Modulating the proliferative and cytotoxic properties of human TIL by a synthetic immune niche of immobilized CCL21 and ICAM1

Abstract

The major challenge in developing an effective adoptive cancer immunotherapy, is the ex-vivo generation of tumor-reactive cells, in sufficient numbers and with enhanced cytotoxic potential. It was recently demonstrated, that culturing of activated murine CD8+ T-cells on a "Synthetic Immune Niche" (SIN), consisting of immobilized CCL21 and ICAM-1, enhances T-cell expansion, increases cytotoxicity against cultured cancer cells and suppresses tumor growth in vivo [1, 2]. In the study reported here, we have tested the effect of the CCL21+ICAM1 SIN, on the expansion and cytotoxic phenotype of Tumor Infiltrating Lymphocytes (TIL), following activation with immobilized anti-CD3/CD28 stimulation, or commercial activation beads. The majority of TIL tested, displayed higher expansion when cultured on the coated SIN compared to cells incubated on uncoated substrate. Comparable enhancement of TIL proliferation was obtained by the CCL21+ICAM1 SIN, in a clinical setting that includes a 14-day rapid expansion procedure (REP), initiated with feeder cells, anti CD3 and IL-2. Co-incubation of post-REP TIL with matching target cancerous cells, demonstrated increased IFN{gamma} secretion beyond baseline in most of the TILs and a significant increase in granzyme B levels following activation on SIN. The SIN did not significantly alter the relative frequency of CD8/CD4 populations, as well as the expression of CD28, CD25 and several exhaustion markers. These results demonstrate the potential capacity of the CCL21+ICAM1 SIN to reinforce TIL-based immunotherapy.