Nature medicine · 2025

Long-term safety of lentiviral or gammaretroviral gene-modified T cell therapies.

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Jadlowsky Julie K, Hexner Elizabeth O, Marshall Amy, Grupp Stephan A, Frey Noelle V, Riley James L, Veloso Elizabeth, McConville Holly, Rogal Walter, Czuczman Cory, Hwang Wei-Ting, Li Yimei, Leskowitz Rachel M, Farrelly Olivia, Karar Jayashree, Christensen Shannon, Barber-Rotenberg Julie, Gaymon Avery, Aronson Naomi, Bernstein Wendy, Melenhorst Jan Joseph, Roche Aoife M, Everett John K, Zolnoski Sonja A, McFarland Alexander G, Reddy Shantan, Petrichenko Angelina, Cook Emma J, Lee Carole, Gonzalez Vanessa E, Alexander Kathleen, Kulikovskaya Irina, Ramírez-Fernández Ángel, Minehart Janna C, Ruella Marco, Gill Saar I, Schuster Stephen J, Cohen Adam D, Garfall Alfred L, Shah Payal D, Porter David L, Maude Shannon L, Levine Bruce L, Siegel Donald L, Chew Anne, McKenna Stephen, Lledo Lester, Davis Megan M, Plesa Gabriela, Herbst Friederike, Stadtmauer Edward A, Tebas Pablo, DiNofia Amanda, Haas Andrew, Haas Naomi B, Myers Regina, O'Rourke Donald M, Svoboda Jakub, Tanyi Janos L, Aplenc Richard, Jacobson Jeffrey M, Ko Andrew H, Cohen Roger B, June Carl H, Bushman Frederic D, Fraietta Joseph A

Аннотация

Long-term risks of gene therapy are not fully understood. In this study, we evaluated safety outcomes in 783 patients over more than 2,200 total patient-years of observation from 38 T cell therapy trials. The trials employed integrating gammaretroviral or lentiviral vectors to deliver engineered receptors to target HIV-1 infection or cancer. Eighteen patients (2.3%) developed secondary malignancies after treatment, with a median onset of 1.94 years (range: 51 d to 14 years). Where possible, incident tumor samples were analyzed for vector copy number, revealing no evidence of high-level marking or other indications of insertional mutagenesis. One T cell lymphoma was detected, but malignant T cells were not marked by vector integration. Analysis of vector integration sites in 176 patients revealed no pathological insertions linked to secondary malignancies, although, in some cases, integration in or near specific genes, including tumor suppressor genes, was associated with modest clonal expansion and sustained T cell persistence. These findings highlight the safety of engineered T cell therapies.

Предметные рубрики MeSH

Humans Genetic Therapy Lentivirus T-Lymphocytes Genetic Vectors Gammaretrovirus HIV Infections Male Middle Aged Neoplasms Adult Female

Long-term safety of lentiviral or gammaretroviral gene-modified T cell therapies.

Ошибки и ограничения

Аннотация

Предметные рубрики MeSH