학술논문
Personalized monitoring of circulating tumor DNA with a specific signature of trackable mutations after chimeric antigen receptor T-cell therapy in follicular lymphoma patients.
Document Type
Academic Journal
Author
Jiménez-Ubieto A; Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), CNIO, CIBERONC, Madrid, Spain.; Martín-Muñoz A; Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), CNIO, CIBERONC, Madrid, Spain.; Altum sequencing Co., Madrid, Spain.; Poza M; Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), CNIO, CIBERONC, Madrid, Spain.; Dorado S; Altum sequencing Co., Madrid, Spain.; Computational Science Department, Carlos III University, Madrid, Spain.; García-Ortiz A; Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), CNIO, CIBERONC, Madrid, Spain.; Revilla E; Departamento de Anatomía Patológica, Hospital Universitario 12 de Octubre, Madrid, Spain.; Sarandeses P; Departamento de Medicina Nuclear, Hospital Universitario 12 de Octubre, Madrid, Spain.; Ruiz-Heredia Y; Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), CNIO, CIBERONC, Madrid, Spain.; Altum sequencing Co., Madrid, Spain.; Baumann T; Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), CNIO, CIBERONC, Madrid, Spain.; Rodríguez A; Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), CNIO, CIBERONC, Madrid, Spain.; Calbacho M; Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), CNIO, CIBERONC, Madrid, Spain.; Sánchez PM; Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), CNIO, CIBERONC, Madrid, Spain.; Pina JMS; Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), CNIO, CIBERONC, Madrid, Spain.; García-Sancho AM; Department of Hematology, Hospital Universitario de Salamanca, IBSAL, CIBERONC, Salamanca, Spain.; Figaredo G; Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), CNIO, CIBERONC, Madrid, Spain.; Rufián L; Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), CNIO, CIBERONC, Madrid, Spain.; Altum sequencing Co., Madrid, Spain.; Rodríguez M; Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), CNIO, CIBERONC, Madrid, Spain.; Altum sequencing Co., Madrid, Spain.; Carneros L; Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), CNIO, CIBERONC, Madrid, Spain.; Martínez-Laperche C; Hospital General Universitario Gregorio Marañón, Madrid, Spain.; Bastos-Oreiro M; Hospital General Universitario Gregorio Marañón, Madrid, Spain.; Wang C; Hosea Precision Medical Technology Co., Ltd., Weihai, Shangdong, China.; Cedena MT; Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), CNIO, CIBERONC, Madrid, Spain.; Rapado I; Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), CNIO, CIBERONC, Madrid, Spain.; de Toledo P; Computational Science Department, Carlos III University, Madrid, Spain.; Gallardo M; Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), CNIO, CIBERONC, Madrid, Spain.; Valeri A; Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), CNIO, CIBERONC, Madrid, Spain.; Ayala R; Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), CNIO, CIBERONC, Madrid, Spain.; Martínez-López J; Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), CNIO, CIBERONC, Madrid, Spain.; Barrio S; Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), CNIO, CIBERONC, Madrid, Spain.; Altum sequencing Co., Madrid, Spain.
Source
Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE
Subject
Language
English
Abstract
Background: CART therapy has produced a paradigm shift in the treatment of relapsing FL patients. Strategies to optimize disease surveillance after these therapies are increasingly necessary. This study explores the potential value of ctDNA monitoring with an innovative signature of personalized trackable mutations.
Method: Eleven FL patients treated with anti-CD19 CAR T-cell therapy were included. One did not respond and was excluded. Genomic profiling was performed before starting lymphodepleting chemotherapy to identify somatic mutations suitable for LiqBio-MRD monitoring. The dynamics of the baseline mutations (4.5 per patient) were further analyzed on 59 cfDNA follow-up samples. PET/CT examinations were performed on days +90, +180, +365, and every six months until disease progression or death.
