Adoptive T-cell therapy, particularly the use of T cells expressing CD19-specific chimeric antigen receptors (CARs), has shown remarkable clinical efficacy against refractory cancers. However, cytokine release syndrome (CRS), a complication associated with immune over-stimulation, is a frequently observed side effect, and severe cases have resulted in patient deaths in clinical trials of adoptive T-cell therapy. Although CRS can be managed by administrating immune-suppressive drugs, current methods for CRS diagnosis relies on indirect measures such as body temperature and blood pressure, leading to imprecisions that may miss the optimal treatment window. Here, we report a strategy to engineer self-modulating T cells that can rapidly ameliorate and/or prevent CRS. We have engineered a single-chain variable fragment (scFv) that efficiently inhibits Interleukin (IL)-6 signaling in primary human T cells. CD19 CAR-T cells engineered to secrete this scFv show significantly lower expression levels of inflammatory cytokines—including IL-2, IL-4, IL-6, IL-8, and tumor necrosis factor (TNF)-a. Importantly, scFv secretion does not hinder the CAR-T cells’ ability to lyse CD19+ target cells, nor does it affect T-cell proliferation and cell-type differentiation upon antigen stimulation. Engineering CAR-T cells to self-regulate inflammatory cytokine production has the potential to prevent CRS without inhibiting the therapeutic efficacy of CAR-T cells.

Engineering self-modulating T cells to prevent cytokine release syndrom in adoptive T-cell therapy

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.