IL-6/IFN-γ double knockdown CAR-T cells reduce the release of multiple cytokines from PBMCs in vitro

• Published in: Human vaccines & immunotherapeutics Vol. 18; no. 1; pp. 1 - 14
• Main Authors: Zhang, Huihui, Lv, Xiaofei, Kong, Qunfang, Tan, Yi
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 31.12.2022; Taylor & Francis Group
• Subjects: Cells, Cultured; Chimeric antigen receptor; cytokine release syndrome; Cytokine Release Syndrome - prevention & control; Cytokines - metabolism; gene knockdown; Gene Knockdown Techniques; Humans; Immunotherapy – Research Paper; Immunotherapy, Adoptive; interferon γ; Interferon-gamma - genetics; interleukin-6; Interleukin-6 - genetics; Leukocytes, Mononuclear - metabolism; Receptors, Chimeric Antigen; T-Lymphocytes - cytology; cytokine release syndrome; Chimeric antigen receptor; gene knockdown; interleukin-6; interferon γ
• ISSN: 2164-5515; 2164-554X
• DOI: 10.1080/21645515.2021.2016005

CD19-targeted chimeric antigen receptor T (anti-CD19 CAR-T) cells have shown good therapeutic results in the treatment of CD19 + B cell acute lymphocytic leukemia and lymphoma. However, severe side reactions and cytotoxicity are great challenges in the application of anti-CD19 CAR-T cell therapy. Cytokine release syndrome (CRS) is the main side effect of CAR-T cell treatment, and interleukin-6 (IL-6) and interferon γ (IFN-γ) are cytokines that play major roles in CRS. Therefore, we investigated double knockdown (KD) of IL-6 and IFN-γ as a potential strategy to manage anti-CD19 CAR-T cell-associated CRS. These improved anti-CD19 CAR-T cells therapy retained the advantages of the original anti-CD19 CAR-T cells and additionally reduced the release of cytokines from CAR-T cells and other immune cells. Moreover, this study presented a novel approach to abrogate CRS through IL-6 and IFN-γ KD, which may potentially inhibit the release of multiple cytokines from CAR-T cells and peripheral blood mononuclear cells (PBMCs), a model of CRS correlate with in vivo features of the CAR-T therapy, thereby reducing the impact of CRS, improving the safety of CAR-T cell treatment, reducing toxicities, and maintaining the function of CAR-T cells.