Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

e-Poster Display Session

73P - aGalCer/antibody complex targeting EGFR-tumor-associated iNKT to restore the immune response

Date

09 Dec 2020

Session

e-Poster Display Session

Presenters

Didier Dubreuil

Citation

Annals of Oncology (2020) 31 (suppl_7): S1441-S1451. 10.1016/annonc/annonc392

Authors

D. Dubreuil1, A. Pattinec2, J. Le Pendu2, J. Douillard3

Author affiliations

  • 1 Université de Nantes, CNRS, Chimie et Interdisciplinarité: Synthèse, Analyse, Modélisation (CEISAM), UMR CNRS 6230, Nantes/FR
  • 2 IMSERM 1232, Pattinec/FR
  • 3 ICO Institut de Cancerologie de l'Ouest René Gauducheau, Saint-Herblain/FR
More

Resources

Abstract 73P

Background

When activated by the α-GalactosylCeramide (αGalCer), iNKT cells can present anti-tumor effect through their own cytotoxic activity or by recruiting and activate other immune cells such as T cells, monocytes or NK cells. With the aim to mediate a local anticancer immune response close to EGFR-tumour environment novel aGalCer analogues have been linked to an anti-EGFR monoclonal antibody carrier used both as vector for the iNKT ligand and ADCC effector. Biological activities of αGalCer and MoAb-conjugates were assessed to highlight dual cytotoxic performances for anticancer therapy.

Methods

αGalCers bearing spacer arm were synthesized and covalently linked to Cetuximab. Free and linked αGalCer analogues were loaded on CD1d tumor cells and co-cultured with iNKTs expanded from healthy donors. Results were obtained on 2D and 3D models, and in vivo. Activity of iNKTs cells was assessed by cytokines dosages in supernantant and by analysis of induced mortality of tumor cells.

Results

Synthetized αGalCer analogues proved to be 103 fold more potent to activate iNKT cells than parent αGalCer and at least 102 fold more efficient to induce tumor cell death. More interestingly, unlike αGalCer, they also proved to be active at a nM range when loaded on several cancer cell lines known as not expressing CD1d (non-CD1d HeLa cells, SW1116, HEK29). We discovered that non-CD1d tumor cells present in fact a very weak CD1d signal that can be mobilized using our ligands. Furthermore, vectorisation of αGalCer analogues with Cetuximab has been shown to specifically activate iNKT at a nM range while keeping ADCC activity, both contributing to the death of loaded tumor cells independently from there RAS mutational status.

Conclusions

We discovered a new family of iNKT agonists as the most potent immunostimulatory agents known today and which have been targeted to the tumour bed using an EGFR-antibody vector. Antibody/αGalCer conjugates appear as promising tool to initiate a immune response close to the tumor in combination with the maintained cytotoxic antibody activity. This dual behavior should open novel perspectives for treatment of EGFR-expressing tumours with an immune mechanism that could reverse resistance related to RAS mutations.

Legal entity responsible for the study

Didier Dubreuil.

Funding

Merck Health Care.

Disclosure

All authors have declared no conflicts of interest.

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings
  • Necessary cookies enable core functionality. The website cannot function properly without these cookies, and you can only disable them by changing your browser preferences.