Cytotoxic T lymphocytes simultaneously targeting multiple tumor-associated antigens to treat ebv negative lymphoma

Ulrike Gerdemann; Usha Katari; Anne S. Christin; Conrad R. Cruz; Tamara Tripic; Alexandra Rousseau; Stephen M. Gottschalk; Barbara Savoldo; Juan F. Vera; Helen E. Heslop; Malcolm K. Brenner; Catherine M. Bollard; Cliona M. Rooney; Ann M. Leen

doi:10.1038/mt.2011.167

Cytotoxic T lymphocytes simultaneously targeting multiple tumor-associated antigens to treat ebv negative lymphoma

Ulrike Gerdemann, Usha Katari, Anne S. Christin, Conrad R. Cruz, Tamara Tripic, Alexandra Rousseau, Stephen M. Gottschalk, Barbara Savoldo, Juan F. Vera, Helen E. Heslop, Malcolm K. Brenner, Catherine M. Bollard, Cliona M. Rooney, Ann M. Leen

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

82 Scopus citations

Abstract

Although immunotherapy with Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) can treat EBV-associated Hodgkin and non-Hodgkin lymphoma (HL/NHL), more than 50% of such tumors are EBV negative. We now describe an approach that allows us to consistently generate, in a single line, CTLs that recognize a wide spectrum of nonviral tumor-associated antigens (TAAs) expressed by human HL/NHL, including Survivin, MAGE-A4, Synovial sarcoma X (SSX2), preferentially expressed antigen in melanoma (PRAME) and NY-ESO-1. We could generate these CTLs from nine of nine healthy donors and five of eight lymphoma patients, irrespective of human leukocyte antigen (HLA) type. We reactivated TAA-directed T cells ex vivo, by stimulation with dendritic cells (DCs) pulsed with overlapping peptide libraries spanning the chosen antigens in the presence of an optimized Th1-polarizing, prosurvival/proliferative and Treg inhibitory cytokine combination. The resultant lines of CD4 and CD8 , polycytokine- producing T cells are directed against a multiplicity of epitopes expressed on the selected TAAs, with cytolytic activity against autologous tumor cells. Infusion of such multispecific monocultures may extend the benefits of CTL therapy to treatment even of EBV negative HL and NHL.

Original language	English (US)
Pages (from-to)	2258-2268
Number of pages	11
Journal	Molecular Therapy
Volume	19
Issue number	12
DOIs	https://doi.org/10.1038/mt.2011.167
State	Published - Dec 2011

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
Pharmacology
Drug Discovery

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Gerdemann, U., Katari, U., Christin, A. S., Cruz, C. R., Tripic, T., Rousseau, A., Gottschalk, S. M., Savoldo, B., Vera, J. F., Heslop, H. E., Brenner, M. K., Bollard, C. M., Rooney, C. M., & Leen, A. M. (2011). Cytotoxic T lymphocytes simultaneously targeting multiple tumor-associated antigens to treat ebv negative lymphoma. Molecular Therapy, 19(12), 2258-2268. https://doi.org/10.1038/mt.2011.167

Gerdemann, U, Katari, U, Christin, AS, Cruz, CR, Tripic, T, Rousseau, A, Gottschalk, SM, Savoldo, B, Vera, JF, Heslop, HE , Brenner, MK, Bollard, CM, Rooney, CM & Leen, AM 2011, 'Cytotoxic T lymphocytes simultaneously targeting multiple tumor-associated antigens to treat ebv negative lymphoma', Molecular Therapy, vol. 19, no. 12, pp. 2258-2268. https://doi.org/10.1038/mt.2011.167

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title = "Cytotoxic T lymphocytes simultaneously targeting multiple tumor-associated antigens to treat ebv negative lymphoma",

abstract = "Although immunotherapy with Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) can treat EBV-associated Hodgkin and non-Hodgkin lymphoma (HL/NHL), more than 50% of such tumors are EBV negative. We now describe an approach that allows us to consistently generate, in a single line, CTLs that recognize a wide spectrum of nonviral tumor-associated antigens (TAAs) expressed by human HL/NHL, including Survivin, MAGE-A4, Synovial sarcoma X (SSX2), preferentially expressed antigen in melanoma (PRAME) and NY-ESO-1. We could generate these CTLs from nine of nine healthy donors and five of eight lymphoma patients, irrespective of human leukocyte antigen (HLA) type. We reactivated TAA-directed T cells ex vivo, by stimulation with dendritic cells (DCs) pulsed with overlapping peptide libraries spanning the chosen antigens in the presence of an optimized Th1-polarizing, prosurvival/proliferative and Treg inhibitory cytokine combination. The resultant lines of CD4 and CD8 , polycytokine- producing T cells are directed against a multiplicity of epitopes expressed on the selected TAAs, with cytolytic activity against autologous tumor cells. Infusion of such multispecific monocultures may extend the benefits of CTL therapy to treatment even of EBV negative HL and NHL.",

