Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors

Area of Science:

• Immunology
• Oncology
• Biomedical Engineering

Background:

• Chimeric antigen receptor (CAR) T cell therapy shows promise in hematologic malignancies but faces challenges in solid tumors.
• Solid tumors present an immunosuppressive microenvironment and cellular heterogeneity, leading to CAR T cell ineffectiveness and tumor escape variants.
• Current systemic delivery methods limit CAR T cell efficacy against solid tumors.

Purpose of the Study:

• To evaluate the efficacy of implantable biopolymer devices for localized delivery of CAR T cells to solid tumors.
• To investigate whether localized CAR T cell delivery can overcome the immunosuppressive tumor microenvironment and prevent tumor escape.
• To assess the combined effect of localized CAR T cell delivery and STING agonists in solid tumor treatment.

Main Methods:

• Developed implantable biopolymer devices for direct delivery of CAR T cells to solid tumor surfaces.
• Utilized immunocompetent orthotopic mouse models of pancreatic cancer and melanoma.
• Administered CAR T cells via biopolymer scaffolds and compared with systemic delivery.
• Codleivered stimulator of IFN genes (STING) agonists with CAR T cells.

Main Results:

• CAR T cells delivered via biopolymer scaffolds migrated effectively and eradicated tumors more efficiently than systemic delivery.
• Localized delivery enhanced CAR T cell exposure to immune cells and prolonged their presence.
• Codelivery of STING agonists stimulated immune responses against non-targeted tumor cells, reducing emergence of escape variants.

Conclusions:

• Implantable biopolymer devices represent a promising strategy to improve CAR T cell therapy for solid tumors.
• Localized delivery enhances CAR T cell function and overcomes key barriers to efficacy in solid tumors.
• Combined therapy with STING agonists offers a potential approach to broaden tumor cell targeting and prevent treatment resistance.