MSLN expression

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

P1, N=9, Active, not recruiting, Fred Hutchinson Cancer Center | Recruiting --> Active, not recruiting | N=15 --> 9

Moreover, mechanistic exploration revealed that the attenuation of autophagy-lysosome function caused by microenvironmental alkalization inhibited the degradation of MSLN. Hence, alkalization of the microenvironment improves the consistency and high expression of the target antigen MSLN and constitutes a routine method for treating diverse solid cancers via MSLN-CAR-T cells.

P1/2, N=49, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Sep 2025

SMRP is a promising serum biomarker for predicting survival in MPM patients treated with ICT and warrants prospective investigation.

a May occur at any point in disease course. CRC, colorectal cancer; D, day; MESO, mesothelioma; NSCLC, non-small cell lung cancer; OVCA, ovarian cancer; PANC, pancreatic cancer; PCLD, preconditioning lymphodepletionDownload figure Open in new tab Download powerpoint Abstract 627 Figure 3 EVEREST-2 phase 1 dose escalation study design

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

Canine mesothelin exhibits molecular and biological characteristics akin to human mesothelin. It could serve as a vital biomarker for diagnosing canine mesotheliomas, applicable to both tissue- and effusion-based samples.

P1, N=70, Recruiting, Light Chain Bioscience - Novimmune SA | N=40 --> 70 | Trial completion date: Sep 2025 --> Sep 2026 | Trial primary completion date: Jun 2025 --> May 2026

These findings serve as a proof-of-concept for using multiple immunogenic peptides as a novel therapeutic approach in TNBC patients.

Further testing of tofacitinib to prevent ADA formation is recommended in applicable non-malignant disease settings. https://www.clinicaltrials.gov/study/NCT04034238.

Our findings indicate that by targeting the protease-sensitive region of MSLN, BsAb 5 has high MSLN-specific anticancer activity that is not inhibited by shed MSLN. BsAb 5 may be a promising immunotherapy candidate for MSLN-expressing cancers.

P1/2, N=113, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Apr 2024 --> Apr 2025 | Trial primary completion date: Apr 2024 --> Apr 2025

Sensitivity of tumor cells to gemcitabine was evaluated...We concluded that MSLN could induce chemoresistance by enhancing migration, invasion, EMT and cancer stem cell traits of pancreatic cancer cells. Targeting MSLN could represent a promising therapeutic strategy for reversing EMT and chemoresistance in pancreatic cancer cells.

HiTs can be isolated from fully human TCR-displaying phage libraries against cell surface-expressed antigens. HiTs are able to fully activate primary T cells both in vivo and in vitro. HiTs may enable the efficacy seen with pHLA-targeting TCRs in solid tumors to be translated to cell surface antigens.

Our results demonstrate that MSLN plays a critical role in BM of NSCLC by modulating the JNK/MET signaling network and thus, provides a potential novel therapeutic target for preventing BM in NSCLC patients.

P2, N=6, Terminated, National Cancer Institute (NCI) | Trial completion date: Mar 2024 --> Dec 2023 | Active, not recruiting --> Terminated; Study was terminated due to slow accrual.

P1/2, N=36, Active, not recruiting, TCR2 Therapeutics | Recruiting --> Active, not recruiting | N=175 --> 36 | Trial completion date: Apr 2026 --> Nov 2028 | Trial primary completion date: Jul 2024 --> Nov 2028

P1/2, N=6, Active, not recruiting, TCR2 Therapeutics | Trial completion date: Dec 2027 --> Oct 2028 | Trial primary completion date: Nov 2023 --> Oct 2028

The collective results demonstrate that mesothelin induces metabolic changes in leukemia cells, facilitating the acquisition of a rapid supply of ATP for proliferation in AML. Therefore, the targeting of mesothelin presents a potentially promising approach to mitigating the progression of AML through the inhibition of glycolysis and mitochondrial respiration in myeloid cells.

Recent advancements in checkpoint inhibitors, adoptive T cell therapies, and cancer vaccines have shown potential in overcoming the immune evasion mechanisms of pancreatic cancer cells. Combining these immunotherapeutic approaches with nanocarriers holds great promise in enhancing the antitumor response and improving patient survival.

P1, N=74, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

P1/2, N=230, Recruiting, A2 Biotherapeutics Inc. | Not yet recruiting --> Recruiting

A 3D cell culture model based on MSLN-expressing multicellular tumor spheroids reveals NA penetration in the first superficial layers. Altogether, these results open the path to novel anticancer strategies based on MSLN-activated internalization of NA incorporating drugs to promote specific accumulation of active treatments in tumors.

In this study, MSLN expression is widely observed in UCS. Moreover, high-MSLN expression is a favorable prognostic factor for UCS, which could be a promising therapeutic target, regardless of HER2 expression. This study was published in the Journal of Gynecologic Oncology.

P1, N=15, Recruiting, Fred Hutchinson Cancer Center | Trial completion date: Sep 2024 --> Jun 2025 | Trial primary completion date: Dec 2023 --> Jun 2024

P1/2, N=230, Not yet recruiting, A2 Biotherapeutics Inc.

P1, N=2, Active, not recruiting, Takeda | Recruiting --> Active, not recruiting | N=21 --> 2

P1, N=42, Not yet recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2027 --> Dec 2024 | Trial primary completion date: Dec 2026 --> Dec 2024

(3) ELISA analysis revealed that the expression levels of IFN-γ, TNF-α, GZMB, PRF1, IL-6, and IL-10 in ovarian cancer cells of the anti-MSLN-iCAR-NK cell group were significantly higher than those in the NK cell group and the control group (all P<0.05). The anti-MSLN-iCAR-NK cells exhibit a strong killing ability against ovarian cancer cells, indicating their potential as a novel immunotherapy approach for ovarian cancer.

P1/2, N=6, Active, not recruiting, TCR2 Therapeutics | Recruiting --> Active, not recruiting | N=140 --> 6 | Trial primary completion date: Jun 2025 --> Nov 2023

P1, N=81, Recruiting, RemeGen Co., Ltd. | Trial completion date: Mar 2024 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Jun 2024

Development of the first-generation CD137-agonist monotherapies utomilumab and urelumab was unsuccessful due to low antitumor efficacy mediated by the epitope recognized on CD137 or hepatotoxicity mediated by FcγR ligand-dependent CD137 activation, respectively. Compared with 3H3, a murine surrogate of urelumab, FS122m and chimeric M9657 displayed significantly lower on-target/off-tumor toxicity. Taken together, M9657 exhibits a promising profile for development as a tumor-targeting immune agonist with potent anticancer activity without systemic immune activation and associated hepatotoxicity.

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. 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.

Furthermore, PET imaging allowed us to compare the pharmacokinetics of epitope-specific VH domain-based PET tracers. Overall, these data are encouraging for the incorporation of PET imaging to assess modified VH domain structures to develop novel anti-MSLN VH domain-based therapeutics in MSLN-positive cancers as well as their companion PET imaging agents.