T lymphocyte engineering with responsive cytokine nanogels for enhanced efficacy and safety of adoptive cell therapy for cancer


Li Tang


Li Tang, Yiran Zheng, Llian Mabardi, Darrell J. Irvine

Author Affiliation: 

Koch Institute, MIT


Adoptive cell transfer (ACT) with autologous tumor-reactive T-cells has recently shown great promise in the treatment of leukemias in clinical trials. However, effective control of solid tumors, in particular resistant, metastatic, or recurrent cancers, remain challenging. One of the major limitations is the rapid decline of T-cell function in the immunosuppressive tumor microenvironment. In order to maintain high numbers of viable antigen-specific cytotoxic T-cells in tumors, co-administration of supporting immunostimulant agents such as cytokines together with transferred cells is often employed. However, the high systemic doses of such agents needed to enhance T-cell functionality inside solid tumors can also result in serious side effects. Here, we developed a cell-responsive nanogel (NG) based on a novel carrier-free delivery strategy to effectively and specifically support adoptively transferred T-cells with recombinant cytokines such as interleukin-2 (IL-2) or interleukin-15 (IL-15). IL-2-Fc or an IL-15 superagonist (IL-15Sa) were chemically crosslinked with a disulfide linker to form these protein NGs, which were subsequently bound to and stably anchored on the plasma membrane of adoptively transferred T-cells ex vivo. These NGs had exceptionally high loading of cytokines (~70 wt%) and released native cytokine proteins in physiological condition in a sustained manner through breakdown of a degradable disulfide linker in response to the reduction activity at the plasma membrane surface of activated T-cells, and thus enabled continuous pseudo-autocrine stimulation of transferred CD8+ T-cells. In a mouse model of subcutaneous B16F10 melanoma tumors, adoptively transferred mouse pmel-1 CD8+ T-cells with optimized IL-15Sa-NGs showed markedly enhanced expansion and persistence in tumors and thus improved the anti-cancer efficacy. Quantification of transferred tumor-specific T-cells in tumors 7 days after transfer showed that surface-bound IL-15Sa-NGs resulted in ~16-fold more tumor-reactive T-cells compared to T-cells supported by an equivalent dose of soluble IL-15Sa administered systemically. Surface-bound IL-15Sa-NGs could be used to ÒbackpackÓ T-cells with doses of cytokine that slowly released and maintained T-cell function over at least 2 weeks in vivo, while the same doses administered systemically as a bolus or repeated lower-dose injections were very toxic, eliciting systemic cytokine syndrome. These data demonstrate that T-cell surface-bound responsive cytokine-NGs provide autocrine support to the tumor-reactive T-cells to enhance efficacy of ACT therapy against solid tumors and safely administered potent adjuvant immunostimulants to donor T-cells.