Possible Combination Treatment for Patients with Cancers not Responsive to Immune Checkpoint Inhibitors

A combination treatment involving a drug stimulating an innate immune receptor could render immune checkpoint inhibitors functional in patients with otherwise unresponsive cancers.

Superresolution image of a group of killer T cells (green and red) surrounding a cancer cell (blue, center). Source: NIH

While immune checkpoint inhibitors have shown great promise for the treatment of relapsed and/or refractory cancers in some patients, many do not respond well to this immunotherapy, potentially due to a reduced or absent anti-tumor T cell response. Thus, recent efforts have focused on combining immune checkpoint inhibitors with drugs that stimulate the anti-cancer T cell response. Roselli et al demonstrated that the direct administration of a molecule activating the innate immune receptor Toll Like Receptor 3 (TLR3), the dsRNA mimic poly A:U, into the tumors of mice can delay cancer development and extend survival.

Following injection of this drug, a population of innate immune cells important for T cell activation, known as CD103+ dendritic cells (DCs), stimulated immunosuppressive T cells in the tumor microenvironment to begin attacking the tumor. This treatment also increased the expression of molecules targeted by immune checkpoint inhibitors, supporting the utility of combination therapy. The additional administration of poly A:U may restore anticancer immunity to patients with cancers not otherwise responsive to immune checkpoint therapy.

Roselli E, Araya P, Nunez NG, et al. (2019) TLR3 Activation of Intratumoral CD103+ Dendritic Cells Modifies the Tumor Infiltrate Conferring Anti-tumor Immunity. Frontiers in Immunology. https://www.frontiersin.org/articles/10.3389/fimmu.2019.00503/full