Harnessing IL-15 Backpacks for Enhanced T Cell Proliferation and Antitumor Response

Cell therapy has shown potential for treating certain patients, but its effectiveness in combating resistant tumors can be enhanced through the use of inflammatory cytokines like interleukin 15 (IL-15). However, the clinical application of IL-15 has been restricted due to its systemic toxicity and limited therapeutic range. To address this, a novel "backpack" method has been developed by Torque, which involves attaching IL-15 to T cells for adoptive transfer. These backpacks are nano-sized particles composed of crosslinked IL-15/IL-15Rα/Fc heterodimers that release fusion proteins to stimulate T cell division autonomously, a process known as Deep Priming.

Torque's primary program, TRQ15-01, utilizes autologous T cells equipped with IL-15 backpacks targeted at specific antigens. The study characterized the T cells' ability to carry backpacks, the kinetics of IL-15 heterodimer release, and T cell expansion by combining IL-15 backpacks with human T cells activated by CD3/CD28 beads. The results showed a consistent loading of T-cells in relation to the concentration of the backpack labeling solution across multiple donors. The backpacks facilitated a substantial expansion of activated T-cells over an extended period through a sustained release of IL-15.

Further research was conducted to understand the impact of IL-15 backpacks on CAR-T cell functionality. Anti-EGFR CAR-expressing human CD3 cells were equipped with IL-15 backpacks and tested in NSG mice with human H1299 tumor xenografts. The results indicated that the backpacks significantly improved CAR-T cell expansion and tumor growth inhibition.

To facilitate the clinical assessment of the backpack technique with antigen-directed T-cells, a new, fully-closed, semi-automated cell manufacturing process was developed. This method uses dendritic cells derived from monocytes and loaded with peptides from various tumor-associated antigens to expand cytotoxic T lymphocytes (CTLs). The final step involves loading the antigen-directed CTLs with IL-15 backpacks to create the TRQ15-01 cell product.

The TRQ15-01 product was found to have controllable and dose-dependent loading of IL-15 backpacks on the antigen-directed T cells. It demonstrated a significantly higher level of expansion both in vitro and in vivo compared to non-backpacked cells. The loading of IL-15 backpacks on human T cells is adjustable, resulting in a slow release of IL-15, sustained cell expansion, and increased anti-tumor activity. Clinical trials for TRQ15-01 are set to begin in 2018.

The study was presented by Pengpeng Cao et al. at the American Association for Cancer Research Annual Meeting in 2018.