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

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

doi:10.1038/s41591-024-03478-6

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

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.

Original language	English
Article number	eabi8795
Journal	Nature Medicine
DOIs	https://doi.org/10.1038/s41591-024-03478-6
State	Accepted/In press - 2025
Externally published	Yes

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10.1038/s41591-024-03478-6

Cite this

Jadlowsky, J. K., Hexner, E. O., Marshall, A., Grupp, S. A., Frey, N. V., Riley, J. L., Veloso, E., McConville, H., Rogal, W., Czuczman, C., Hwang, W. T., Li, Y., Leskowitz, R. M., Farrelly, O., Karar, J., Christensen, S., Barber-Rotenberg, J., Gaymon, A., Aronson, N., ... Fraietta, J. A. (Accepted/In press). Long-term safety of lentiviral or gammaretroviral gene-modified T cell therapies. Nature Medicine, Article eabi8795. https://doi.org/10.1038/s41591-024-03478-6

@article{619d8d0495f748e684cd4506db03a0bb,

title = "Long-term safety of lentiviral or gammaretroviral gene-modified T cell therapies",

abstract = "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.",

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

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.",

year = "2025",

doi = "10.1038/s41591-024-03478-6",

language = "English",

journal = "Nature Medicine",

issn = "1078-8956",

}

Jadlowsky, JK, Hexner, EO, Marshall, A, Grupp, SA, Frey, NV, Riley, JL, Veloso, E, McConville, H, Rogal, W, Czuczman, C, Hwang, WT, Li, Y, Leskowitz, RM, Farrelly, O, Karar, J, Christensen, S, Barber-Rotenberg, J, Gaymon, A, Aronson, N , Bernstein, W, Melenhorst, JJ, Roche, AM, Everett, JK, Zolnoski, SA, McFarland, AG, Reddy, S, Petrichenko, A, Cook, EJ, Lee, C, Gonzalez, VE, Alexander, K, Kulikovskaya, I, Ramírez-Fernández, Á, Minehart, JC, Ruella, M, Gill, SI, Schuster, SJ, Cohen, AD, Garfall, AL, Shah, PD, Porter, DL, Maude, SL, Levine, BL, Siegel, DL, Chew, A, McKenna, S, Lledo, L, Davis, MM, Plesa, G, Herbst, F, Stadtmauer, EA, Tebas, P, DiNofia, A, Haas, A, Haas, NB, Myers, R, O’Rourke, DM, Svoboda, J, Tanyi, JL, Aplenc, R, Jacobson, JM, Ko, AH, Cohen, RB, June, CH, Bushman, FD & Fraietta, JA 2025, 'Long-term safety of lentiviral or gammaretroviral gene-modified T cell therapies', Nature Medicine. https://doi.org/10.1038/s41591-024-03478-6

TY - JOUR

T1 - Long-term safety of lentiviral or gammaretroviral gene-modified T cell therapies

AU - Jadlowsky, Julie K.

AU - Hexner, Elizabeth O.

AU - Marshall, Amy

AU - Grupp, Stephan A.

AU - Frey, Noelle V.

AU - Riley, James L.

AU - Veloso, Elizabeth

AU - McConville, Holly

AU - Rogal, Walter

AU - Czuczman, Cory

AU - Hwang, Wei Ting

AU - Li, Yimei

AU - Leskowitz, Rachel M.

AU - Farrelly, Olivia

AU - Karar, Jayashree

AU - Christensen, Shannon

AU - Barber-Rotenberg, Julie

AU - Gaymon, Avery

AU - Aronson, Naomi

AU - Bernstein, Wendy

AU - Melenhorst, Jan Joseph

AU - Roche, Aoife M.

AU - Everett, John K.

AU - Zolnoski, Sonja A.

AU - McFarland, Alexander G.

AU - Reddy, Shantan

AU - Petrichenko, Angelina

AU - Cook, Emma J.

AU - Lee, Carole

AU - Gonzalez, Vanessa E.

AU - Alexander, Kathleen

AU - Kulikovskaya, Irina

AU - Ramírez-Fernández, Ángel

AU - Minehart, Janna C.

AU - Ruella, Marco

AU - Gill, Saar I.

AU - Schuster, Stephen J.

AU - Cohen, Adam D.

AU - Garfall, Alfred L.

AU - Shah, Payal D.

AU - Porter, David L.

AU - Maude, Shannon L.

AU - Levine, Bruce L.

AU - Siegel, Donald L.

AU - Chew, Anne

AU - McKenna, Stephen

AU - Lledo, Lester

AU - Davis, Megan M.

AU - Plesa, Gabriela

AU - Herbst, Friederike

AU - Stadtmauer, Edward A.

AU - Tebas, Pablo

AU - DiNofia, Amanda

AU - Haas, Andrew

AU - Haas, Naomi B.

AU - Myers, Regina

AU - O’Rourke, Donald M.

AU - Svoboda, Jakub

AU - Tanyi, Janos L.

AU - Aplenc, Richard

AU - Jacobson, Jeffrey M.

AU - Ko, Andrew H.

AU - Cohen, Roger B.

AU - June, Carl H.

AU - Bushman, Frederic D.

AU - Fraietta, Joseph A.

PY - 2025

Y1 - 2025

N2 - 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.

AB - 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.

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U2 - 10.1038/s41591-024-03478-6

DO - 10.1038/s41591-024-03478-6

M3 - Article

C2 - 39833408

AN - SCOPUS:85217207010

SN - 1078-8956

JO - Nature Medicine

JF - Nature Medicine

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