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

Area of Science:

• Immunotherapy
• Cancer Biology
• Cellular Engineering

Background:

• Chimeric antigen receptor (CAR) T-cell therapy faces challenges in maintaining effector function against solid tumors due to repeated antigen exposure.
• This limitation hinders the efficacy of current CAR T-cell treatments in patients with solid malignancies.

Purpose of the Study:

• To engineer CAR T cells with enhanced and sustained effector functions for improved solid tumor treatment.
• To develop a novel chimeric cytokine receptor strategy to overcome CAR T-cell exhaustion.

Main Methods:

• Designed and expressed a novel chimeric cytokine receptor (GM18) linking CAR T-cell activation to GM-CSF and IL-18 receptor signaling.
• Evaluated GM18-engineered CAR T-cell function in repeat stimulation assays mimicking chronic antigen exposure.
• Assessed in vivo anti-tumor efficacy in solid tumor xenograft models.

Main Results:

• GM18 expression significantly enhanced CAR T-cell expansion and cytokine production under chronic stimulation compared to unmodified CAR T cells.
• CAR.GM18 T cells demonstrated superior effector function in an antigen- and activation-dependent manner.
• In vivo studies showed potent tumor regression mediated by CAR.GM18 T cells at doses ineffective for standard CAR T cells.

Conclusions:

• The novel GM18 chimeric cytokine receptor strategy effectively endows CAR T cells with sustained effector function.
• This approach holds significant potential for enhancing CAR T-cell therapy against solid tumors by overcoming T-cell exhaustion.
• Hijacking endogenous cytokine signaling pathways represents a promising avenue for bolstering T-cell-mediated anti-tumor immunity.