FHBG PET/CT imaging of CD34-TK75 transduced donor T cells in relapsed allogeneic stem cell transplant patients: Safety and feasibility

Linda G. Eissenberg; Michael P. Rettig; Julie K. Ritchey; Julie L. Prior; Sally W. Schwarz; Jennifer Frye; Brian S. White; Robert S. Fulton; Armin Ghobadi; Matthew L. Cooper; Daniel R. Couriel; Muhammad Esa Seegulam; David Piwnica-Worms; Farrokh Dehdashti; Kenneth Cornetta; John F. DiPersio

doi:10.1038/mt.2015.48

FHBG PET/CT imaging of CD34-TK75 transduced donor T cells in relapsed allogeneic stem cell transplant patients: Safety and feasibility

Linda G. Eissenberg, Michael P. Rettig, Julie K. Ritchey, Julie L. Prior, Sally W. Schwarz, Jennifer Frye, Brian S. White, Robert S. Fulton, Armin Ghobadi, Matthew L. Cooper, Daniel R. Couriel, Muhammad Esa Seegulam, David Piwnica-Worms, Farrokh Dehdashti, Kenneth Cornetta, John F. DiPersio

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Abstract

Described herein is a first-in-man attempt to both genetically modify T cells with an imagable suicide gene and track these transduced donor T cells in allogeneic stem cell transplantation recipients using noninvasive positron emission tomography/computerized tomography (PET/CT) imaging. A suicide gene encoding a human CD34-Herpes Simplex Virus-1-thymidine kinase (CD34-TK75) fusion enabled enrichment of retrovirally transduced T cells (TdT), control of graft-versus-host disease and imaging of TdT migration and expansion in vivo in mice and man. Analysis confirmed that CD34-TK75-enriched TdT contained no replication competent γ-retrovirus, were sensitive to ganciclovir, and displayed characteristic retroviral insertion sites (by targeted sequencing). Affinity-purified CD34-TK75 + -selected donor T cells (1.0-13 × 10 5)/kg were infused into eight patients who relapsed after allogeneic stem cell transplantation. Six patients also were administered 9-[4-(18 F)fluoro-3-hydroxymethyl-butyl]guanine ([ 18 F]FHBG) to specifically track the genetically modified donor T cells by PET/CT at several time points after infusion. All patients were assessed for graft-versus-host disease, response to ganciclovir, circulating TdT cells (using both quantitative polymerase chain reaction and [ 18 F]FHBG PET/CT imaging), TdT cell clonal expansion, and immune response to the TdT. This phase 1 trial demonstrated that genetically modified T cells and [ 18 F]FHBG can be safely infused in patients with relapsed hematologic malignancies after allogeneic stem cell transplantation.

Original language	English
Pages (from-to)	1110-1122
Number of pages	13
Journal	Molecular Therapy
Volume	23
Issue number	6
DOIs	https://doi.org/10.1038/mt.2015.48
State	Published - Jun 1 2015

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Eissenberg, L. G., Rettig, M. P., Ritchey, J. K., Prior, J. L., Schwarz, S. W., Frye, J., White, B. S., Fulton, R. S., Ghobadi, A., Cooper, M. L., Couriel, D. R., Seegulam, M. E., Piwnica-Worms, D., Dehdashti, F., Cornetta, K., & DiPersio, J. F. (2015). FHBG PET/CT imaging of CD34-TK75 transduced donor T cells in relapsed allogeneic stem cell transplant patients: Safety and feasibility. Molecular Therapy, 23(6), 1110-1122. https://doi.org/10.1038/mt.2015.48

@article{613b76c44c784372a9660caeba128666,

title = "FHBG PET/CT imaging of CD34-TK75 transduced donor T cells in relapsed allogeneic stem cell transplant patients: Safety and feasibility",

abstract = "Described herein is a first-in-man attempt to both genetically modify T cells with an imagable suicide gene and track these transduced donor T cells in allogeneic stem cell transplantation recipients using noninvasive positron emission tomography/computerized tomography (PET/CT) imaging. A suicide gene encoding a human CD34-Herpes Simplex Virus-1-thymidine kinase (CD34-TK75) fusion enabled enrichment of retrovirally transduced T cells (TdT), control of graft-versus-host disease and imaging of TdT migration and expansion in vivo in mice and man. Analysis confirmed that CD34-TK75-enriched TdT contained no replication competent γ-retrovirus, were sensitive to ganciclovir, and displayed characteristic retroviral insertion sites (by targeted sequencing). Affinity-purified CD34-TK75 + -selected donor T cells (1.0-13 × 10 5)/kg were infused into eight patients who relapsed after allogeneic stem cell transplantation. Six patients also were administered 9-[4-(18 F)fluoro-3-hydroxymethyl-butyl]guanine ([ 18 F]FHBG) to specifically track the genetically modified donor T cells by PET/CT at several time points after infusion. All patients were assessed for graft-versus-host disease, response to ganciclovir, circulating TdT cells (using both quantitative polymerase chain reaction and [ 18 F]FHBG PET/CT imaging), TdT cell clonal expansion, and immune response to the TdT. This phase 1 trial demonstrated that genetically modified T cells and [ 18 F]FHBG can be safely infused in patients with relapsed hematologic malignancies after allogeneic stem cell transplantation.",

