Massachusetts Institute of Technology
Adoptive cell transfer (ACT) with autologous tumor-reactive T-cells has recently shown great promise in the treatment of leukemia 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 antigen-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 (~91.5 wt%) and released native cytokine proteins in response to antigen stimulation on T cell surface, and enabled selective expansion of transferred CD8+ T-cells in tumor microenvironment. 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. Surface-bound IL-15Sa-NGs could be used to “backpack” T-cells with doses of cytokine that slowly released and maintained T-cell function over weeks in vivo, while the same doses administered systemically as a bolus or repeated lower-dose injections were lethally toxic, eliciting systemic cytokine syndrome. These data demonstrate that T-cell surface-bound antigen responsive cytokine-NGs provide autocrine support to the tumor-reactive T-cells to enhance efficacy and safety of ACT therapy against solid tumors.
Date of Talk:
March 30, 2016