Differentiation of naive cord-blood T cells into CD19-specific cytolytic effectors for posttransplantation adoptive immunotherapy

Lisa Marie Serrano, Timothy Pfeiffer, Simon Olivares, Tontanai Numbenjapon, Jennifer Bennitt, Daniel Kim, David Smith, George McNamara, Zaid S Al-Kadhimi, Joseph Rosenthal, Stephen J. Forman, Michael C. Jensen, Laurence J.N. Cooper

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

Disease relapse is a barrier to achieving therapeutic success after unrelated umbilical cord-blood transplantation (UCBT) for B-lineage acute lymphoblastic leukemia (B-ALL). While adoptive transfer of donor-derived tumor-specific T cells is a conceptually attractive approach to eliminating residual disease after allogeneic hematopoietic stem cell transplantation, adoptive immunotherapy after UCBT is constrained by the difficulty of generating antigen-specific T cells from functionally naive umbilical cord-blood (UCB)-derived T cells. Therefore, to generate T cells that recognize B-ALL, we have developed a chimeric immunoreceptor to redirect the specificity of T cells for CD19, a B-lineage antigen, and expressed this transgene in UCB-derived T cells. An ex vivo process, which is compliant with current good manufacturing practice for T-cell trials, has been developed to genetically modify and numerically expand UCB-derived T cells into CD19-specific effector cells. These are capable of CD19-restricted cytokine production and cytolysis in vitro, as well as mediating regression of CD19+ tumor and being selectively eliminated in vivo. Moreover, time-lapse microscopy of the genetically modified T-cell clones revealed an ability to lyse CD19+ tumor cells specifically and repetitively. These data provide the rationale for infusing UCB-derived CD19-specific T cells after UCBT to reduce the incidence of CD19+ B-ALL relapse.

Original languageEnglish (US)
Pages (from-to)2643-2652
Number of pages10
JournalBlood
Volume107
Issue number7
DOIs
StatePublished - Apr 1 2006

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Adoptive Immunotherapy
T-cells
Fetal Blood
Blood Cells
Blood
T-Lymphocytes
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Tumors
Transplantation
T-Cell Antigen Receptor Specificity
Antigens
Recurrence
Neoplasms
Adoptive Transfer
Hematopoietic Stem Cell Transplantation
Transgenes
Stem cells
Microscopy
Clone Cells
Microscopic examination

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Serrano, L. M., Pfeiffer, T., Olivares, S., Numbenjapon, T., Bennitt, J., Kim, D., ... Cooper, L. J. N. (2006). Differentiation of naive cord-blood T cells into CD19-specific cytolytic effectors for posttransplantation adoptive immunotherapy. Blood, 107(7), 2643-2652. https://doi.org/10.1182/blood-2005-09-3904

Differentiation of naive cord-blood T cells into CD19-specific cytolytic effectors for posttransplantation adoptive immunotherapy. / Serrano, Lisa Marie; Pfeiffer, Timothy; Olivares, Simon; Numbenjapon, Tontanai; Bennitt, Jennifer; Kim, Daniel; Smith, David; McNamara, George; Al-Kadhimi, Zaid S; Rosenthal, Joseph; Forman, Stephen J.; Jensen, Michael C.; Cooper, Laurence J.N.

In: Blood, Vol. 107, No. 7, 01.04.2006, p. 2643-2652.

Research output: Contribution to journalArticle

Serrano, LM, Pfeiffer, T, Olivares, S, Numbenjapon, T, Bennitt, J, Kim, D, Smith, D, McNamara, G, Al-Kadhimi, ZS, Rosenthal, J, Forman, SJ, Jensen, MC & Cooper, LJN 2006, 'Differentiation of naive cord-blood T cells into CD19-specific cytolytic effectors for posttransplantation adoptive immunotherapy', Blood, vol. 107, no. 7, pp. 2643-2652. https://doi.org/10.1182/blood-2005-09-3904
Serrano, Lisa Marie ; Pfeiffer, Timothy ; Olivares, Simon ; Numbenjapon, Tontanai ; Bennitt, Jennifer ; Kim, Daniel ; Smith, David ; McNamara, George ; Al-Kadhimi, Zaid S ; Rosenthal, Joseph ; Forman, Stephen J. ; Jensen, Michael C. ; Cooper, Laurence J.N. / Differentiation of naive cord-blood T cells into CD19-specific cytolytic effectors for posttransplantation adoptive immunotherapy. In: Blood. 2006 ; Vol. 107, No. 7. pp. 2643-2652.
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abstract = "Disease relapse is a barrier to achieving therapeutic success after unrelated umbilical cord-blood transplantation (UCBT) for B-lineage acute lymphoblastic leukemia (B-ALL). While adoptive transfer of donor-derived tumor-specific T cells is a conceptually attractive approach to eliminating residual disease after allogeneic hematopoietic stem cell transplantation, adoptive immunotherapy after UCBT is constrained by the difficulty of generating antigen-specific T cells from functionally naive umbilical cord-blood (UCB)-derived T cells. Therefore, to generate T cells that recognize B-ALL, we have developed a chimeric immunoreceptor to redirect the specificity of T cells for CD19, a B-lineage antigen, and expressed this transgene in UCB-derived T cells. An ex vivo process, which is compliant with current good manufacturing practice for T-cell trials, has been developed to genetically modify and numerically expand UCB-derived T cells into CD19-specific effector cells. These are capable of CD19-restricted cytokine production and cytolysis in vitro, as well as mediating regression of CD19+ tumor and being selectively eliminated in vivo. Moreover, time-lapse microscopy of the genetically modified T-cell clones revealed an ability to lyse CD19+ tumor cells specifically and repetitively. These data provide the rationale for infusing UCB-derived CD19-specific T cells after UCBT to reduce the incidence of CD19+ B-ALL relapse.",
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