author = "Eissenberg, {Linda G.} and Rettig, {Michael P.} and Ritchey, {Julie K.} and Prior, {Julie L.} and Schwarz, {Sally W.} and Jennifer Frye and White, {Brian S.} and Fulton, {Robert S.} and Armin Ghobadi and Cooper, {Matthew L.} and Couriel, {Daniel R.} and Seegulam, {Muhammad Esa} and David Piwnica-Worms and Farrokh Dehdashti and Kenneth Cornetta and DiPersio, {John F.}",

note = "Publisher Copyright: {\textcopyright} 2015 The American Society of Gene & Cell Therapy.",

year = "2015",

month = jun,

day = "1",

doi = "10.1038/mt.2015.48",

language = "English",

volume = "23",

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Eissenberg, LG, Rettig, MP, Ritchey, JK, Prior, JL, Schwarz, SW, Frye, J, White, BS, Fulton, RS , Ghobadi, A, Cooper, ML, Couriel, DR, Seegulam, ME, Piwnica-Worms, D, Dehdashti, F, Cornetta, K & DiPersio, JF 2015, 'FHBG PET/CT imaging of CD34-TK75 transduced donor T cells in relapsed allogeneic stem cell transplant patients: Safety and feasibility', Molecular Therapy, vol. 23, no. 6, pp. 1110-1122. https://doi.org/10.1038/mt.2015.48

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T1 - FHBG PET/CT imaging of CD34-TK75 transduced donor T cells in relapsed allogeneic stem cell transplant patients

T2 - Safety and feasibility

AU - Eissenberg, Linda G.

AU - Rettig, Michael P.

AU - Ritchey, Julie K.

AU - Prior, Julie L.

AU - Schwarz, Sally W.

AU - Frye, Jennifer

AU - White, Brian S.

AU - Fulton, Robert S.

AU - Ghobadi, Armin

AU - Cooper, Matthew L.

AU - Couriel, Daniel R.

AU - Seegulam, Muhammad Esa

AU - Piwnica-Worms, David

AU - Dehdashti, Farrokh

AU - Cornetta, Kenneth

AU - DiPersio, John F.

PY - 2015/6/1

Y1 - 2015/6/1

N2 - Described herein is a first-in-man attempt to both genetically modify T cells with an imagable suicide gene and track these transduced donor T cells in allogeneic stem cell transplantation recipients using noninvasive positron emission tomography/computerized tomography (PET/CT) imaging. A suicide gene encoding a human CD34-Herpes Simplex Virus-1-thymidine kinase (CD34-TK75) fusion enabled enrichment of retrovirally transduced T cells (TdT), control of graft-versus-host disease and imaging of TdT migration and expansion in vivo in mice and man. Analysis confirmed that CD34-TK75-enriched TdT contained no replication competent γ-retrovirus, were sensitive to ganciclovir, and displayed characteristic retroviral insertion sites (by targeted sequencing). Affinity-purified CD34-TK75 + -selected donor T cells (1.0-13 × 10 5)/kg were infused into eight patients who relapsed after allogeneic stem cell transplantation. Six patients also were administered 9-[4-(18 F)fluoro-3-hydroxymethyl-butyl]guanine ([ 18 F]FHBG) to specifically track the genetically modified donor T cells by PET/CT at several time points after infusion. All patients were assessed for graft-versus-host disease, response to ganciclovir, circulating TdT cells (using both quantitative polymerase chain reaction and [ 18 F]FHBG PET/CT imaging), TdT cell clonal expansion, and immune response to the TdT. This phase 1 trial demonstrated that genetically modified T cells and [ 18 F]FHBG can be safely infused in patients with relapsed hematologic malignancies after allogeneic stem cell transplantation.

AB - Described herein is a first-in-man attempt to both genetically modify T cells with an imagable suicide gene and track these transduced donor T cells in allogeneic stem cell transplantation recipients using noninvasive positron emission tomography/computerized tomography (PET/CT) imaging. A suicide gene encoding a human CD34-Herpes Simplex Virus-1-thymidine kinase (CD34-TK75) fusion enabled enrichment of retrovirally transduced T cells (TdT), control of graft-versus-host disease and imaging of TdT migration and expansion in vivo in mice and man. Analysis confirmed that CD34-TK75-enriched TdT contained no replication competent γ-retrovirus, were sensitive to ganciclovir, and displayed characteristic retroviral insertion sites (by targeted sequencing). Affinity-purified CD34-TK75 + -selected donor T cells (1.0-13 × 10 5)/kg were infused into eight patients who relapsed after allogeneic stem cell transplantation. Six patients also were administered 9-[4-(18 F)fluoro-3-hydroxymethyl-butyl]guanine ([ 18 F]FHBG) to specifically track the genetically modified donor T cells by PET/CT at several time points after infusion. All patients were assessed for graft-versus-host disease, response to ganciclovir, circulating TdT cells (using both quantitative polymerase chain reaction and [ 18 F]FHBG PET/CT imaging), TdT cell clonal expansion, and immune response to the TdT. This phase 1 trial demonstrated that genetically modified T cells and [ 18 F]FHBG can be safely infused in patients with relapsed hematologic malignancies after allogeneic stem cell transplantation.

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FHBG PET/CT imaging of CD34-TK75 transduced donor T cells in relapsed allogeneic stem cell transplant patients: Safety and feasibility

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