Related Experiment Video
Updated: Sep 9, 2025
Studying Interactions between Myeloid Cells and CAR T Cells In Vitro and In Vivo
Published on: July 25, 2025
Structure-guided engineering of CCL27 enhances natural ligand CAR T-cells against CCR10 for multiple myeloma
Abstract:
Despite the success of BCMA CAR-Ts, many multiple myeloma patients relapse and require additional therapeutic options. Our group previously identified the chemokine receptor CCR10 as a potential alternate target to address this need. Here, we validated CCR10 expression on primary myeloma tumors and sought to develop CAR T-cells against CCR10, utilizing its natural ligand CCL27 as a CAR binding element. However, CARs based on the native CCL27 sequence were ineffective. We thus utilized computational modeling and structure-guided engineering to inform rational mutations along the CCL27-CCR10 interface, exploiting a hydrophobic pocket on CCR10. This effort identified CCL27 mutants with an additional N-terminal aromatic amino acid that dramatically improved the efficacy of CCL27-based CAR-Ts to near that of current anti-BCMA CAR-Ts. We validated key amino acid contacts at the CCL27-CCR10 interface, which contribute to increased CAR binding avidity, predicted to be influenced by increased Van der Waals interactions. Lastly, we found that the CCL27 mutants have no toxicity in the hematopoietic compartment. This work illustrates the potential of engineering natural ligand CAR-Ts beyond their wild-type sequences and underscores the translational potential of engineered CCL27 mutant CAR-Ts.
Insights
Engineered CCL27 variants targeting the chemokine receptor CCR10 show significant promise for treating relapsed multiple myeloma. These modified CAR T-cells demonstrate efficacy comparable to current BCMA CAR-Ts without impacting the hematopoietic compartment.
Area of Science:
- Immunotherapy
- Oncology
- Molecular Biology
Background:
- Chimeric antigen receptor (CAR) T-cell therapy targeting BCMA has shown success in multiple myeloma but relapse remains a challenge.
- CCR10 has been identified as a potential alternative target for multiple myeloma therapy.
- Developing effective CAR T-cells targeting novel antigens requires optimizing ligand-receptor interactions.
Purpose of the Study:
- To develop and validate CCR10-targeting CAR T-cells for multiple myeloma treatment.
- To engineer the natural ligand CCL27 for enhanced binding to CCR10.
- To assess the efficacy and safety of engineered CCL27-based CAR T-cells.
Main Methods:
- Validation of CCR10 expression on primary multiple myeloma tumors.
- Development of CAR T-cells utilizing CCL27 as a binding element.
- Computational modeling and structure-guided engineering to mutate CCL27.
- Assessment of CAR T-cell efficacy and binding avidity.
- Evaluation of toxicity in the hematopoietic compartment.
Main Results:
- Engineered CCL27 mutants with an N-terminal aromatic amino acid significantly enhanced CAR T-cell efficacy against CCR10.
- Modified CAR T-cells achieved efficacy near that of anti-BCMA CAR T-cells.
- Key amino acid contacts at the CCL27-CCR10 interface were identified, contributing to increased binding avidity via Van der Waals interactions.
- Engineered CCL27 mutants showed no observed toxicity in the hematopoietic compartment.
Conclusions:
- Engineering natural ligand-based CAR T-cells beyond their wild-type sequences is a viable strategy.
- Mutant CCL27-based CAR T-cells targeting CCR10 represent a promising therapeutic approach for multiple myeloma.
- This approach holds translational potential for overcoming challenges in CAR T-cell therapy for hematologic malignancies.
