Chimeric antigen receptor T cells self-neutralizing IL6 storm in patients with hematologic malignancy

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor (CAR) T-cell therapy shows promise for hematologic malignancies but is associated with cytokine release syndrome (CRS) and neurotoxicity.
• Elevated interleukin-6 (IL6) is a hallmark of CRS, and IL1 has been implicated in CAR T-cell-induced neurotoxicity.
• Current management of CRS often involves IL6 receptor blockade with Tocilizumab.

Purpose of the Study:

• To evaluate the safety and efficacy of genetically engineered CAR T-cells secreting anti-IL6 single-chain variable fragment (scFv) and IL1 receptor antagonist (IL1RA).
• To assess the impact of these engineered CAR T-cells on IL6 and IL1B levels, CRS, neurotoxicity, and therapeutic response in patients with hematologic malignancy.

Main Methods:

• Clinical investigation of anti-CD19 and anti-BCMA CAR T-cells (41BBζ) engineered to secrete anti-IL6 scFv and IL1RA.
• Monitoring of IL6 and IL1B levels, CRS severity, neurotoxicity, CAR T-cell expansion, and treatment response in patients.

Main Results:

• Engineered CAR T-cells maintained low IL6 and IL1B levels during CRS, eliminating the need for Tocilizumab.
• Patients experienced mild to moderate CRS and no neurotoxicity.
• High rates of complete response (CR) and significant CAR T-cell expansion were observed.

Conclusions:

• CAR T-cells engineered to secrete anti-IL6 scFv and IL1RA can self-neutralize IL6 storms and maintain low IL1B levels.
• This strategy effectively minimizes IL6- and IL1-associated toxicities, including neurotoxicity, during CAR T-cell therapy.
• The engineered CAR T-cell approach preserves therapeutic efficacy while enhancing safety.