Transcriptomic analysis reveals optimal cytokine combinations for SARS-CoV-2-specific T cell therapy products

Jessica Durkee-Shock, Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA.
Christopher A. Lazarski, Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA.
Mariah A. Jensen-Wachspress, Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA.
Anqing Zhang, GW Cancer Center, George Washington University, Washington, DC, USA.
Aran Son, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Vaishnavi V. Kankate, Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA.
Naomi E. Field, Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA.
Kathleen Webber, Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA.
Haili Lang, Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA.
Susan R. Conway, Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA.
Patrick J. Hanley, Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA.
Catherine M. Bollard, Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA.
Michael D. Keller, Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA.
Daniella M. Schwartz, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Document Type

Journal Article

Publication Date

6-9-2022

Journal

Molecular therapy. Methods & clinical development

Volume

25

DOI

10.1016/j.omtm.2022.04.013

Keywords

COVID-19; RNA-seq; SARS-CoV-2; cytokines; immunocompromised; manufacturing; therapeutic viral-specific T cells

Abstract

Adoptive T cell immunotherapy has been used to restore immunity against multiple viral targets in immunocompromised patients after bone-marrow transplantation and has been proposed as a strategy for preventing coronavirus 2019 (COVID-19) in this population. Ideally, expanded severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-virus-specific T cells (CSTs) should demonstrate marked cell expansion, T cell specificity, and CD8+ T cell skewing prior to adoptive transfer. However, current methodologies using IL-4 + IL-7 result in suboptimal specificity, especially in CD8 cells. Using a microexpansion platform, we screened various cytokine cocktails (IL-4 + IL-7, IL-15, IL-15 + IL-4, IL-15 + IL-6, and IL-15 + IL-7) for the most favorable culture conditions. IL-15 + IL-7 optimally balanced T cell expansion, polyfunctionality, and CD8+ T cell skewing of a final therapeutic T cell product. Additionally, the transcriptomes of CD4 and CD8 T cells cultured with IL-15 + IL-7 displayed the strongest induction of antiviral type I interferon (IFN) response genes. Subsequently, microexpansion results were successfully translated to a Good Manufacturing Practice (GMP)-applicable format where IL-15 + IL-7 outperformed IL-4 + IL-7 in specificity and expansion, especially in the desirable CD8 T cell compartment. These results demonstrate the functional implications of IL-15-, IL-4-, and IL-7-containing cocktails for therapeutic T cell expansion, which could have broad implication for cellular therapy, and pioneer the use of RNA sequencing (RNA-seq) to guide viral-specific T cell (VST) product manufacturing.

Department

Pediatrics

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