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Published on: January 17, 2025
Tuning CAR-T cells by targeting cancer-associated glycan in pancreatic cancer
Sangwoo Park1,2,3, Cassidy E Ho1,2, Eli P Darnell1,2,3
1Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
Abstract:
Chimeric antigen receptor (CAR) T cell therapy has transformed cancer treatment but its efficacy remains limited in solid tumors due to antigen heterogeneity, an immunosuppressive microenvironment, and the glycocalyx barrier. The glycocalyx, composed of dense glycoproteins such as MUC1, is markedly expanded in cancers, where it impedes immune cell access and antigen engagement, thereby reducing efficacy. In most adenocarcinomas, Tn antigen, comprising N-acetylgalactosamine linked to serine or threonine, is overexpressed. Tn-MUC1, a truncated form of MUC1 decorated with Tn antigen, is frequently overexpressed in pancreatic cancer. Here, we incorporate a non-signaling glyco-bridge binder recognizing Tn-MUC1 into mesothelin-directed CAR-T cells. This bridge enhances tumor recognition and cytotoxicity by increasing avidity and facilitating CAR activation in a density- and affinity-dependent manner. To broaden its applicability, we design a tandem Helix pomatia agglutinin (HPA) lectin-based bridge that recognizes Tn antigens across cancer types. CAR-T cells with the HPA-bridge exhibit superior cytotoxicity in pancreatic cancer models.
Insights
Researchers developed a novel glyco-bridge for CAR T-cell therapy to overcome solid tumor challenges. This innovation enhances T-cell targeting of cancer cells, improving treatment efficacy in pancreatic cancer models.
Area of Science:
- Oncology
- Immunotherapy
- Glycobiology
Background:
- Chimeric antigen receptor (CAR) T cell therapy shows promise but faces limitations in solid tumors.
- The tumor glycocalyx, particularly MUC1, creates a barrier, hindering CAR T-cell function.
- Overexpressed Tn antigen on MUC1 (Tn-MUC1) is prevalent in pancreatic cancer and impedes immune responses.
Purpose of the Study:
- To engineer CAR T-cells with enhanced recognition and efficacy against solid tumors, specifically pancreatic cancer.
- To develop a glyco-bridge strategy to overcome the immunosuppressive glycocalyx barrier.
- To investigate the potential of a novel Tn antigen-binding glyco-bridge for CAR T-cell therapy.
Main Methods:
- Incorporation of a non-signaling glyco-bridge binder recognizing Tn-MUC1 into mesothelin-directed CAR T-cells.
- Design of a tandem Helix pomatia agglutinin (HPA) lectin-based bridge for broader Tn antigen recognition.
- Evaluation of CAR T-cell cytotoxicity and tumor recognition in pancreatic cancer models.
Main Results:
- The glyco-bridge significantly enhanced tumor recognition and CAR T-cell cytotoxicity.
- CAR T-cell activation was improved in a density- and affinity-dependent manner.
- CAR T-cells equipped with the HPA-bridge demonstrated superior efficacy in pancreatic cancer models.
Conclusions:
- Glyco-bridge engineering represents a promising strategy to enhance CAR T-cell therapy for solid tumors.
- Targeting Tn-MUC1 with novel CAR T-cell designs can overcome the glycocalyx barrier.
- The HPA-lectin bridge offers a versatile approach for improving CAR T-cell activity across various cancer types.
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