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Updated: Jun 28, 2026
A Real-time Potency Assay for Chimeric Antigen Receptor T Cells Targeting Solid and Hematological Cancer Cells
Published on: November 12, 2019
Functional enhancement of mesothelin-targeted TRuC-T cells by a PD1-CD28 chimeric switch receptor
Derrick McCarthy1, Michael Lofgren2, Amy Watt2
1TCR2 Therapeutics, Inc., 100 Binney Street, Suite 710, Cambridge, MA, 02142, USA.
Abstract:
T cells expressing a mesothelin (MSLN)-specific T cell receptor fusion construct (TRuC®), called TC-210, have demonstrated robust antitumor activity in preclinical models of mesothelioma, ovarian cancer, and lung cancer. However, they are susceptible to suppression by the programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) axis and lack intrinsic costimulatory signaling elements. To enhance the function of anti-MSLN TRuC-T cells, chimeric switch receptors (CSRs) have been designed to co-opt the immunosuppressive PD-1/PD-L1 axis and to deliver a CD28-mediated costimulatory signal. Here, we report that coexpression of the PD1-CD28 CSR in TRuC-T cells enhanced T cell receptor signaling, increased proinflammatory effector cytokines, decreased anti-inflammatory cytokines, and sustained effector function in the presence of PD-L1 when compared with TC-210. Anti-MSLN TRuC-T cells engineered to coexpress PD1-CD28 CSRs comprising the ectodomain of PD-1 and the intracellular domain of CD28 linked by the transmembrane domain of PD-1 were selected for integration into an anti-MSLN TRuC-T cell therapy product called TC-510. In vitro, TC-510 showed significant improvements in persistence and resistance to exhaustion upon chronic stimulation by tumor cells expressing MSLN and PD-L1 when compared with TC-210. In vivo, TC-510 showed a superior ability to provide durable protection following tumor rechallenge, versus TC-210. These data demonstrate that integration of a PD1-CD28 CSR into TRuC-T cells improves effector function, resistance to exhaustion, and prolongs persistence. Based on these findings, TC-510 is currently being evaluated in patients with MSLN-expressing solid tumors.
Insights
Engineered T cells targeting mesothelin (MSLN) show improved anti-tumor activity. Co-expressing a chimeric switch receptor (CSR) enhances T cell function and persistence, leading to better outcomes in preclinical cancer models.
Area of Science:
- Immunotherapy
- Oncology
- Cellular Therapy
Background:
- T cell receptor fusion constructs (TRuC®) targeting mesothelin (MSLN) demonstrate preclinical antitumor activity.
- Existing TRuC T cells (TC-210) are limited by programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) mediated suppression and lack of costimulation.
- Chimeric switch receptors (CSRs) can overcome these limitations by co-opting PD-1/PD-L1 signaling and providing CD28-mediated costimulation.
Purpose of the Study:
- To enhance the function and persistence of anti-MSLN TRuC T cells.
- To evaluate the efficacy of a PD1-CD28 CSR engineered TRuC T cell therapy (TC-510) in preclinical models.
Main Methods:
- Designed and engineered anti-MSLN TRuC T cells (TC-510) to coexpress a PD1-CD28 CSR.
- Assessed T cell receptor signaling, cytokine production, effector function, persistence, and resistance to exhaustion in vitro.
- Evaluated in vivo antitumor efficacy and durable protection following tumor rechallenge.
Main Results:
- TC-510 demonstrated enhanced T cell receptor signaling, increased proinflammatory cytokines, and sustained effector function compared to TC-210, even in the presence of PD-L1.
- In vitro, TC-510 exhibited improved persistence and resistance to exhaustion upon chronic stimulation by MSLN- and PD-L1-expressing tumor cells.
- In vivo, TC-510 provided superior durable protection against tumor rechallenge compared to TC-210.
Conclusions:
- Integration of a PD1-CD28 CSR into TRuC T cells significantly improves effector function, resistance to exhaustion, and prolongs persistence.
- TC-510 represents a promising advancement in cellular therapy for MSLN-expressing solid tumors.
- TC-510 is currently under clinical evaluation in patients with MSLN-expressing solid tumors.
