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Published on: May 9, 2025
Genetic retargeting of E3 ligases to enhance CAR T cell therapy
Isabel C Lane1, Gabriele Kembuan1, Jeannie Carreiro2
1Cancer Center, Massachusetts General Hospital, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
Abstract:
Chimeric antigen receptor (CAR) T cell therapies are medical breakthroughs in cancer treatment. However, treatment failure is often caused by CAR T cell dysfunction. Additional approaches are needed to overcome inhibitory signals that limit anti-tumor potency. Here, we developed bifunctional fusion "degrader" proteins that bridge one or more target proteins and an E3 ligase complex to enforce target ubiquitination and degradation. Conditional degradation strategies were developed using inducible degrader transgene expression or small molecule-dependent E3 recruitment. We further engineered degraders to block SMAD-dependent TGFβ signaling using a domain from the SARA protein to target both SMAD2 and SMAD3. SMAD degrader CAR T cells were less susceptible to suppression by TGFβ and demonstrated enhanced anti-tumor potency in vivo. These results demonstrate a clinically suitable synthetic biology platform to reprogram E3 ligase target specificity for conditional, multi-specific endogenous protein degradation, with promising applications including enhancing the potency of CAR T cell therapy.
Insights
New degrader proteins enhance chimeric antigen receptor (CAR) T-cell therapy by overcoming tumor suppression. This synthetic biology approach improves CAR T-cell function and anti-tumor potency for cancer treatment.
Area of Science:
- Biotechnology
- Immunotherapy
- Synthetic Biology
Background:
- Chimeric antigen receptor (CAR) T-cell therapies represent a significant advancement in cancer treatment.
- CAR T-cell dysfunction and inhibitory signals limit their anti-tumor efficacy.
- Overcoming these limitations is crucial for improving therapeutic outcomes.
Purpose of the Study:
- To develop novel bifunctional fusion degrader proteins to enhance CAR T-cell therapy.
- To engineer conditional and multi-specific protein degradation strategies.
- To investigate the potential of these degraders in overcoming TGFβ-mediated suppression.
Main Methods:
- Designed bifunctional fusion "degrader" proteins to link target proteins with E3 ligase complexes.
- Developed conditional degradation using inducible transgene expression or small molecule-dependent E3 recruitment.
- Engineered SMAD degraders targeting SMAD2 and SMAD3 to block TGFβ signaling.
Main Results:
- SMAD degrader CAR T-cells exhibited reduced susceptibility to TGFβ-induced suppression.
- Engineered CAR T-cells demonstrated enhanced anti-tumor potency in vivo.
- Validated a clinically suitable synthetic biology platform for endogenous protein degradation.
Conclusions:
- The developed degrader protein platform offers a versatile tool for reprogramming E3 ligase specificity.
- Conditional and multi-specific protein degradation can enhance the potency of CAR T-cell therapy.
- This approach holds significant promise for improving cancer treatment strategies.
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