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Pluripotent stem cell-derived CD19-CAR iT cells effectively eradicate B-cell lymphoma in vivo

Cellular & Molecular Immunology volume 18, pages 773–775 (2021)Cite this article

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Chimeric antigen receptor T cell (CAR-T) therapy is one of the most promising approaches in cancer treatment.1 However, the limited availability of patient-derived T cells narrows its universal applicability. Thus, it is necessary to invent new methods to obtain alternative T-cell sources. Pluripotent stem cells (PSCs), which have unlimited culture potential and are amenable to gene editing, are ideal for generating induced T (iT) cells. Conventional PSC-derived iT cells in culture dishes exhibit extremely low activity in vivo, and their properties are only partially defined.2,3 Our group has recently developed a de novo two-step approach to generate functional iT cells from PSCs driven by the synergistic expression of Runx1 and Hoxa9.4 Here, we further tested the translational potential of these de novo iT cells in CAR-T cell therapy research.

The antitumor effect of regenerated CD19-CAR iT cells in vivo was further examined using a B-cell lymphoma (BCL) model established as previously reported.7 Briefly, to construct the BCL model, 1.5 × 106 Ka539-luciferase tumor cells were inoculated into irradiated C57BL/6 mice. After 14 days, the BCL mice were adoptively transferred retro-orbitally with 6.0 × 106 CD19-CAR iT cells, while the tumor-bearing mice treated with Ctrl-CAR iT cells were used as control. The percentages of BCL tumor cells (CD19+) were analyzed by flow cytometry in the peripheral blood (PB) of tumor-bearing mice, and the size of the tumor burden was measured weekly by bioluminescent imaging (BLI). (Fig. 1d). To evaluate the proliferating ability of the CD19-CAR iT cells in response to tumor stimulation in vivo, we prestained CD19-CAR iT cells with eFluor670 in vitro and chased the eFluor670 signals in PB at day 3 and day 6 after CD19-CAR iT cell infusion. Our results showed that CD19-CAR iT cells proliferated more vigorously than Ctrl-CAR iT cells in BCL mice (Fig. 1e). Then, we measured the percentage of CD19+ tumor cells in the PB of CD19-CAR iT cell-treated or Ctrl-CAR iT cell-treated mice. As early as 7 days after treatment with CD19-CAR iT cells, there was a decrease of PB tumor cells (lower than 0.5%), which was sustained for at least one month. In contrast, the percentage of CD19+ tumor cells in the PB of control mice was more than 32% at day 14 and day 21 (p < 0.001) (Fig. 1f, g). We also used BLI to monitor tumor development. As shown by BLI, CD19-CAR iT cells effectively eliminated tumor cells, while Ctrl-CAR iT cell-treated BCL mice developed tumors more rapidly, which resulted in euthanasia of these mice at a moribund phase (days 22–28 after iT cell infusion) (Fig. 1h). Compared with the observations in Ctrl-CAR iT-treated mice, complete tumor remission and no tumor recurrence were observed for over 70 days in CD19-CAR iT-treated mice. (Fig. 1i). These results further illustrate that PSC-derived CAR iT cells could effectively eliminate tumor cells in vivo.

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Acknowledgements

This work was supported by the CAS Key Research Program of Frontier Sciences (QYZDB-SSW-SMC057), the Strategic Priority Research Program of Chinese Academy of Sciences (XDA16010601), the National Key R&D Program of China (2019YFA0110203), the Major Research and Development Project of Guangzhou Regenerative Medicine and Health Guangdong Laboratory (2018GZR110104006), the Health and Medical Care Collaborative Innovation Program of Guangzhou Scientific and Technology (201803040017), the Science and Technology Planning Project of Guangdong Province (2017B030314056), and the National Natural Science Foundation of China (81925002, 81970099, 31900814).

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  1. These authors contributed equally: Cui Lv, Shoubing Chen

Authors and Affiliations

  1. School of Life Sciences, University of Science and Technology of China, Hefei, China

    Cui Lv, Shoubing Chen, Fangxiao Hu & Jinyong Wang

  2. CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China

    Cui Lv, Shoubing Chen, Fangxiao Hu, Dehao Huang, Tongjie Wang, Juan Du, Jinyong Wang & Hongling Wu

  3. Guangdong Provincial Key Laboratory of Stem cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China

    Cui Lv, Shoubing Chen, Fangxiao Hu, Dehao Huang, Tongjie Wang, Juan Du, Jinyong Wang & Hongling Wu

  4. Guangzhou Regenerative Medicine and Health-Guangdong Laboratory (GRMH-GDL), Guangdong, China

    Juan Du, Jinyong Wang & Hongling Wu

  5. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China

    Juan Du & Jinyong Wang

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Contributions

C.L. and S.C. performed the experiments and analyzed the data. F.H. and D.H. participated in multiple experiments. J.W. and H.W. conceptualized and supervised this study and wrote and edited the manuscript. T.W. and J.D. reviewed the manuscript and provided feedback, and all authors approved the manuscript in its final form.

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Correspondence to Jinyong Wang or Hongling Wu.

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Lv, C., Chen, S., Hu, F. et al. Pluripotent stem cell-derived CD19-CAR iT cells effectively eradicate B-cell lymphoma in vivo. Cell Mol Immunol 18, 773–775 (2021). https://doi.org/10.1038/s41423-020-0429-4

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