多数接受治疗的患者都会复发。CAR T 后失败的模式以前没有被描述过，这可能为耐药机制提供了见解，从而指导未来的治疗策略。
方法和材料：这是一项对 2015 年至 2019 年期间在国立癌症研究所指定的综合癌症中心接受抗 CD19 CAR T 治疗的 R/R 大 B 细胞淋巴瘤患者的回顾性分析。分析治疗前后的正电子发射/计算机断层扫描（PET/CT）以评估现有病变（局部失败）和新的、非重叠病变（新发失败）的进展情况，并确定高风险进展的病变。
结果：共确定了 63 名患者的 469 个预处理病变。中位随访 12.6 个月时，36 名患者（57%）复发。大多数（n=31；86%）存在局部失败的成分，13 名患者（36%）表现为单纯局部失败。即使在进展时，84%的复发性患者继续有一部分预处理病变保持 PET/CT 分辨率。局部失败高风险的病变包括直径≥5cm（比值比[OR]，2.34；95%置信区间[CI]，1.55-3.55；P<0.001）、最大标准摄取值（SUVmax）≥10（OR，2.08；95%CI，1.38-3.12；P<0.001）或结外病变（OR，1.49；95%CI，1.10-2.04；P=0.01）。在 69 名符合生存分析条件的患者中，任何≥5cm 的病变（n=46；67%）的无进展生存率（风险比[HR]，2.41；95%CI，1.15-5.04；P=0.02）和总生存率（HR，3.36；95%CI，1.17-9.96；P=0.02）均较差。
结论：CAR T 后复发的大多数患者经历了局部进展的部分。此外，具有高危特征的病变，特别是大尺寸的病变，与较差的治疗效果和患者生存相关。综上所述，这些观察结果表明，病变特异性耐药可能导致 CAR T 治疗失败。针对高危病变（如放疗）的局部定向治疗可能是一种可行的策略，可以在选择的患者中预防 CAR T 失败。
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