Synthetic immune niche (sin) for enhancement of T-cell therapies

Introduction: Adoptive immunotherapy is based on ex vivo expansion and stimulation of T-cells, followed by their transfer into patients. The ex vivo culturing step provides an opportunity for modulating the properties of transferred T-cells, enhancing their antitumor abilities, and increasing their expansion.

Materials and Methods: We have developed synthetic surfaces coated with the chemokine CCL21 together with the adhesion molecule intercellular adhesion molecule 1 (ICAM1) for increasing the proliferation and functionality of mouse and human CD8⁺T-cells, activated by antigen-loaded dendritic cells or activation microbeads.

Results and discussion: We first evaluated the effect of various molecular components of the lymph node, alone or in combination, for their capacity to mimic the physiological microenvironment encountered by T-cells during their activation and expansion in the lymph node. We found that substrates coated with a combination of CCL21+ICAM1 enhance the proliferation of ovalbumin-specific murine CD4⁺ and CD8+T-cells. The latter cell population, cultured on this substrate also displayed augmented cytotoxic activity toward ovalbumin-expressing melanoma cells, both in-vitro and in-vivo. This increase in specific cytotoxic activity was associated with a major increase in the cellular levels of the killing-mediator granzyme B. Initial experiments, carried out with microbead-activated human cells are currently in progress.

Conclusions: Our results suggest that that synthetic lymph-node mimetic surfaces may be used for enhancing T-cell expansion and generation of T-cells with augmented cytotoxic function, for use in cancer immunotherapy.