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Risk of Second Tumors and T-Cell Lymphoma after CAR T-Cell Therapy
Mark P Hamilton1, Takeshi Sugio1, Troy Noordenbos1
1From 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.).
Background:
The 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.
Methods:
We 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.
Results:
A 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.
Conclusions:
Our 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.).
Insights
Second tumors after CAR T-cell therapy are rare. A case study found no viral vector integration in a patient who developed T-cell lymphoma, suggesting other causes for secondary malignancies.
Area of Science:
- Oncology
- Immunotherapy
- Genetics
Background:
- Chimeric antigen receptor (CAR) T-cell therapy is a promising cancer treatment.
- Concerns exist regarding the risk of secondary tumors, particularly T-cell neoplasms, following CAR T-cell therapy.
- The role of viral vector integration in these secondary malignancies requires further investigation.
Purpose of the Study:
- To investigate the occurrence and characteristics of second tumors in patients treated with CAR T-cell therapy.
- To analyze a specific case of secondary T-cell lymphoma in detail using comprehensive molecular, genetic, and cellular techniques.
- To assess the potential link between viral vector integration and the development of secondary T-cell neoplasms.
Main Methods:
- Retrospective review of clinical data from 724 patients who received CAR T-cell therapy.
- In-depth molecular, genetic, and cellular analysis of tumor samples, CAR T cells, and normal hematopoietic cells from a patient with secondary T-cell lymphoma.
- Utilized multiple techniques to detect oncogenic retroviral integration.
Main Results:
- A total of 724 patients were included in the study.
- One patient developed a lethal T-cell lymphoma after receiving axicabtagene ciloleucel for diffuse large B-cell lymphoma.
- Both lymphomas exhibited distinct immunophenotypes and genomic profiles, were Epstein-Barr virus-positive, and associated with DNMT3A/TET2 mutant clonal hematopoiesis. No viral vector integration was detected.
Conclusions:
- Second tumors following CAR T-cell therapy appear to be rare.
- The study provides a framework for evaluating clonal relationships and monitoring viral vectors.
- The findings suggest that factors beyond viral vector integration may contribute to secondary T-cell malignancies.
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