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Engineering TAG-72 and CD30 CAR-T Cells for T Cell Malignancies
Van To1,2, Vera J Evtimov1,2, Runzhe Shu1,2
1Cartherics Pty Ltd, Notting Hill, Victoria, Australia.
Background:
T cell malignancies represent a broad, highly heterogeneous subset of lymphomas with poor prognosis. Chimeric antigen receptor (CAR)-T cell therapy holds great promise in treating B cell lymphoma and multiple myeloma. However, understanding its efficacy in treating T cell lymphoma remains challenging, primarily due to the lack of tumor-specific targets and intra-tumor heterogeneity.
Methods:
In this proof-of-concept study, we developed and characterized three distinct CAR-T cells targeting tumor-associated glycoprotein 72 (TAG-72), C-C chemokine receptor type 4 (CCR4) and tumor necrosis factor receptor CD30 respectively and assessed their anti-tumor efficacy against T cell malignancies in vitro.
Results:
TAG-72 and CD30 CAR-T cells each demonstrated comparable expansion potential and eliminated tumor cells expressing their respective target antigens. Subsequently, we explored the advantages of targeting two antigens through the pooling of these CAR-T cells. In instances where target antigen expression was low (as determined by flow cytometry), dual targeting of TAG-72 and CD30 was able to elicit cytotoxic function.
Conclusion:
These findings define TAG-72 and CD30-targeting CAR-T cells as a promising strategy against T cell malignancies and highlight the potential of dual or combination CAR-T cell therapies for this aggressive disease.
Insights
Chimeric antigen receptor (CAR)-T cell therapy shows promise for T cell malignancies. Targeting TAG-72 and CD30 antigens with CAR-T cells demonstrated efficacy, especially in combination therapy for aggressive cancers.
Area of Science:
- Oncology
- Immunotherapy
- Cellular Therapy
Background:
- T cell malignancies are a diverse group of lymphomas with poor outcomes.
- Chimeric antigen receptor (CAR)-T cell therapy is effective for B cell lymphomas but faces challenges in T cell lymphomas due to target scarcity and heterogeneity.
- Identifying effective CAR-T cell targets is crucial for improving T cell malignancy treatment.
Purpose of the Study:
- To develop and evaluate CAR-T cells targeting tumor-associated glycoprotein 72 (TAG-72), C-C chemokine receptor type 4 (CCR4), and CD30 for T cell malignancies.
- To assess the anti-tumor efficacy of these CAR-T cells in vitro.
- To explore the potential of dual-targeting strategies.
Main Methods:
- Development and characterization of three distinct CAR-T cell lines targeting TAG-72, CCR4, and CD30.
- In vitro assessment of CAR-T cell expansion and cytotoxic function against T cell malignancies.
- Evaluation of pooled CAR-T cells for dual-antigen targeting.
Main Results:
- TAG-72 and CD30 CAR-T cells exhibited comparable expansion and effectively eliminated target antigen-expressing tumor cells.
- Dual targeting of TAG-72 and CD30 CAR-T cells showed enhanced cytotoxic function, particularly when target antigen expression was low.
- Flow cytometry confirmed antigen expression levels influencing CAR-T cell efficacy.
Conclusions:
- CAR-T cells targeting TAG-72 and CD30 represent a promising therapeutic strategy for T cell malignancies.
- Combination or dual-targeting CAR-T cell therapies hold potential for treating aggressive T cell lymphomas.
- Further research into novel CAR-T cell targets and strategies is warranted for T cell malignancies.
