SynNotch CAR circuits enhance solid tumor recognition and promote persistent antitumor activity in mouse models

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor (CAR) T cell therapies are effective against hematological malignancies but face challenges in solid tumors.
• These challenges include identifying tumor-specific antigens, avoiding on-target/off-tumor toxicities, and overcoming suppressive tumor microenvironments.

Purpose of the Study:

• To enhance the specificity and persistent antitumor activity of CAR T cells for solid tumors.
• To identify novel tumor-specific antigens and utilize synthetic Notch (synNotch) CAR circuits for improved therapeutic outcomes.

Main Methods:

• Identification of alkaline phosphatase placental-like 2 (ALPPL2) as a tumor-specific antigen in solid tumors like mesothelioma and ovarian cancer.
• Development of synNotch CAR circuits for combinatorial targeting of ALPPL2 with other antigens (MCAM, mesothelin, HER2).
• Evaluation of synNotch CAR T cells in mouse models of human mesothelioma and ovarian cancer.

Main Results:

• SynNotch CAR T cells demonstrated superior control of tumor burden compared to constitutive CAR T cells in preclinical models.
• synNotch-controlled expression prevented CAR-mediated tonic signaling, promoting long-lived memory and non-exhausted T cell phenotypes.
• ALPPL2 was validated as a viable target for cell therapy in multiple solid tumors.

Conclusions:

• SynNotch CAR circuits offer multifaceted therapeutic benefits for solid tumor treatment.
• ALPPL2 is a promising target for developing effective CAR T cell therapies against various solid tumors.
• This study establishes synNotch CAR T cells as a strategy to overcome current limitations in CAR T cell therapy for solid tumors.