Engineering sonogenetic EchoBack-CAR T cells.

in Cell by Longwei Liu, Peixiang He, Yuxuan Wang, Fengyi Ma, Dulei Li, Zhiliang Bai, Yunjia Qu, Linshan Zhu, Chi Woo Yoon, Xi Yu, Yixuan Huang, Zhengyu Liang, Yiming Zhang, Kunshu Liu, Tianze Guo, Yushun Zeng, Qifa Zhou, H Kay Chung, Rong Fan, Yingxiao Wang

TLDR

  • The study engineered ultrastable CAR T cells, called EchoBack-CAR T cells, which showed improved potency and persistence for solid tumor treatment.

Abstract

Chimeric antigen receptor (CAR) T cell therapy for solid tumors encounters challenges such as on-target off-tumor toxicity, exhaustion, and limited T cell persistence. Here, we engineer sonogenetic EchoBack-CAR T cells using an ultrasensitive heat-shock promoter screened from a library and integrated with a positive feedback loop from CAR signaling, enabling long-lasting CAR expression upon focused-ultrasound (FUS) stimulation. EchoBack-hGD2CAR T cells, targeting disialoganglioside GD2, exhibited potent cytotoxicity and persistence in 3D glioblastoma (GBM) models. In mice, EchoBack-hGD2CAR T cells suppressed GBM without off-tumor toxicity and outperformed their constitutive counterparts. Single-cell RNA sequencing revealed enhanced cytotoxicity and reduced exhaustion in EchoBack-CAR T cells compared with the standard CAR T cells. This EchoBack design was further adapted to target prostate-specific membrane antigen (EchoBack-PSMACAR) for prostate cancer treatment, demonstrating long-lasting tumor suppression with minimal off-tumor toxicity. Thus, the sonogenetic EchoBack-CAR T cells can serve as a versatile, efficient, and safe strategy for solid tumor treatment.

Overview

  • The study aimed to engineer chimeric antigen receptor (CAR) T cells for solid tumors, addressing challenges of on-target off-tumor toxicity, exhaustion, and limited T cell persistence.
  • The researchers used an ultrasensitive heat-shock promoter screened from a library and integrated with a positive feedback loop from CAR signaling to create EchoBack-CAR T cells.
  • EchoBack-CAR T cells were tested in 3D glioblastoma models, targeting disialoganglioside GD2, and demonstrated potent cytotoxicity and persistence.

Comparative Analysis & Findings

  • EchoBack-hGD2CAR T cells exhibited more potent cytotoxicity and persistence compared to standard CAR T cells, as observed through single-cell RNA sequencing.
  • EchoBack-CAR T cells showed enhanced cytotoxicity and reduced exhaustion compared to standard CAR T cells, as revealed by single-cell RNA sequencing.
  • EchoBack-CAR T cells outperformed their constitutive counterparts in suppressing glioblastoma in mice without causing off-tumor toxicity.

Implications and Future Directions

  • The EchoBack design can be adapted to target multiple solid tumors, including prostate cancer, providing a versatile and efficient strategy for treatment.
  • The study highlights the potential of sonogenetic CAR T cells for improving T cell persistence and reducing off-tumor toxicity, which can lead to more effective and safe treatments for solid tumors.
  • Future studies can focus on further optimizing the EchoBack design and exploring its potential for treating various types of solid tumors.
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