Primary polyclonal human T lymphocytes targeted to carcino-embryonic antigens and neural cell adhesion molecule tumor antigens by CD3zeta-based chimeric immune receptors.
AuthorsGilham, David E
O'Neill, Alison C
Guest, Ryan D
Hawkins, Robert E
AffiliationCRC Department of Medical Oncology, Paterson Institute for Cancer Research, University of Manchester, UK.
MetadataShow full item record
AbstractAntigen-specific T lymphocytes are attractive as potential anticancer agents. The generation of large numbers of antigen-specific T cells is possible through the use of gene therapy to express targeting receptors on the T lymphocyte. Activated T lymphocytes were transduced to express carcino-embryonic antigen or neural cell adhesion molecule targeted CD3zeta chimeric immune receptors. The chimeric receptors were expressed as homodimers and also as heterodimers with the native CD3zeta. T lymphocyte populations were expanded in the absence of selection for the modified cells and were shown to produce cytokines when cultured in the presence of immobilized purified protein antigen. These lymphocytes also responded by cytokine production and cytolytic activity when challenged with tumor-cell lines expressing the antigen recognized by the chimeric immune receptor. The cytolytic activity appears to be largely perforin mediated. Furthermore, soluble carcino-embryonic antigen did not interfere with the functional activity of the carcino-embryonic antigen-targeted lymphocytes. Long-term (5-day) stimulation of the modified lymphocytes by protein antigen resulted in reduced viability similar to that induced by anti-CD3 antibodies alone. Viability was improved by a costimulatory signal indicating that such signals may be vital in the maintenance of long-term functional activity of receptor modified T lymphocytes.
CitationPrimary polyclonal human T lymphocytes targeted to carcino-embryonic antigens and neural cell adhesion molecule tumor antigens by CD3zeta-based chimeric immune receptors., 25 (2):139-51 J. Immunother.
JournalJournal of Immunotherapy
- A recombinant anti-carcinoembryonic antigen immunoreceptor with combined CD3zeta-CD28 signalling targets T cells from colorectal cancer patients against their tumour cells.
- Authors: Hombach A, Schlimper C, Sievers E, Frank S, Schild HH, Sauerbruch T, Schmidt-Wolf IG, Abken H
- Issue date: 2006 Aug
- The role of extracellular spacer regions in the optimal design of chimeric immune receptors: evaluation of four different scFvs and antigens.
- Authors: Guest RD, Hawkins RE, Kirillova N, Cheadle EJ, Arnold J, O'Neill A, Irlam J, Chester KA, Kemshead JT, Shaw DM, Embleton MJ, Stern PL, Gilham DE
- Issue date: 2005 May-Jun
- Tumor-specific T cell activation by recombinant immunoreceptors: CD3 zeta signaling and CD28 costimulation are simultaneously required for efficient IL-2 secretion and can be integrated into one combined CD28/CD3 zeta signaling receptor molecule.
- Authors: Hombach A, Wieczarkowiecz A, Marquardt T, Heuser C, Usai L, Pohl C, Seliger B, Abken H
- Issue date: 2001 Dec 1
- Engineering γδT cells limits tonic signaling associated with chimeric antigen receptors.
- Authors: Fisher J, Sharma R, Don DW, Barisa M, Hurtado MO, Abramowski P, Porter L, Day W, Borea R, Inglott S, Anderson J, Pe'er D
- Issue date: 2019 Sep 10
- CD3ζ-based chimeric antigen receptors mediate T cell activation via cis- and trans-signalling mechanisms: implications for optimization of receptor structure for adoptive cell therapy.
- Authors: Bridgeman JS, Ladell K, Sheard VE, Miners K, Hawkins RE, Price DA, Gilham DE
- Issue date: 2014 Feb