Transcriptomic analysis reveals optimal cytokine combinations for SARS-CoV-2-specific T cell therapy products
Molecular therapy. Methods & clinical development
COVID-19; RNA-seq; SARS-CoV-2; cytokines; immunocompromised; manufacturing; therapeutic viral-specific T cells
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.
Durkee-Shock, Jessica; Lazarski, Christopher A.; Jensen-Wachspress, Mariah A.; Zhang, Anqing; Son, Aran; Kankate, Vaishnavi V.; Field, Naomi E.; Webber, Kathleen; Lang, Haili; Conway, Susan R.; Hanley, Patrick J.; Bollard, Catherine M.; Keller, Michael D.; and Schwartz, Daniella M., "Transcriptomic analysis reveals optimal cytokine combinations for SARS-CoV-2-specific T cell therapy products" (2022). GW Authored Works. Paper 1141.