Serial surveillance by circulating tumor DNA profiling after chimeric antigen receptor T therapy for the guidance of r/r diffuse large B cell lymphoma precise treatment

Linghui Zhou; Houli Zhao; Yang Shao; Xin Chen; Ruimin Hong; Linqin Wang; Fang Ni; Arnon Nagler; Yongxian Hu; He Huang

doi:10.7150/jca.60390

Serial surveillance by circulating tumor DNA profiling after chimeric antigen receptor T therapy for the guidance of r/r diffuse large B cell lymphoma precise treatment

J Cancer. 2021 Jul 13;12(18):5423-5431. doi: 10.7150/jca.60390. eCollection 2021.

Authors

Linghui Zhou^{1

2

3

4}, Houli Zhao^{1

2

3

4}, Yang Shao⁵, Xin Chen⁵, Ruimin Hong^{1

2

3

4}, Linqin Wang^{1

2

3

4}, Fang Ni^{1

2

3

4}, Arnon Nagler⁶, Yongxian Hu^{1

2

3

4}, He Huang^{1

2

3

4}

Affiliations

¹ Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine.
² Institute of Hematology, Zhejiang University.
³ Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy.
⁴ Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou 311121, China.
⁵ Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China.
⁶ Chaim Sheba Medical Center, Tel Hashomer, Israel, Tel Hashomer, Israel.

Abstract

Background: Circulating tumor DNA (ctDNA) released from tumor cells carries the tumor-associated genetic and epigenetic characteristics of cancer patients. Next-generation sequencing (NGS) facilitates the application of ctDNA profiling for identification and monitoring of minimal residual disease (MRD) in cancer, and can serve as the guidance for precise treatment. Methods: In this study, we profiled genomic alterations in the baseline, relapsed, and progressive tumor samples of eight diffuse large B cell lymphoma (DLBCL) patients (NCT03118180) after chimeric antigen receptor T (CAR-T) cell therapy. Results: The median follow-up was 41 months. 4 (50%) patients achieved complete remission (CR), 1 (12.5%) patient achieved partial remission (PR), and the other 3 (37.5%) patients showed no response. 3 of 5 patients who achieved remission relapsed within 4 months after CAR-T therapy, while the rest 2 patients remained CR for more than 3 years. Based on the positron emission tomography-computed tomography (PET-CT) scan, the current gold standard for evaluating response to therapy in lymphoma, the sensitivity and specificity of our ctDNA profiling in detecting tumor-related ctDNA mutations were 94.7% and 83.3%, respectively. The median numbers of baseline plasma ctDNA mutations in patients who remained long-term CR and patients who relapsed or became refractory to CAR-T therapy were 3 and 14.3, respectively. GNA13, SOCS1, TNFAIP3 and XPO1 mutations appeared to be associated with poor prognosis after CAR-T cell therapy. Our results also suggested that lenalidomide might relieve relapsed lymphoma with mutations in NFKBIA 202C>T (p.Q68*) and NFKBIE 433A>T (p.K145*) by targeting NF-Kappa B signaling. In addition, the inhibitor selinexor may be another choice for refractory or relapse (r/r) DLBCL patients after CAR-T cell treatment. Conclusion: Serial ctDNA monitoring is an emerging technology for the surveillance of disease status and prognosis prediction. In this work, we demonstrated the use of serial ctDNA monitoring in r/r DLBCL patients after CD19-targeted CAR-T cell therapy. Our longitudinal NGS profiling revealed the changes of ctDNA mutation in accordance with prognosis, and shed some light on exploring more targeted treatment options together with CAR-T cell therapy.

Keywords: CAR-T; DLBCL; ctDNA; precise treatment.