Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas

Brian J. Sworder; David M. Kurtz; Stefan K. Alig; Matthew J. Frank; Navika Shukla; Andrea Garofalo; Charles W. Macaulay; Mohammad Shahrokh Esfahani; Mari N. Olsen; James Hamilton; Hitomi Hosoya; Mark Hamilton; Jay Y. Spiegel; John H. Baird; Takeshi Sugio; Mia Carleton; Alexander F.M. Craig; Sheren F. Younes; Bita Sahaf; Natasha D. Sheybani; Joseph G. Schroers-Martin; Chih Long Liu; Jean S. Oak; Michael C. Jin; Sara Beygi; Andreas Hüttmann; Christine Hanoun; Ulrich Dührsen; Jason R. Westin; Michael S. Khodadoust; Yasodha Natkunam; Robbie G. Majzner; Crystal L. Mackall; Maximilian Diehn; David B. Miklos; Ash A. Alizadeh

doi:10.1016/j.ccell.2022.12.005

Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas

Brian J. Sworder, David M. Kurtz, Stefan K. Alig, Matthew J. Frank, Navika Shukla, Andrea Garofalo, Charles W. Macaulay, Mohammad Shahrokh Esfahani, Mari N. Olsen, James Hamilton, Hitomi Hosoya, Mark Hamilton, Jay Y. Spiegel, John H. Baird, Takeshi Sugio, Mia Carleton, Alexander F.M. Craig, Sheren F. Younes, Bita Sahaf, Natasha D. SheybaniJoseph G. Schroers-Martin, Chih Long Liu, Jean S. Oak, Michael C. Jin, Sara Beygi, Andreas Hüttmann, Christine Hanoun, Ulrich Dührsen, Jason R. Westin, Michael S. Khodadoust, Yasodha Natkunam, Robbie G. Majzner, Crystal L. Mackall, Maximilian Diehn, David B. Miklos, Ash A. Alizadeh

Lymphoma-Myeloma

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

35 Scopus citations

Abstract

Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches.

Original language	English (US)
Pages (from-to)	210-225.e5
Journal	Cancer cell
Volume	41
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2022.12.005
State	Published - Jan 9 2023

Keywords

cell-free DNA
chimeric antigen receptor T cells
circulating tumor DNA
ctDNA
genomics
immunotherapy
large B cell lymphoma
MRD
oncology
precision medicine

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccell.2022.12.005

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Sworder, B. J., Kurtz, D. M., Alig, S. K., Frank, M. J., Shukla, N., Garofalo, A., Macaulay, C. W., Shahrokh Esfahani, M., Olsen, M. N., Hamilton, J., Hosoya, H., Hamilton, M., Spiegel, J. Y., Baird, J. H., Sugio, T., Carleton, M., Craig, A. F. M., Younes, S. F., Sahaf, B., ... Alizadeh, A. A. (2023). Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas. Cancer cell, 41(1), 210-225.e5. https://doi.org/10.1016/j.ccell.2022.12.005

Sworder, BJ, Kurtz, DM, Alig, SK, Frank, MJ, Shukla, N, Garofalo, A, Macaulay, CW, Shahrokh Esfahani, M, Olsen, MN, Hamilton, J, Hosoya, H, Hamilton, M, Spiegel, JY, Baird, JH, Sugio, T, Carleton, M, Craig, AFM, Younes, SF, Sahaf, B, Sheybani, ND, Schroers-Martin, JG, Liu, CL, Oak, JS, Jin, MC, Beygi, S, Hüttmann, A, Hanoun, C, Dührsen, U, Westin, JR, Khodadoust, MS, Natkunam, Y, Majzner, RG, Mackall, CL, Diehn, M, Miklos, DB & Alizadeh, AA 2023, 'Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas', Cancer cell, vol. 41, no. 1, pp. 210-225.e5. https://doi.org/10.1016/j.ccell.2022.12.005

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title = "Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas",

abstract = "Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches.",

keywords = "cell-free DNA, chimeric antigen receptor T cells, circulating tumor DNA, ctDNA, genomics, immunotherapy, large B cell lymphoma, MRD, oncology, precision medicine",

author = "Sworder, {Brian J.} and Kurtz, {David M.} and Alig, {Stefan K.} and Frank, {Matthew J.} and Navika Shukla and Andrea Garofalo and Macaulay, {Charles W.} and {Shahrokh Esfahani}, Mohammad and Olsen, {Mari N.} and James Hamilton and Hitomi Hosoya and Mark Hamilton and Spiegel, {Jay Y.} and Baird, {John H.} and Takeshi Sugio and Mia Carleton and Craig, {Alexander F.M.} and Younes, {Sheren F.} and Bita Sahaf and Sheybani, {Natasha D.} and Schroers-Martin, {Joseph G.} and Liu, {Chih Long} and Oak, {Jean S.} and Jin, {Michael C.} and Sara Beygi and Andreas H{\"u}ttmann and Christine Hanoun and Ulrich D{\"u}hrsen and Westin, {Jason R.} and Khodadoust, {Michael S.} and Yasodha Natkunam and Majzner, {Robbie G.} and Mackall, {Crystal L.} and Maximilian Diehn and Miklos, {David B.} and Alizadeh, {Ash A.}",

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doi = "10.1016/j.ccell.2022.12.005",

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T1 - Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas

AU - Sworder, Brian J.

AU - Kurtz, David M.

AU - Alig, Stefan K.

AU - Frank, Matthew J.

AU - Shukla, Navika

AU - Garofalo, Andrea

AU - Macaulay, Charles W.

AU - Shahrokh Esfahani, Mohammad

AU - Olsen, Mari N.

AU - Hamilton, James

AU - Hosoya, Hitomi

AU - Hamilton, Mark

AU - Spiegel, Jay Y.

AU - Baird, John H.

AU - Sugio, Takeshi

AU - Carleton, Mia

AU - Craig, Alexander F.M.

AU - Younes, Sheren F.

AU - Sahaf, Bita

AU - Sheybani, Natasha D.

AU - Schroers-Martin, Joseph G.

AU - Liu, Chih Long

AU - Oak, Jean S.

AU - Jin, Michael C.

AU - Beygi, Sara

AU - Hüttmann, Andreas

AU - Hanoun, Christine

AU - Dührsen, Ulrich

AU - Westin, Jason R.

AU - Khodadoust, Michael S.

AU - Natkunam, Yasodha

AU - Majzner, Robbie G.

AU - Mackall, Crystal L.

AU - Diehn, Maximilian

AU - Miklos, David B.

AU - Alizadeh, Ash A.

PY - 2023/1/9

Y1 - 2023/1/9

N2 - Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches.

AB - Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches.

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KW - chimeric antigen receptor T cells

KW - circulating tumor DNA

KW - ctDNA

KW - genomics

KW - immunotherapy

KW - large B cell lymphoma

KW - MRD

KW - oncology

KW - precision medicine

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AN - SCOPUS:85145830265

SN - 1535-6108

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SP - 210-225.e5

JO - Cancer cell

JF - Cancer cell

IS - 1

ER -

Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas

Abstract

Keywords

ASJC Scopus subject areas

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