Back to Search
Start Over
Regional Delivery of Chimeric Antigen Receptor-Engineered T Cells Effectively Targets HER2 + Breast Cancer Metastasis to the Brain.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2018 Jan 01; Vol. 24 (1), pp. 95-105. Date of Electronic Publication: 2017 Oct 23. - Publication Year :
- 2018
-
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 .<br /> (©2017 American Association for Cancer Research.)
- Subjects :
- Animals
Brain Neoplasms therapy
Breast Neoplasms genetics
Breast Neoplasms immunology
Breast Neoplasms metabolism
CD28 Antigens genetics
Cytokines metabolism
Cytotoxicity, Immunologic
Disease Models, Animal
Female
Humans
Inflammation Mediators metabolism
Lymphocyte Activation genetics
Lymphocyte Activation immunology
Receptor, ErbB-2 genetics
Receptors, Chimeric Antigen genetics
Recombinant Fusion Proteins genetics
Recombinant Fusion Proteins metabolism
Tumor Necrosis Factor Receptor Superfamily, Member 9 genetics
Xenograft Model Antitumor Assays
Brain Neoplasms immunology
Brain Neoplasms secondary
Breast Neoplasms pathology
Immunotherapy, Adoptive methods
Receptors, Antigen, T-Cell metabolism
Receptors, Chimeric Antigen metabolism
T-Lymphocytes immunology
T-Lymphocytes metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 24
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 29061641
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-17-2041