• Mark P Hamilton, Takeshi Sugio, Troy Noordenbos, Shuyu Shi, Philip L Bulterys, Chih Long Liu, Xiaoman Kang, Mari N Olsen, Zinaida Good, Saurabh Dahiya, Matthew J Frank, Bita Sahaf, Crystal L Mackall, Dita Gratzinger, Maximilian Diehn, Ash A Alizadeh, and David B Miklos.
• From the Divisions of Oncology (M.P.H., T.S., T.N., C.L.L., X.K., M.N.O., A.A.A.) and Blood and Marrow Transplantation and Cellular Therapy (M.P.H., S.D., M.J.F., D.B.M.), Department of Medicine, the Center for Cancer Cell Therapy (M.P.H., Z.G., S.D., M.J.F., B.S., C.L.M., D.B.M.), Stanford Cancer Institute (T.S., T.N., C.L.L., X.K., M.N.O., C.L.M., M.D., A.A.A., D.B.M.), the Department of Pathology (P.L.B., D.G.), the Department of Biomedical Data Science (Z.G.), the Division of Hematology and Oncology, Department of Pediatrics (C.L.M.), the Department of Radiation Oncology (M.D.), and the Institute for Stem Cell Biology and Regenerative Medicine (M.D., A.A.A.), School of Medicine, and the Department of Bioengineering, Schools of Medicine and Engineering (S.S.), Stanford University, Stanford, CA; and the Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands (T.N.).
• N. Engl. J. Med. 2024 Jun 13; 390 (22): 204720602047-2060.

BackgroundThe risk of second tumors after chimeric antigen receptor (CAR) T-cell therapy, especially the risk of T-cell neoplasms related to viral vector integration, is an emerging concern.MethodsWe reviewed our clinical experience with adoptive cellular CAR T-cell therapy at our institution since 2016 and ascertained the occurrence of second tumors. In one case of secondary T-cell lymphoma, a broad array of molecular, genetic, and cellular techniques were used to interrogate the tumor, the CAR T cells, and the normal hematopoietic cells in the patient.ResultsA total of 724 patients who had received T-cell therapies at our center were included in the study. A lethal T-cell lymphoma was identified in a patient who had received axicabtagene ciloleucel therapy for diffuse large B-cell lymphoma, and both lymphomas were deeply profiled. Each lymphoma had molecularly distinct immunophenotypes and genomic profiles, but both were positive for Epstein-Barr virus and were associated with DNMT3A and TET2 mutant clonal hematopoiesis. No evidence of oncogenic retroviral integration was found with the use of multiple techniques.ConclusionsOur results highlight the rarity of second tumors and provide a framework for defining clonal relationships and viral vector monitoring. (Funded by the National Cancer Institute and others.).Copyright © 2024 Massachusetts Medical Society.

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