Hypoimmune anti-CD19 chimeric antigen receptor T cells provide lasting tumor control in fully immunocompetent allogeneic humanized mice

Xiaomeng Hu, Karl Manner, Rowena DeJesus, Kathy White, Corie Gattis, Priscilla Ngo, Christopher Bandoro, Eleonore Tham, Elaine Y. Chu, Chi Young, Frank Wells, Ronald Basco, Annabelle Friera, Divy Kangeyan, Pascal Beauchesne, William E. Dowdle, Tobias Deuse, Terry J. Fry, Aaron E. Foster, Sonja Schrepfer

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Manufacturing autologous chimeric antigen receptor (CAR) T cell therapeutics is complex, and many patients experience treatment delays or cannot be treated at all. Although current allogeneic CAR products have the potential to overcome manufacturing bottlenecks, they are subject to immune rejection and failure to persist in the host, and thus do not provide the same level of efficacy as their autologous counterparts. Here, we aimed to develop universal allogeneic CAR T cells that evade the immune system and produce a durable response. We generated human hypoimmune (HIP) T cells with disrupted B2M, CIITA, and TRAC genes using CRISPR-Cas9 editing. In addition, CD47 and anti-CD19 CAR were expressed using lentiviral transduction. These allogeneic HIP CD19 CAR T cells were compared to allogeneic CD19 CAR T cells that only expressed the anti-CD19 CAR (allo CAR T). In vitro assays for cancer killing and exhaustion revealed no differences between allo CAR T and HIP CAR T cells, confirming that the HIP edits did not negatively affect T cell performance. Clearance of CD19+ tumors by HIP CAR T cells in immunodeficient NSG mice was comparable to that of allo CAR T cells. In fully immunocompetent humanized mice, HIP CAR T cells significantly outperformed allo CAR T cells, showed improved persistence and expansion, and provided lasting cancer clearance. Furthermore, CD47-targeting safety strategies reliably and specifically eliminated HIP CAR T cells. These findings suggest that universal allogeneic HIP CAR T cell-based therapeutics might overcome the limitations associated with poor persistence of allogeneic CAR T cells and exert durable anti-tumor responses.

Original languageEnglish (US)
Article number2020
JournalNature Communications
Issue number1
StatePublished - Apr 10 2023


  • Humans
  • Mice
  • Animals
  • Receptors, Chimeric Antigen/genetics
  • CD47 Antigen
  • T-Lymphocytes
  • Neoplasms
  • Hematopoietic Stem Cell Transplantation
  • Receptors, Antigen, T-Cell/genetics

ASJC Scopus subject areas

  • Physics and Astronomy(all)
  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)


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