Format

Send to

Choose Destination

See 1 citation found by title matching your search:

PLoS One. 2015 Jun 1;10(6):e0128151. doi: 10.1371/journal.pone.0128151. eCollection 2015.

Sleeping Beauty Transposition of Chimeric Antigen Receptors Targeting Receptor Tyrosine Kinase-Like Orphan Receptor-1 (ROR1) into Diverse Memory T-Cell Populations.

Author information

1
Pediatrics, Children's Cancer Hospital, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America; University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, United States of America.
2
Medicine, Moores Cancer Center, University of California San Diego, San Diego, California, United States of America.
3
Pediatrics, Children's Cancer Hospital, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
4
Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
5
Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.

Abstract

T cells modified with chimeric antigen receptors (CARs) targeting CD19 demonstrated clinical activity against some B-cell malignancies. However, this is often accompanied by a loss of normal CD19+ B cells and humoral immunity. Receptor tyrosine kinase-like orphan receptor-1 (ROR1) is expressed on sub-populations of B-cell malignancies and solid tumors, but not by healthy B cells or normal post-partum tissues. Thus, adoptive transfer of T cells specific for ROR1 has potential to eliminate tumor cells and spare healthy tissues. To test this hypothesis, we developed CARs targeting ROR1 in order to generate T cells specific for malignant cells. Two Sleeping Beauty transposons were constructed with 2nd generation ROR1-specific CARs signaling through CD3ζ and either CD28 (designated ROR1RCD28) or CD137 (designated ROR1RCD137) and were introduced into T cells. We selected for T cells expressing CAR through co-culture with γ-irradiated activating and propagating cells (AaPC), which co-expressed ROR1 and co-stimulatory molecules. Numeric expansion over one month of co-culture on AaPC in presence of soluble interleukin (IL)-2 and IL-21 occurred and resulted in a diverse memory phenotype of CAR+ T cells as measured by non-enzymatic digital array (NanoString) and multi-panel flow cytometry. Such T cells produced interferon-γ and had specific cytotoxic activity against ROR1+ tumors. Moreover, such cells could eliminate ROR1+ tumor xenografts, especially T cells expressing ROR1RCD137. Clinical trials will investigate the ability of ROR1-specific CAR+ T cells to specifically eliminate tumor cells while maintaining normal B-cell repertoire.

PMID:
26030772
PMCID:
PMC4451012
DOI:
10.1371/journal.pone.0128151
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center