author = "Ulrike Gerdemann and Usha Katari and Christin, {Anne S.} and Cruz, {Conrad R.} and Tamara Tripic and Alexandra Rousseau and Gottschalk, {Stephen M.} and Barbara Savoldo and Vera, {Juan F.} and Heslop, {Helen E.} and Brenner, {Malcolm K.} and Bollard, {Catherine M.} and Rooney, {Cliona M.} and Leen, {Ann M.}",

note = "Funding Information: We thank Tara Gray for sample collection. This work was supported in by an NIH-NCI P50 CA126752 SPORE in lymphoma. U.G. is supported by the Leukemia and Lymphoma Society. H.E.H. is supported by a Dan L Duncan chair and M.K.B. by a Fayez Sarofim chair. The authors declare no competing financial interests.",

year = "2011",

month = dec,

doi = "10.1038/mt.2011.167",

language = "English (US)",

volume = "19",

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AU - Gerdemann, Ulrike

AU - Katari, Usha

AU - Christin, Anne S.

AU - Cruz, Conrad R.

AU - Tripic, Tamara

AU - Rousseau, Alexandra

AU - Gottschalk, Stephen M.

AU - Savoldo, Barbara

AU - Vera, Juan F.

AU - Heslop, Helen E.

AU - Brenner, Malcolm K.

AU - Bollard, Catherine M.

AU - Rooney, Cliona M.

AU - Leen, Ann M.

N1 - Funding Information: We thank Tara Gray for sample collection. This work was supported in by an NIH-NCI P50 CA126752 SPORE in lymphoma. U.G. is supported by the Leukemia and Lymphoma Society. H.E.H. is supported by a Dan L Duncan chair and M.K.B. by a Fayez Sarofim chair. The authors declare no competing financial interests.

PY - 2011/12

Y1 - 2011/12

N2 - Although immunotherapy with Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) can treat EBV-associated Hodgkin and non-Hodgkin lymphoma (HL/NHL), more than 50% of such tumors are EBV negative. We now describe an approach that allows us to consistently generate, in a single line, CTLs that recognize a wide spectrum of nonviral tumor-associated antigens (TAAs) expressed by human HL/NHL, including Survivin, MAGE-A4, Synovial sarcoma X (SSX2), preferentially expressed antigen in melanoma (PRAME) and NY-ESO-1. We could generate these CTLs from nine of nine healthy donors and five of eight lymphoma patients, irrespective of human leukocyte antigen (HLA) type. We reactivated TAA-directed T cells ex vivo, by stimulation with dendritic cells (DCs) pulsed with overlapping peptide libraries spanning the chosen antigens in the presence of an optimized Th1-polarizing, prosurvival/proliferative and Treg inhibitory cytokine combination. The resultant lines of CD4 and CD8 , polycytokine- producing T cells are directed against a multiplicity of epitopes expressed on the selected TAAs, with cytolytic activity against autologous tumor cells. Infusion of such multispecific monocultures may extend the benefits of CTL therapy to treatment even of EBV negative HL and NHL.

AB - Although immunotherapy with Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) can treat EBV-associated Hodgkin and non-Hodgkin lymphoma (HL/NHL), more than 50% of such tumors are EBV negative. We now describe an approach that allows us to consistently generate, in a single line, CTLs that recognize a wide spectrum of nonviral tumor-associated antigens (TAAs) expressed by human HL/NHL, including Survivin, MAGE-A4, Synovial sarcoma X (SSX2), preferentially expressed antigen in melanoma (PRAME) and NY-ESO-1. We could generate these CTLs from nine of nine healthy donors and five of eight lymphoma patients, irrespective of human leukocyte antigen (HLA) type. We reactivated TAA-directed T cells ex vivo, by stimulation with dendritic cells (DCs) pulsed with overlapping peptide libraries spanning the chosen antigens in the presence of an optimized Th1-polarizing, prosurvival/proliferative and Treg inhibitory cytokine combination. The resultant lines of CD4 and CD8 , polycytokine- producing T cells are directed against a multiplicity of epitopes expressed on the selected TAAs, with cytolytic activity against autologous tumor cells. Infusion of such multispecific monocultures may extend the benefits of CTL therapy to treatment even of EBV negative HL and NHL.

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Cytotoxic T lymphocytes simultaneously targeting multiple tumor-associated antigens to treat ebv negative lymphoma

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