Comprehensive approach for identifying the T cell subset origin of CD3 and CD28 antibody-activated chimeric antigen receptor-modified T cells

Michael Schmueck-Henneresse, Bilal Omer, Thomas Shum, Haruko Tashiro, Maksim Mamonkin, Natalia Lapteva, Sandhya Sharma, Lisa Rollins, Gianpietro Dotti, Petra Reinke, Hans Dieter Volk, Cliona M. Rooney

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Abstract

The outcome of therapy with chimeric Ag receptor (CAR)-modified T cells is strongly influenced by the subset origin of the infused T cells. However, because polyclonally activated T cells acquire a largely CD45RO+CCR7- effector memory phenotype after expansion, regardless of subset origin, it is impossible to know which subsets contribute to the final T cell product. To determine the contribution of naive T cell, memory stem T cell, central memory T cell, effector memory T cell, and terminally differentiated effector T cell populations to the CD3 and CD28-activated CAR-modified T cells that we use for therapy, we followed the fate and function of individually sorted CAR-modified T cell subsets after activation with CD3 and CD28 Abs (CD3/28), transduction and culture alone, or after reconstitution into the relevant subset-depleted population. We show that all subsets are sensitive to CAR transduction, and each developed a distinct T cell functional profile during culture. Naive-derived T cells showed the greatest rate of proliferation but had more limited effector functions and reduced killing compared with memory-derived populations. When cultured in the presence of memory T cells, naive-derived T cells show increased differentiation, reduced effector cytokine production, and a reduced reproliferative response to CAR stimulation. CD3/28-activated T cells expanded in IL-7 and IL-15 produced greater expansion of memory stem T cells and central memory T cell-derived T cells compared with IL-2. Our strategy provides a powerful tool to elucidate the characteristics of CAR-modified T cells, regardless of the protocol used for expansion, reveals the functional properties of each expanded T cell subset, and paves the way for a more detailed evaluation of the effects of manufacturing changes on the subset contribution to in vitro-expanded T cells.

LanguageEnglish (US)
Pages348-362
Number of pages15
JournalJournal of Immunology
Volume199
Issue number1
DOIs
StatePublished - Jul 1 2017

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T-Lymphocyte Subsets
T-Cell Antigen Receptor
T-Lymphocytes
Antibodies
Stem Cells
Population
Interleukin-15
Interleukin-7
Cell- and Tissue-Based Therapy

ASJC Scopus subject areas

  • Immunology

Cite this

Schmueck-Henneresse, M., Omer, B., Shum, T., Tashiro, H., Mamonkin, M., Lapteva, N., ... Rooney, C. M. (2017). Comprehensive approach for identifying the T cell subset origin of CD3 and CD28 antibody-activated chimeric antigen receptor-modified T cells. Journal of Immunology, 199(1), 348-362. DOI: 10.4049/jimmunol.1601494

Comprehensive approach for identifying the T cell subset origin of CD3 and CD28 antibody-activated chimeric antigen receptor-modified T cells. / Schmueck-Henneresse, Michael; Omer, Bilal; Shum, Thomas; Tashiro, Haruko; Mamonkin, Maksim; Lapteva, Natalia; Sharma, Sandhya; Rollins, Lisa; Dotti, Gianpietro; Reinke, Petra; Volk, Hans Dieter; Rooney, Cliona M.

In: Journal of Immunology, Vol. 199, No. 1, 01.07.2017, p. 348-362.

Research output: Contribution to journalArticle

Schmueck-Henneresse, M, Omer, B, Shum, T, Tashiro, H, Mamonkin, M, Lapteva, N, Sharma, S, Rollins, L, Dotti, G, Reinke, P, Volk, HD & Rooney, CM 2017, 'Comprehensive approach for identifying the T cell subset origin of CD3 and CD28 antibody-activated chimeric antigen receptor-modified T cells' Journal of Immunology, vol. 199, no. 1, pp. 348-362. DOI: 10.4049/jimmunol.1601494
Schmueck-Henneresse M, Omer B, Shum T, Tashiro H, Mamonkin M, Lapteva N et al. Comprehensive approach for identifying the T cell subset origin of CD3 and CD28 antibody-activated chimeric antigen receptor-modified T cells. Journal of Immunology. 2017 Jul 1;199(1):348-362. Available from, DOI: 10.4049/jimmunol.1601494
Schmueck-Henneresse, Michael ; Omer, Bilal ; Shum, Thomas ; Tashiro, Haruko ; Mamonkin, Maksim ; Lapteva, Natalia ; Sharma, Sandhya ; Rollins, Lisa ; Dotti, Gianpietro ; Reinke, Petra ; Volk, Hans Dieter ; Rooney, Cliona M./ Comprehensive approach for identifying the T cell subset origin of CD3 and CD28 antibody-activated chimeric antigen receptor-modified T cells. In: Journal of Immunology. 2017 ; Vol. 199, No. 1. pp. 348-362
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