MSLN expression

Our strategy confers superior antitumor efficacy relative to clinically trialed M28z CAR-T cells by directly targeting heterogeneous tumor antigen expression. These results constitute the foundation for developing a new class of clinically translatable TRAIL-armored CAR-T cell immunotherapies for the treatment of a wider range of malignancies.

Analysis of a public single-cell RNA-sequencing dataset of human pancreatic cancer tissues revealed that MSLN was predominantly expressed in malignant ductal cells while showing negligible expression in normal ductal cells and stromal cells. These findings demonstrate that MSLNpep inhibits tumor-cell migration and enables targeted delivery of therapeutic payloads to MSLN-high pancreatic tumors, supporting its use as a peptide ligand for cancer therapy.

The optimal anti-MSLN×4-1BB bsAb HK013-G1 exhibited synergistic antitumour effects by inducing an ADCC effect (innate immunity) and stimulating the 4-1BB signaling pathway (adaptive immunity) upon cross-bridging with MSLN with no systemic toxicity, which may offer the promise of an improved therapeutic window relative to that of 4-1BB agonists.

P1, N=12, Recruiting, University of Pennsylvania | Trial primary completion date: Feb 2025 --> Feb 2026

Alterations in inflammatory signaling pathways occurred following KO cell exposure to CM containing sMSLN, and CM from cancer cells with intact peritoneal metastasis provoked increased KO cell secretion of IL-1α. While excess sMSLN inhibits cell clustering and peritoneal colonization, sMSLN may also promote PDAC peritoneal metastasis independent of MUC-16.

The experiments and analyses demonstrate the accuracy and effectiveness of the system, with an area under the curve of 81.03%, an accuracy of 73.67%, a sensitivity of 71.54%, a precision of 76.78%, and a F1-score of 72.61%, surpassing both single-modality and dual-modality models. RPMSNet highlights its potential for early diagnosis and personalized treatment in precision medicine.

Our results provide preclinical evidence that a subset of colorectal cancers expressing high mesothelin levels can be effectively targeted by MSLN-CAR-based immunotherapy. The potential therapeutic impact of these findings is enhanced by the fact that frequently MSLN-overexpressing CRCs display worse prognosis and resistance to standard care.

Noted, NbHSA-uPA-A1-PE24 has better enrichment at tumor, and shows robust anti-tumor effects in multiple preclinical models, such as pancreatic cancer and gastric cancer models. The results indicate that this strategy has greater potential and higher safety for application in tumor treatment, providing new ideas and strategies for the development of immunotoxins for cancer patients.

Activated hYP218 CAR T cells persist in the tumour microenvironment and retain their cytotoxic activity. Addition of pembrolizumab in larger tumours enhance CAR T cell efficacy.

Our study highlights the safety and therapeutic efficacy of multiple-chain DAP-CAR-T cell therapy targeting MSLN to treat patients with ovarian cancer and mesothelioma.

Furthermore, in vivo studies indicated that 177Lu-DOTA-amatuximab exhibited limited side effects. The development of 89Zr/177Lu-labeled amatuximab may provide novel insights into the formulation of precision diagnostic and therapeutic strategies for MSLN- overexpressing tumors, including PDAC.

P=N/A, N=371, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed | Trial completion date: Sep 2025 --> Oct 2024 | Trial primary completion date: Sep 2025 --> Oct 2024