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Clin Cancer Res. 2018 Jan 1;24(1):95-105. doi: 10.1158/1078-0432.CCR-17-2041. Epub 2017 Oct 23.

Regional Delivery of Chimeric Antigen Receptor-Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain.

Author information

1
Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.
2
T Cell Therapeutics Research Laboratory, City of Hope, Duarte, California.
3
Department of Neurosurgery, Keck School of Medicine at University of Southern California, Los Angeles, California.
4
Division of Neurosurgery, Beckman Research Institute, City of Hope, Duarte, California.
5
Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, California.
6
Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California. sforman@coh.org cbrown@coh.org.

Abstract

Purpose: Metastasis to the brain from breast cancer remains a significant clinical challenge, and may be targeted with CAR-based immunotherapy. CAR design optimization for solid tumors is crucial due to the absence of truly restricted antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we have optimized HER2-CAR T cells for the treatment of breast to brain metastases, and determined optimal second-generation CAR design and route of administration for xenograft mouse models of breast metastatic brain tumors, including multifocal and leptomeningeal disease.Experimental Design: HER2-CAR constructs containing either CD28 or 4-1BB intracellular costimulatory signaling domains were compared for functional activity in vitro by measuring cytokine production, T-cell proliferation, and tumor killing capacity. We also evaluated HER2-CAR T cells delivered by intravenous, local intratumoral, or regional intraventricular routes of administration using in vivo human xenograft models of breast cancer that have metastasized to the brain.Results: Here, we have shown that HER2-CARs containing the 4-1BB costimulatory domain confer improved tumor targeting with reduced T-cell exhaustion phenotype and enhanced proliferative capacity compared with HER2-CARs containing the CD28 costimulatory domain. Local intracranial delivery of HER2-CARs showed potent in vivo antitumor activity in orthotopic xenograft models. Importantly, we demonstrated robust antitumor efficacy following regional intraventricular delivery of HER2-CAR T cells for the treatment of multifocal brain metastases and leptomeningeal disease.Conclusions: Our study shows the importance of CAR design in defining an optimized CAR T cell, and highlights intraventricular delivery of HER2-CAR T cells for treating multifocal brain metastases. Clin Cancer Res; 24(1); 95-105. ©2017 AACR.

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