A Chimeric GM-CSF/IL18 Receptor to Sustain CAR T-cell Function

• Published in: Cancer discovery 2021-07, Vol.11 (7), p.1661-1671
• Main Authors: Lange, Shannon, Sand, Laurens G L, Bell, Matthew, Patil, Sagar L, Langfitt, Deanna, Gottschalk, Stephen
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Humans; Immunotherapy, Adoptive; Interleukin-18; Leukocytes, Mononuclear; Mice; Neoplasms - therapy; Receptors, Chimeric Antigen; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; Xenograft Model Antitumor Assays
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.CD-20-0896

The inability of chimeric antigen receptor (CAR) T cells to sustain their effector function after repeated exposure to tumor cells is a major obstacle to their success in patients with solid tumors. To overcome this limitation, we designed a novel chimeric cytokine receptor to create an autocrine loop that links activation-dependent GM-CSF production by CAR T cells to IL18 receptor signaling (GM18). Expression of GM18 in CAR T cells enhanced their effector function in an antigen- and activation-dependent manner. In repeat stimulation assays, which mimic chronic antigen exposure, CAR.GM18 T cells had a significantly greater ability to expand and produce cytokines in comparison with their unmodified counterparts targeting EPHA2 or HER2. , CAR.GM18 T cells induced tumor regression at cell doses at which standard CAR T cells were ineffective in two solid tumor xenograft models. Thus, our study highlights the potential of hijacking cytokines that are physiologically secreted by T cells to bolster their antitumor activity. SIGNIFICANCE: We designed a chimeric cytokine receptor (GM18) that links CAR T-cell activation to MYD88 signaling. GM18 endows CAR T cells with sustained effector function in the setting of chronic antigen exposure, resulting in potent antitumor activity in preclinical solid tumor models. .