Logic-Gated ROR1 Chimeric Antigen Receptor Expression Rescues T Cell-Mediated Toxicity to Normal Tissues and Enables Selective Tumor Targeting

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2019 Mar 20

PMID 30889382

Citations 170

Authors

Shivani Srivastava

Alexander I Salter

Denny Liggitt

Sushma Yechan-Gunja

Megha Sarvothama

Kirsten Cooper

Kimberly S Smythe

Jarrod A Dudakov

Robert H Pierce

Christoph Rader

Stanley R Riddell

Affiliations

Soon will be listed here.

Abstract

Many potential targets for CAR-T cells in solid tumors are expressed in some normal tissues, raising concern for off-tumor toxicity. Following lymphodepletion, CAR-T cells targeting the tumor-associated antigen ROR1 lysed tumors in mice but induced lethal bone marrow failure due to recognition of ROR1 stromal cells. To improve selectivity, we engineered T cells with synthetic Notch (synNotch) receptors specific for EpCAM or B7-H3, which are expressed on ROR1 tumor cells but not ROR1 stromal cells. SynNotch receptors induced ROR1 CAR expression selectively within the tumor, resulting in tumor regression without toxicity when tumor cells were segregated from, but not when co-localized with, normal ROR1 cells. This strategy, thus, permits safe targeting of tumors that are sufficiently separated from normal cells.

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