Mesothelin-targeting T cells bearing a novel T cell receptor fusion construct (TRuC) exhibit potent antitumor efficacy against solid tumors

Our plain-English summary of Mesothelin-targeting T cells bearing a novel T cell receptor fusion construct (TRuC) exhibit potent antitumor efficacy against solid tumors, by J. Ding, S. Guyette, B. Schrand, et al (Oncoimmunology, 2023).

The study

• Authors: J. Ding, S. Guyette, B. Schrand, J. Geirut, H. Horton, G. Guo, G. Delgoffe, A. Menk, P.A. Baeuerle, R. Hofmeister, R. Tighe
• Journal: Oncoimmunology
• Published: 2023;12(1):2182058
• Cited by: 33 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

T cell Receptor (TCR) Fusion Construct (TRuC®) T cells harness all signaling subunits of the TCR to activate T cells and eliminate tumor cells, with minimal release of cytokines. While adoptive cell therapy with chimeric antigen receptor (CAR)-T cells has shown unprecedented clinical efficacy against B-cell malignancies, monotherapy with CAR-T cells has suboptimal clinical efficacy against solid tumors, probably because of the artificial signaling properties of the CAR. TRuC-T cells may address the suboptimal efficacy of existing CAR-T therapies for solid tumors. Here, we report that mesothelin (MSLN)-specific TRuC-T cells (referred to as TC-210 T cells) potently kill MSLN+ tumor cells in vitro and efficiently eradicate MSLN+ mesothelioma, lung, and ovarian cancers in xenograft mouse tumor models. When benchmarked against MSLN-targeted BBζ CAR-T cells (MSLN-BBζ CAR-T cells), TC-210 T cells show an overall comparable level of efficacy; however, TC-210 T cells consistently show faster tumor rejection kinetics that are associated with earlier intratumoral accumulation and earlier signs of activation. Furthermore, in vitro and ex vivo metabolic profiling suggests TC-210 T cells have lower glycolytic activity and higher mitochondrial metabolism than MSLN-BBζ CAR-T cells. These data highlight TC-210 T cells as a promising cell therapy for treating MSLN-expressing cancers. The differentiated profile from CAR-T cells may translate into better efficacy and safety of TRuC-T cells for solid tumors.

© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.

In plain English

This was a laboratory and mouse study of an experimental cell therapy, not a study of asbestos exposure or of patients. The authors engineered human donor T cells with a T cell receptor fusion construct (TRuC) targeting mesothelin (MSLN), called TC-210 T cells, and compared them with mesothelin-targeted 4-1BB-CD3zeta CAR-T cells carrying the same MH1 binder. In 24-hour culture assays TC-210 T cells killed mesothelin-expressing mesothelioma (MSTO-M-Luc), lung (A549-M-Luc) and ovarian (OVCAR3-Luc) tumour cells, spared mesothelin-negative C30 cells, and released IFN-gamma, IL-2, GM-CSF and TNF-alpha only against mesothelin-positive cells. In NSG mice bearing intraperitoneal OVCAR3-Luc tumours, tumours were undetectable in 6 of 7 animals by day 13 after TC-210 infusion and these mice remained tumour-free to day 27, while a small tumour remained in one mouse after initial regression. In subcutaneous models both TC-210 and CAR-T cells eliminated tumours, but regression and eradication occurred earlier with TC-210 (MSTO model: regression day 10 versus day 13; eradication day 20 versus day 27), with more intratumoral T cells at day 7 and lower plasma cytokines. TC-210 T cells also showed lower glycolytic activity, higher spare respiratory capacity with no appreciable difference in basal oxidative metabolism, and significantly higher mitochondrial mass in tumour-infiltrating CD8+ but not CD4+ cells. The authors concluded TC-210 is a promising therapy for mesothelin-overexpressing solid tumours.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Preclinical laboratory study: in vitro assays with engineered human T cells and tumour cell lines plus xenograft experiments in NSG mice
• Who was studied: Primary human T cells from donors transduced to express the MSLN TRuC or CAR; four tumour cell lines (A549, MSTO-211H, OVCAR3, C30); NOD scid gamma (NSG) mice bearing subcutaneous or intraperitoneal tumours (n = 10 or n = 5 mice per group)
• Exposure: Treatment with mesothelin-targeted TRuC-T cells (TC-210), compared with mesothelin-targeted 4-1BB-CD3zeta CAR-T cells using the same MH1 binder, and with nontransduced T cells or vehicle; 2 x 10^6 T cells intravenously in the A549 model
• Main results:
  • In vitro, TC-210 T cells killed mesothelin-expressing tumour cells but not mesothelin-negative C30 cells
  • TC-210 T cells proliferated only in response to MSLN-positive MSTO-M-Luc cells
  • In the intraperitoneal OVCAR3-Luc model, tumours were undetectable in 6 of 7 TC-210-treated animals by day 13 and the mice remained tumour-free to day 27; one mouse had a small residual tumour
  • In the subcutaneous A549-M-Luc model both cell products eliminated tumours in all animals, with slightly faster clearance by TC-210 T cells
  • Plasma cytokines (GM-CSF, IFN-gamma, IL-2, IL-4, IL-5, granzymes A and B) rose in both treated groups but were significantly lower in TC-210-treated mice than in CAR-T-treated mice
  • In the MSTO-M-Luc mesothelioma model, regression began on day 10 with TC-210 versus day 13 with CAR-T, and eradication occurred on day 20 versus day 27
  • Significantly more T cells accumulated in tumours of TC-210-treated mice at day 7 post-infusion; at day 10 the same trend was not statistically significant
  • Metabolic profiling: basal oxidative metabolism was similar between the two products, spare respiratory capacity was higher and extracellular acidification rate (glycolysis) lower in TC-210 T cells
  • Ex vivo, intratumoral CD4+ TC-210 T cells had significantly lower glucose uptake than CD4+ CAR-T cells, with a similar trend in CD8+ cells
  • Mitochondrial mass was significantly higher in CD8+ TC-210 T cells than in CD8+ CAR-T cells; the trend for CD4+ cells was not statistically significant
• The authors' conclusion: The authors concluded that TC-210 T cells are a promising treatment for mesothelin-overexpressing solid tumours, infiltrating and rejecting tumours more rapidly while producing fewer pro-inflammatory cytokines than second-generation mesothelin-targeted CAR-T cells, with further research warranted
• Limitations the authors state:
  • The authors state that in vitro assays and mouse xenograft models poorly predict cytokine release syndrome, so it is unclear whether lower cytokine levels mean a better safety profile
  • The study did not explore the mechanism behind the rapid accumulation of TC-210 T cells in the tumour microenvironment; the gene expression and metabolic findings are described as hypothesis-generating
  • Because few CD8+ CAR-T cells were available, the phenotypic comparison was restricted to the CD4+ subset
  • The authors state that future studies of the persistence and memory phenotype of MSLN-targeted TRuC-T cells compared with CAR-T cells are warranted

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma, Ovarian cancer.

Medical terms in this study, explained in our Lexicon: Mesothelin, Cytokine, CAR-T Cell, Mesothelioma, Ovarian Cancer.

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