Systemically administered low-affinity HER2 CAR T cells mediate antitumor efficacy without toxicity

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor (CAR) T-cell therapy for solid tumors requires careful evaluation of target antigens to balance efficacy and toxicity.
• Human epidermal growth factor receptor 2 (HER2) is a promising target but carries a risk of on-target, off-tumor adverse events.
• Developing safe and effective CAR T-cell therapies for HER2+ solid tumors necessitates understanding the therapeutic window.

Purpose of the Study:

• To investigate the impact of CAR T-cell affinity for murine HER2 (mHER2) on safety and efficacy in an immunocompetent tumor model.
• To evaluate the influence of CAR T-cell dose and lymphodepletion on therapeutic outcomes.
• To determine optimal CAR designs for targeting HER2 in solid tumors while minimizing toxicity.

Main Methods:

• Generated and screened antibodies for mHER2 affinity and specificity.
• Designed and tested HER2-targeted CAR constructs for T-cell function in vitro.
• Assessed the safety and efficacy of various HER2 CAR T-cells in immunocompetent mouse models with HER2+ tumors and in normal mice.

Main Results:

• High-affinity HER2 CAR T-cells caused toxicity in normal HER2-expressing tissues but showed limited tumor infiltration and efficacy.
• Low-affinity HER2 CAR T-cells effectively infiltrated HER2+ tumors and controlled tumor growth without inducing toxicity.
• Toxicity from high-affinity CAR T-cells was independent of tumor burden and correlated with CAR T-cell proliferation.

Conclusions:

• High-affinity CARs targeting antigens like HER2, which are present on normal tissues, present a significant disadvantage.
• Low-affinity HER2 CAR T-cells offer a safe and effective strategy for tumor regression in HER2-expressing solid tumors.
• This study identifies a potential therapeutic approach for solid tumors with high HER2 expression using low-affinity CAR T-cells.