Chimeric antigen receptor-T cells with cytokine neutralizing capacity

Area of Science:

• Immunotherapy
• Oncology
• Molecular Engineering

Background:

• Chimeric antigen receptor (CAR)-T cell therapy shows promise against hematologic malignancies but causes cytokine release syndrome (CRS).
• Interleukin-6 (IL-6) is a key driver of CRS pathogenesis, necessitating strategies to mitigate its effects.

Purpose of the Study:

• To engineer T cells with an intrinsic capacity to neutralize IL-6 and prevent CRS.
• To evaluate the safety and efficacy of CAR-T cells co-expressing an IL-6 neutralizing receptor.

Main Methods:

• Designed a membrane-bound, non-signaling IL-6 receptor (mbaIL6) for surface expression on T cells.
• Constructed CAR-T cells co-expressing mbaIL6 and an anti-CD19 CAR.
• Assessed IL-6 neutralization, T cell function, and antitumor activity in vitro and in vivo xenograft models.

Main Results:

• Surface-expressed mbaIL6 effectively removed IL-6 from culture supernatants and neutralized IL-6 signaling.
• Co-expression of mbaIL6 did not impair CAR-T cell cytotoxicity or proliferation in vitro.
• CAR-T cells with mbaIL6 significantly reduced systemic IL-6 levels in vivo without compromising antitumor efficacy.

Conclusions:

• CAR-T cells engineered with an on-board IL-6 neutralizing system offer a novel strategy to mitigate CRS.
• This approach has the potential to improve the safety profile of CAR-T cell therapy for cancer patients.