HLA-E single-chain trimer shields gene-edited allogeneic CAR T cells from NK cell attack

Area of Science:

• Immunology
• Cell Therapy
• Oncology

Background:

• Allogeneic chimeric antigen receptor (CAR) T cell therapies offer advantages in scalability and availability for treating malignant disorders.
• Current strategies involve deleting TCR and MHC-I/II to prevent graft-versus-host disease (GvHD) and rejection.
• MHC-I ablation can trigger NK cell activation via the "missing-self" response, posing a challenge for allogeneic CAR T cell therapy.

Purpose of the Study:

• To develop universal allogeneic CAR T cells (UCARTs) that evade NK cell "missing-self" recognition.
• To assess the in vitro and in vivo performance of these engineered UCARTs compared to autologous CAR T cells.
• To identify strategies for optimal resistance against diverse NK cell populations.

Main Methods:

• Utilized an HLA single-chain trimer (ScT) platform to present a specific signal peptide (VMAPRTLIL) on HLA-E (HLA-ESP-1C).
• Investigated the impact of HLA-ESP-1C expression on UCART resistance to NKG2A+ and NKG2C+ NK cells.
• Examined the combined effect of HLA-ESP-1C expression with CD54 and CD58 ablation on UCARTs against heterogeneous NK cells.
• Evaluated UCART19 efficacy in a humanized mouse model with allogeneic NK cells.

Main Results:

• Successfully generated UCART cells resistant to NK cell "missing-self" response.
• HLA-ESP-1C conferred resistance to NKG2A+ cells with minimal activation of NKG2C+ cells.
• Combined HLA-ESP-1C expression with CD54 and CD58 ablation provided optimal resistance to diverse NK cell populations.
• UCART19 cells demonstrated potent tumor control in a humanized mouse model.

Conclusions:

• Engineered UCARTs can overcome NK cell-mediated rejection, enhancing allogeneic CAR T cell therapy potential.
• The HLA-ESP-1C strategy, combined with CD54/CD58 ablation, represents a promising approach for developing effective universal CAR T cells.
• This updated strategy holds potential for broader clinical applications of allogeneic CAR T cell therapy.