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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. Benjamin O Tschumi1,
  2. Justyna Iwaszkiewicz2,
  3. Lianjun Zhang1,
  4. Stéphanie Corgnac1,
  5. Jean-Pierre Mach1,
  6. Pedro Romero1 and
  7. Alena Donda3
  1. Aff1 grid.9851.50000000121654204University of Lausanne Epalinges Switzerland
  2. Aff2 grid.419765.80000000122233006Swiss Institute of Bioinformatics Lausanne Switzerland
  3. Aff3 Ludwig Center for Cancer Research Zurich Switzerland

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Meeting abstracts

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.