In vivo generation of human CD19‐CAR T cells results in B‐cell depletion and signs of cytokine release syndrome
oleh: Anett Pfeiffer, Frederic B Thalheimer, Sylvia Hartmann, Annika M Frank, Ruben R Bender, Simon Danisch, Caroline Costa, Winfried S Wels, Ute Modlich, Renata Stripecke, Els Verhoeyen, Christian J Buchholz
| Format: | Article |
|---|---|
| Diterbitkan: | Springer Nature 2018-11-01 |
Deskripsi
Abstract Chimeric antigen receptor (CAR) T cells brought substantial benefit to patients with B‐cell malignancies. Notwithstanding, CAR T‐cell manufacturing requires complex procedures impeding the broad supply chain. Here, we provide evidence that human CD19‐CAR T cells can be generated directly in vivo using the lentiviral vector CD8‐LV specifically targeting human CD8+ cells. Administration into mice xenografted with Raji lymphoma cells and human peripheral blood mononuclear cells led to CAR expression solely in CD8+ T cells and efficacious elimination of CD19+ B cells. Further, upon injection of CD8‐LV into mice transplanted with human CD34+ cells, induction of CAR T cells and CD19+ B‐cell depletion was observed in 7 out of 10 treated animals. Notably, three mice showed elevated levels of human cytokines in plasma. Tissue‐invading CAR T cells and complete elimination of the B‐lymphocyte‐rich zones in spleen were indicative of a cytokine release syndrome. Our data demonstrate the feasibility of in vivo reprogramming of human CD8+ CAR T cells active against CD19+ cells, yet with similar adverse effects currently notorious in the clinical practice.