Enhanced antilymphoma efficacy of CD19-redirected influenza MP1-specific CTLs by cotransfer of T cells modified to present influenza MP1

Laurence J.N. Cooper, Zaid S Al-Kadhimi, Lisa Marie Serrano, Timothy Pfeiffer, Simon Olivares, Adrian Castro, Wen Chung Chang, Sergio Gonzalez, David Smith, Stephen J. Forman, Michael C. Jensen

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

To enhance the in vivo antitumor activity of adoptively transferred, CD19-specific chimeric antigen receptor (CAR)-redirected cytototic T lymphocytes (CTLs), we studied the effect of restimulating CAR+ CTLs through their endogenous virus-specific T-cell antigen receptor (TcR) by the cotransfer of angineered T-cell antigen-presenting cells (T-APCs). Using influenza A matrix protein 1 (MP1) as a model antigen, we show that ex vivo-expanded CD4 + and CD8+ T-APCs expressing a hygromycin phosphotransferase-MP1 fusion protein (HyMP1) process and present MP1 to autologous human leukocyte antigen (HLA)-restricted, MP1-specific CD4 + and CD8+ CTL precursors. The MP1-specific CTLs are amenable to subsequent genetic modification to express a CD19-specific CAR, designated CD19R, and acquire HLA-unresfricted reactivity toward CD19 + leukemia and lymphoma tumor targets while maintaining HLA-restricted MP1 specificity. The restimulation of MP1 × CD19 dual-specific CTLs in vivo by the adoptive transfer of irradiated HyMP1 + T-APCs resulted in the enhanced antilymphoma potency of bispecific effector cells, as measured by elimination of the biophotonic signal of established firefly luciferase-expressing Burkitt tymphoma xenografts in nonobese diabetic/severe combined immunodeficiency (KOD/scid) animals compared with control groups restimulated by Hy+MP1neg T-APCs. Engineered T-APCs are a novel and versatile antigen-delivery system for generating antigen-specific T cells in vitro and enhancing the in vivo effector functioning of CAR-redirected antitumor effector cells.

Original languageEnglish (US)
Pages (from-to)1622-1631
Number of pages10
JournalBlood
Volume105
Issue number4
DOIs
StatePublished - Feb 15 2005

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T-cells
Human Influenza
T-Lymphocytes
Viral Tumor Antigens
Antigen-Presenting Cells
Antigen Receptors
Proteins
HLA Antigens
hygromycin-B kinase
Antigens
Firefly Luciferases
Severe Combined Immunodeficiency
Adoptive Transfer
T-Cell Antigen Receptor
Viruses
Heterografts
Tumors
Lymphoma
Leukemia
Animals

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Enhanced antilymphoma efficacy of CD19-redirected influenza MP1-specific CTLs by cotransfer of T cells modified to present influenza MP1. / Cooper, Laurence J.N.; Al-Kadhimi, Zaid S; Serrano, Lisa Marie; Pfeiffer, Timothy; Olivares, Simon; Castro, Adrian; Chang, Wen Chung; Gonzalez, Sergio; Smith, David; Forman, Stephen J.; Jensen, Michael C.

In: Blood, Vol. 105, No. 4, 15.02.2005, p. 1622-1631.

Research output: Contribution to journalArticle

Cooper, LJN, Al-Kadhimi, ZS, Serrano, LM, Pfeiffer, T, Olivares, S, Castro, A, Chang, WC, Gonzalez, S, Smith, D, Forman, SJ & Jensen, MC 2005, 'Enhanced antilymphoma efficacy of CD19-redirected influenza MP1-specific CTLs by cotransfer of T cells modified to present influenza MP1', Blood, vol. 105, no. 4, pp. 1622-1631. https://doi.org/10.1182/blood-2004-03-1208
Cooper, Laurence J.N. ; Al-Kadhimi, Zaid S ; Serrano, Lisa Marie ; Pfeiffer, Timothy ; Olivares, Simon ; Castro, Adrian ; Chang, Wen Chung ; Gonzalez, Sergio ; Smith, David ; Forman, Stephen J. ; Jensen, Michael C. / Enhanced antilymphoma efficacy of CD19-redirected influenza MP1-specific CTLs by cotransfer of T cells modified to present influenza MP1. In: Blood. 2005 ; Vol. 105, No. 4. pp. 1622-1631.
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abstract = "To enhance the in vivo antitumor activity of adoptively transferred, CD19-specific chimeric antigen receptor (CAR)-redirected cytototic T lymphocytes (CTLs), we studied the effect of restimulating CAR+ CTLs through their endogenous virus-specific T-cell antigen receptor (TcR) by the cotransfer of angineered T-cell antigen-presenting cells (T-APCs). Using influenza A matrix protein 1 (MP1) as a model antigen, we show that ex vivo-expanded CD4 + and CD8+ T-APCs expressing a hygromycin phosphotransferase-MP1 fusion protein (HyMP1) process and present MP1 to autologous human leukocyte antigen (HLA)-restricted, MP1-specific CD4 + and CD8+ CTL precursors. The MP1-specific CTLs are amenable to subsequent genetic modification to express a CD19-specific CAR, designated CD19R, and acquire HLA-unresfricted reactivity toward CD19 + leukemia and lymphoma tumor targets while maintaining HLA-restricted MP1 specificity. The restimulation of MP1 × CD19 dual-specific CTLs in vivo by the adoptive transfer of irradiated HyMP1 + T-APCs resulted in the enhanced antilymphoma potency of bispecific effector cells, as measured by elimination of the biophotonic signal of established firefly luciferase-expressing Burkitt tymphoma xenografts in nonobese diabetic/severe combined immunodeficiency (KOD/scid) animals compared with control groups restimulated by Hy+MP1neg T-APCs. Engineered T-APCs are a novel and versatile antigen-delivery system for generating antigen-specific T cells in vitro and enhancing the in vivo effector functioning of CAR-redirected antitumor effector cells.",
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AU - Serrano, Lisa Marie

AU - Pfeiffer, Timothy

AU - Olivares, Simon

AU - Castro, Adrian

AU - Chang, Wen Chung

AU - Gonzalez, Sergio

AU - Smith, David

AU - Forman, Stephen J.

AU - Jensen, Michael C.

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