Results: After a median follow-up of 36 months, all patients achieved a CR as the best response. Two patients progressed. The most frequently mutated genes were CREBBP, KMT2D and EP300. Simultaneous analysis of ctDNA and PET/CT was available for 18 time-points. When PET/CT was positive, two out of four ctDNA samples were LiqBio-MRD negative. These two negative samples corresponded to women with a unique mesenteric mass in two evaluations and never relapsed. Meanwhile, 14 PET/CT negative images were mutation-free based on our LiqBio-MRD analysis (100%). None of the patients had a negative LiqBio-MRD test by day +7. Interestingly, all durably responding patients had undetectable ctDNA at or around three months after infusion. Two patients presented discordant results by PET/CT and ctDNA levels. No progression was confirmed in these cases. All the progressing patients were LiqBio-MRD positive before progression.
Conclusion: This is a proof-of-principle for using ctDNA to monitor response to CAR T-cell therapy in FL. Our results confirm that a non-invasive liquid biopsy MRD analysis may correlate with response and could be used to monitor response. Harmonized definitions of ctDNA molecular response and pinpointing the optimal timing for assessing ctDNA responses are necessary for this setting. If using ctDNA analysis, we suggest restricting follow-up PET/CT in CR patients to a clinical suspicion of relapse, to avoid false-positive results.
Competing Interests: AMM, SD, YRH, LR and MR are are employees of Altum Sequencing Co. RA, JM-L, and SB are equity shareholders of Altum Sequencing Co. CW is an employee of Hosea Precision Medical Technology Co. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Jiménez-Ubieto, Martín-Muñoz, Poza, Dorado, García-Ortiz, Revilla, Sarandeses, Ruiz-Heredia, Baumann, Rodríguez, Calbacho, Sánchez, Pina, García-Sancho, Figaredo, Rufián, Rodríguez, Carneros, Martínez-Laperche, Bastos-Oreiro, Wang, Cedena, Rapado, de Toledo, Valeri, Ayala, Martínez-López and Barrio.)
Method: Eleven FL patients treated with anti-CD19 CAR T-cell therapy were included. One did not respond and was excluded. Genomic profiling was performed before starting lymphodepleting chemotherapy to identify somatic mutations suitable for LiqBio-MRD monitoring. The dynamics of the baseline mutations (4.5 per patient) were further analyzed on 59 cfDNA follow-up samples. PET/CT examinations were performed on days +90, +180, +365, and every six months until disease progression or death.
Results: After a median follow-up of 36 months, all patients achieved a CR as the best response. Two patients progressed. The most frequently mutated genes were CREBBP, KMT2D and EP300. Simultaneous analysis of ctDNA and PET/CT was available for 18 time-points. When PET/CT was positive, two out of four ctDNA samples were LiqBio-MRD negative. These two negative samples corresponded to women with a unique mesenteric mass in two evaluations and never relapsed. Meanwhile, 14 PET/CT negative images were mutation-free based on our LiqBio-MRD analysis (100%). None of the patients had a negative LiqBio-MRD test by day +7. Interestingly, all durably responding patients had undetectable ctDNA at or around three months after infusion. Two patients presented discordant results by PET/CT and ctDNA levels. No progression was confirmed in these cases. All the progressing patients were LiqBio-MRD positive before progression.
Conclusion: This is a proof-of-principle for using ctDNA to monitor response to CAR T-cell therapy in FL. Our results confirm that a non-invasive liquid biopsy MRD analysis may correlate with response and could be used to monitor response. Harmonized definitions of ctDNA molecular response and pinpointing the optimal timing for assessing ctDNA responses are necessary for this setting. If using ctDNA analysis, we suggest restricting follow-up PET/CT in CR patients to a clinical suspicion of relapse, to avoid false-positive results.
Competing Interests: AMM, SD, YRH, LR and MR are are employees of Altum Sequencing Co. RA, JM-L, and SB are equity shareholders of Altum Sequencing Co. CW is an employee of Hosea Precision Medical Technology Co. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Jiménez-Ubieto, Martín-Muñoz, Poza, Dorado, García-Ortiz, Revilla, Sarandeses, Ruiz-Heredia, Baumann, Rodríguez, Calbacho, Sánchez, Pina, García-Sancho, Figaredo, Rufián, Rodríguez, Carneros, Martínez-Laperche, Bastos-Oreiro, Wang, Cedena, Rapado, de Toledo, Valeri, Ayala, Martínez-López and Barrio.)