Functional enhancement of mesothelin-targeted TRuC-T cells by a PD1-CD28 chimeric switch receptor

Our plain-English summary of Functional enhancement of mesothelin-targeted TRuC-T cells by a PD1-CD28 chimeric switch receptor, by D. McCarthy, M. Lofgren, A. Watt, et al (Cancer Immunology, Immunotherapy, 2023).

The study

• Authors: D. McCarthy, M. Lofgren, A. Watt, H. Horton, P. Kieffer-Kwon, J. Ding, S. Kobold, P.A. Baeuerle, R. Hofmeister, D.A. Gutierrez, R. Tighe
• Journal: Cancer Immunology, Immunotherapy
• Published: 2023;72(12):4195-4207
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2023. The Author(s).

In plain English

This was a laboratory and animal study of engineered human T cells aimed at mesothelin (MSLN)-expressing tumours. The authors made T cells carrying an anti-MSLN T cell receptor fusion construct (TRuC, called TC-210) alone, or together with a PD1-CD28 chimeric switch receptor (CSR) using either the PD-1 transmembrane domain (PD1TM) or the CD28 transmembrane domain (CD28TM). Cells were tested against the mesothelioma line MSTO-211H engineered to express MSLN, or MSLN plus PD-L1, and against MSLN-negative A2780 (C30) cells. Killing of tumour cells was similar for all three products, but CSR-bearing cells released more IL-2, TNF-alpha and GM-CSF; blocking PD-1 reduced this back toward TC-210 levels. PD-1 expression was similar in the two CSR groups (mean MFI of 4870 for PD1TM and 4770 for CD28TM) and about 18-fold higher than endogenous PD-1 in TC-210 (mean MFI 268). PD1TM was chosen for the product TC-510. In mice (n=10 per group), both TC-210 and TC-510 cleared tumours; after rechallenge on Day 44, all TC-210 mice relapsed while 1/8 TC-510 mice did.

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 of engineered human T cells (in vitro assays) with a mouse xenograft experiment
• Who was studied: Primary human T cells from commercially sourced healthy volunteer donors, tumour cell lines (MSTO-211H mesothelioma, A2780/C30), and female class I/class II negative NSG mice, 10 per treatment group
• Exposure: Anti-mesothelin TRuC-T cells (TC-210) with or without a PD1-CD28 chimeric switch receptor using PD1TM or CD28TM; mice dosed with 2.0 x 10^6 TRuC+ T cells intravenously
• Main results:
  • Cytotoxicity against MSTO cells expressing MSLN, with or without PD-L1, was similar for all three TRuC-T cell products
  • CSR-bearing TRuC-T cells produced significantly more proinflammatory cytokines (IL-2, TNF-alpha, GM-CSF) than TC-210 against both target lines
  • PD-1 expression was comparable in the two CSR groups: mean MFI of 4870 for PD1TM and 4770 for CD28TM
  • Chimeric receptor PD-1 levels were about 18-fold higher than endogenous PD-1 in TC-210 alone (mean MFI of 268)
  • Adding a PD-1-blocking antibody reduced the extra cytokine production by CSR-bearing cells to at least TC-210 levels
  • In repeated in vitro stimulation, TC-510 kept expanding and showed a less exhausted phenotype, while TC-210, PD1TM-Mutant and PD1Trunc cultures contracted with LAG3 and TIGIT coexpression
  • In mice, both TC-210 and TC-510 cleared tumours by Day 17; after rechallenge on Day 44 all TC-210 treated mice had tumour recurrence, versus 1/8 in the TC-510 group
  • TC-510 mice that rejected rechallenge tumours stayed protected to 244 days after T cell administration
  • The CD28TM version was selected against because of heightened activation sensitivity; the PD1TM CSR was chosen for TC-510
• The authors' conclusion: The authors concluded that adding a PD1-CD28 chimeric switch receptor to anti-MSLN TRuC-T cells improved effector function, resistance to exhaustion and persistence, mainly through CD28 costimulation, and that TC-510 was being tested in a Phase 1/2 trial
• Limitations the authors state:
  • The authors noted the artificial, nonphysiological nature of the in vitro assays and the xenograft mouse model's lack of an intact immune system and of human PD-L1 or MSLN on normal tissues
  • The authors said the failure of the PD-1 dominant-negative receptor to enhance function may reflect limits of their assays or an intrinsic resistance of TRuC-T cells to PD-1 suppression

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelin, Mesothelioma, Ovarian Cancer, Lung Cancer, PD-L1, PD-1/PD-L1, Cytokine.

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