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Updated: Nov 16, 2025
A Real-time Potency Assay for Chimeric Antigen Receptor T Cells Targeting Solid and Hematological Cancer Cells
Published on: November 12, 2019
Engineered CAR-T cells targeting TAG-72 and CD47 in ovarian cancer
Runzhe Shu1, Vera J Evtimov1, Maree V Hammett1
1Cartherics Pty, Ltd., Clayton, VIC 3168, Australia.
Abstract:
Chimeric antigen receptor (CAR) T cells have revolutionized blood cancer immunotherapy; however, their efficacy against solid tumors has been limited. A common mechanism of tumor escape from single target therapies is downregulation or mutational loss of the nominal epitope. Targeting multiple antigens may thus improve the effectiveness of CAR immunotherapies. We generated dual CAR-T cells targeting two tumor antigens: TAG-72 (tumor-associated glycoprotein 72) and CD47. TAG-72 is a pan-adenocarcinoma oncofetal antigen, highly expressed in ovarian cancers, with increased expression linked to disease progression. CD47 is ubiquitously overexpressed in multiple tumor types, including ovarian cancer; it is a macrophage "don't eat me" signal. However, CD47 is also expressed on many normal cells. To avoid this component of the dual CAR-T cells killing healthy tissue, we designed a truncated CD47 CAR devoid of intracellular signaling domains. The CD47 CAR facilitates binding to CD47+ cells, increasing the prospect of TAG-72+ cell elimination via the TAG-72 CAR. Furthermore, we could reduce the damage to normal tissue by monomerizing the CD47 CAR. Our results indicate that the co-expression of the TAG-72 CAR and the CD47-truncated monomer CAR on T cells could be an effective, dual CAR-T cell strategy for ovarian cancer, also applicable to other adenocarcinomas.
Insights
Dual CAR-T cells targeting TAG-72 and CD47 show promise for solid tumors. This strategy enhances tumor cell elimination while minimizing damage to healthy tissues, offering a new approach for ovarian and other adenocarcinomas.
Area of Science:
- Immunotherapy
- Oncology
- Biotechnology
Background:
- Chimeric antigen receptor (CAR) T-cell therapy has transformed blood cancer treatment but faces challenges in solid tumors.
- Tumor escape mechanisms, such as antigen loss, limit the effectiveness of single-target therapies.
- Developing multi-antigen targeting CAR T-cells is crucial for improving solid tumor immunotherapy.
Purpose of the Study:
- To engineer dual CAR-T cells targeting both TAG-72 and CD47 antigens for enhanced efficacy against solid tumors.
- To mitigate on-target, off-tumor toxicity associated with CD47 targeting by employing a truncated, monomerized CD47 CAR.
Main Methods:
- Generation of dual CAR-T cells co-expressing a TAG-72 CAR and a modified CD47 CAR.
- Design of a truncated CD47 CAR lacking intracellular signaling domains to reduce off-tumor effects.
- Monomerization of the CD47 CAR to further limit interactions with normal CD47-expressing cells.
Main Results:
- The dual CAR-T cells demonstrated effective targeting of tumor cells expressing both TAG-72 and CD47.
- The truncated, monomerized CD47 CAR component successfully reduced damage to normal tissues.
- The engineered T-cells showed potential for improved tumor cell elimination compared to single-target CARs.
Conclusions:
- Co-expression of TAG-72 CAR and a truncated, monomerized CD47 CAR represents a promising dual CAR-T cell strategy for ovarian cancer.
- This approach may also be applicable to other adenocarcinomas expressing TAG-72 and CD47.
- The dual-targeting strategy offers a potential solution to antigen loss escape mechanisms and reduces on-target, off-tumor toxicity.
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