Skip to content

Advertisement

  • Poster presentation
  • Open Access

Tumor targeting of innate and adaptive immunity by the adoptive cell transfer of engineered T lymphocytes co-expressing iNKT and tumor-specific MHC-I TCRs

  • 1,
  • 2,
  • 1,
  • 1,
  • 1,
  • 1 and
  • 3
Journal for ImmunoTherapy of Cancer20142 (Suppl 3) :P11

https://doi.org/10.1186/2051-1426-2-S3-P11

  • Published:

Keywords

  • iNKT Cell
  • HER2 Positive Tumor
  • Adoptive Cell Transfer
  • scFv Fragment
  • CD1d Molecule

CD1d-restricted invariant NKT cells (iNKT) exert potent anti-tumor effects by virtue of their ability to transactivate NK cells, dendritic cells and T lymphocytes. However, their use in cancer immunotherapy has been limited by their short-lived activation followed by a phase of long-term anergy after a single injection of the high affinity CD1d ligand alpha-galactosylceramide (αGC). Instead, we have demonstrated that repeated injections of recombinant soluble αGC-loaded CD1d molecules resulted in the sustained iNKT and NK cell activation, which correlated with prolonged antitumor effects when the αGC/sCD1d was fused to an anti-tumor scFv fragment. In addition, we recently showed that αGC/CD1d-antitumor fusion protein greatly increased the efficacy of a therapeutic peptide/CpG-based cancer vaccine, first as an adjuvant during T cell priming and second, as a therapeutic agent to redirect immune responses to the tumor site.

To optimize the synergy between iNKT cells and cytotoxic T lymphocytes (CTLs), we aim at conferring both antigen specificities to the same T lymphocyte by transducing iNKT cells with high avidity MHC-I-restricted TCR, or conversely transduce CTLs with the CD1d-restricted iNKT invTCR. Indeed, the simultaneous triggering of transduced HLA-A2/NY-ESO-I TCR and of the endogenous iNKT TCR led to increased cytokine secretion and killing of HLA-A2 and HER2 positive tumor cells, when pulsed with the antigenic peptide and coated with the CD1d-anti-HER2 fusion protein. To reduce TCR mispairing between endogenous and transduced TCRs, we are developing human and mouse single chain iNKT TCRs (iNKT scTv) fused to CAR-derived activation domains. The stability between the murine Va and Vb variable domains of the iNKT scTv is being optimized by site-directed mutagenesis and by spacer design. The resulting variants transduced in MHC-I-restricted T cells are tested for their binding to αGC/CD1d multimer and for TCR function. In vivo studies will involve the adoptive transfer of iNKT scTv-transduced tumor-specific CTLs in immunized mice grafted with tumor cells co-expressing the MHC-I-restricted and CD1d-targeted antigens.

It is expected that this approach will confer CD1d-glycolipid specificity to tumor-specific CD8 T cells, in which a major advantage is the availability of a single invariant TCR that can be offered to all patients independently of their MHC-I haplotype.

Authors’ Affiliations

(1)
University of Lausanne, Epalinges, Switzerland
(2)
Swiss Institute of Bioinformatics, Lausanne, Switzerland
(3)
Ludwig Center for Cancer Research, Zurich, Switzerland

Copyright

© Tschumi et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Advertisement