MSLN overexpression

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.

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.

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.

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.

When tested in vivo in mouse CRC xenografts, NK-92cl45 consistently impaired tumor growth only in MSLN-overexpressing xenografts, while wild-type NK-92 cells displayed negligible activity.ConclusionMSLN is a good target for CAR-based adoptive immunotherapy, being poorly expressed in normal tissues. Our results showed both in vitro and in vivo that MSLN CAR-NK-92 can be a valid alternative treatment in MSLN-overexpressing CRCs that belong to a poor prognosis subtype frequently resistant to standard care.

We have previously developed CT-0508, a chimeric antigen receptor macrophage (CAR-M) targeting HER2 which showed efficacy in a variety of pre-clinical models and is currently in a Phase I clinical trial for patients with HER2+ solid tumors. The presented results demonstrate that CT-1119, an autologous human anti-mesothelin CAR-M, can cause phagocytosis, tumor cell killing, and pro-inflammatory cytokine release in response to stimulation with mesothelin. These results show that CAR-M is a feasible approach for the treatment of mesothelin expressing sold tumors via the potential for induction of a systemic anti-tumor response.

Our data demonstrate that mesothelin expression is frequent and highly homogeneous in ovarian cancer and prompt for future anti-mesothelin therapy studies in this tumor type.

No such switch was seen between the mesothelin-interpretable primary tumors and their nodal metastases of 59 cancers, and only 1 mesothelin-positive tumor had a mixture of positive and negative lymph node metastases. In conclusion, mesothelin expression is frequent and highly homogeneous in ovarian cancer.

Conclusions The presented results demonstrate that CT-1119, an autologous human anti-mesothelin CAR-M, can cause phagocytosis, tumor cell killing, and pro-inflammatory cytokine release in response to stimulation with mesothelin. These results show that CAR-M is a feasible approach for the treatment of mesothelin expressing sold tumors via the potential for induction of a systemic anti-tumor response.

The dosimetry estimation study showed that the effective dose of I-anti-MSLN was 0.185 mSv/MBq, which is within the range of acceptable doses for further nuclear medicine translational research. Taken together, these results suggest that this radiotracer has the potential for detecting mesothelin-overexpressing tumors.

In addition, in the survival analysis of 392 patients with gastric cancer, patients with rs3764247 CC genotype had poorer survival than patients with AA + AC genotype after adjusting for age, sex, TNM stage, and Lauren classification (HR = 2.07, p = 0.029). Our findings indicated that MSLN could be an oncogene whose polymorphisms were closely related to the risk and prognosis of gastric cancer.

MSLN‑specific T cells activated by these DCs showed more specific killing capability against naturally expressed MSLN‑HCC70 and artificially MSLN‑overexpressing MDA‑MB‑231 compared with parental MDA‑MB‑231 in both two dimensional (2D)‑ and 3D‑culture systems. In conclusion, the results demonstrated the efficacy of MSLN‑SmartDC to promote MSLN‑specific T cells response against TNBC and RPS3 can enhance the cytolytic activity of these T cells providing an alternative treatment approach for patients with TNBC.