Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor (CAR) T cell therapy faces challenges in solid tumors, including limited T cell trafficking, persistence, and anti-tumor activity.
• Synthetic engineering offers strategies to overcome these limitations for improved therapeutic responses.

Purpose of the Study:

• To engineer CAR T cells targeting tumor-associated glycoprotein-72 (TAG72) with enhanced signaling for potent anti-tumor activity.
• To evaluate the efficacy of membrane-bound IL-12 (mbIL12) engineered CAR T cells in solid tumor models.

Main Methods:

• CAR T cells were engineered to target TAG72, incorporating CD28 transmembrane and 4-1BB co-stimulatory domains.
• An optimized membrane-bound IL-12 (mbIL12) molecule was engineered into CAR T cells to enhance IFNγ production and signaling.
• In vitro and in vivo studies were conducted using ovarian cancer xenograft models and immunocompetent mouse models.

Main Results:

• Engineered CAR T cells demonstrated potent anti-tumor activity and IFNγ secretion, driven by IL-12 signaling.
• Improved antigen-dependent T cell proliferation and tumor cell killing were observed in vitro.
• Robust in vivo efficacy, durable anti-tumor responses, and beneficial effects on the tumor microenvironment were achieved with locoregional administration.

Conclusions:

• Engineering CAR T cells with mbIL12 is a clinically applicable strategy to enhance efficacy against solid tumors.
• Locoregional delivery of engineered CAR T cells promotes durable responses against regional and systemic disease.
• This approach improves CAR T cell function and overcomes the immunosuppressive tumor microenvironment.