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.
Highlights
Chimeric antigen receptor (CAR) T cells brought substantial benefit to patients with B-cell malignancies
Toward in situ generation of CAR T cells, here we report that CD19-reactive CD8+ CAR T cells can be generated in humanized mice upon a single systemic administration of CD8-LV
To test the hypothesis that CD19-CAR T cells can be directly generated in vivo, we packaged the genetic information for a CD19-CAR harboring the FMC63 scFv and the CD28f signaling domain into CD8-LV
Summary
Chimeric antigen receptor (CAR) T cells brought substantial benefit to patients with B-cell malignancies. We provide evidence that human CD19-CAR T cells can be generated directly in vivo using the lentiviral vector CD8-LV targeting human CD8+ cells. The genetic modification of T cells with chimeric antigen receptors (CARs) recognizing surface antigens on malignant cells has become a valid immune therapeutic option for cancer patients (Lim & June, 2017). Efforts to generate allogeneic CAR T cells which are compatible for transplantation into HLA-matched patients are ongoing (Qasim et al, 2017). Even if this can be achieved, CAR T cells will still remain a complex product to manufacture. Some of the animals developed symptoms reminiscent of the cytokine release syndrome (CRS) sporadically observed in CAR T-cell-treated patients (Hay et al, 2017)
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