MSLN overexpression

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.

Given that mesothelin is overexpressed in many solid tumours and has antigenic properties, this molecule could be considered an antigenic target for the treatment of many malignancies. Consequently, we also review the literature to report on mesothelin-targeting therapies for HSOC that have been recently investigated in many clinical studies.

Rationale: Mesothelin targeted thorium-227 conjugate (Th-MSLN) is a novel targeted alpha therapy developed to treat mesothelin overexpressing cancers... Zr-MSLN PET imaging reflected mesothelin expression and matched with Th-MSLN tumor uptake, biodistribution, and antitumor activity. Our data support the clinical exploration of Zr-MSLN PET imaging together with Th-MSLN therapy, both using the same antibody-chelator conjugate.

Anetumab ravtansine showed a manageable safety profile and was not superior to vinorelbine. Further studies are needed to define active treatments in relapsed mesothelin-expressing malignant pleural mesothelioma.

Histopathological analysis indicated that CD4+ and CD8+ MSLN CAR T cells infiltrated pancreatic tumor tissue and led to cancer cell eradication. Our results demonstrated the anti-tumor efficacy of MSLN CAR T cell therapy against pancreatic cancer, suggesting its therapeutic potential.

Most importantly, the expression of CSC markers was independent of MSLN expression, and manipulation of MSLN expression did not affect CSC markers. In conclusion, MSLN expression is not involved in driving the CSC phenotype.

Antibody single-chain variable region (scFv) sequences derived from amatuximab recognizing MSLN and from either blinatumomab or AMG330 targeting CD3 were used to engineer and express two MSLN/CD3-targeting BsAbs: MSLN AMA -CD3 L2K and MSLN AMA -CD3 AMG respectively...Chemotherapy (DA) consisted of 3 doses of 1.5 mg/kg daunorubicin iv and 5 doses of 50 mg/kg cytarabine ip...Conclusion These data validate the efficacy of MSLN-targeting BsAbs in PDX models with endogenous MSLN expression. Because prior MSLN-directed therapies appeared safe in humans, MSLN-targeting BsAbs could be ideal immunotherapies for MSLN-positive pediatric AML patients.

MSLN expression was equally distributed among different OC histologies, but in HGSOC conferred survival advantage. Moreover, its expression significantly decreased from primary to recurrent OC.

Several MSLN-targeted monoclonal antibodies, antibody-drug conjugates, immunotoxins, cancer vaccines, and cellular therapies have been tested in the clinical setting. The biological rationale underpinning MSLN-targeted immunotherapies and their potential to improve MPM patient outcomes are reviewed.

These findings shed the light on the pivotal dual immunoregulatory role HOTAIR and MALAT1 in BC.

In conclusion, our study revealed that early administration of amatuximab alone or in combination with GEM significantly suppressed the liver metastases of mesothelin-expressing pancreatic cancer cells. A phase II clinical trial of amatuximab as part of an adjuvant chemotherapy regimen for resected pancreatic cancer is expected.

TC-210 expansion and serum cytokine levels were serially measured. Seven patients (6 MPM, 1 ovarian) received a single gavo-cel intravenous infusion at the initial dose of 5x107/m2 either alone (dose level [DL] 0, n=1) or following lymphodepletion (LD) (DL1, n=6) with fludarabine (30mg/m2/day x4) and cyclophosphamide (600mg/m2/day x3)...Four patients had received ≥4 lines of therapy, including immune checkpoint inhibitors (n=5), the anti-mesothelin ADC anetumab ravtansine (n=1), and anti-mesothelin mRNA CAR-T (n=1)...CRS and pneumonitis events resolved with tocilizumab and corticosteroids... Intravenous systemic administration of gavo-cel was generally safe and resulted in three of seven patients having objective partial response. Dose escalation is ongoing at 1x108/m2. Updated clinical and translational data will be presented.

The studies confirm the great therapeutic potential of Anetumab ravtansine. However, a favorable treatment outcome requires strong Mesothelin expression in tumor cells. Future clinical trials may benefit from a more rigorous selection of appropriate patients based on the level of Mesothelin expression in their tumor tissue. If, in addition, it is possible to better control side effects by introducing protective measures and by doing so to increase the maximum tolerated dose, Anetumab ravtansine has the potency to become a valuable therapeutic tool, especially in the field of gynecological oncology.

EMD can be very challenging to treat, and in the setting of recurrence often indicates incurable disease, thus novel therapeutic strategies for this group of patients are urgently needed. Our findings support additional studies of how MSLN may be functionally implicated in the development of EMD as well as clinical trials that evaluate MSLN targeting in AML.

Conclusions Forced expression of CXCR6 in anti-mesothelin CAR T cells increased the accumulation of CAR T cells at the CXCL16-positive tumor site, resulting in improved survival of treated mice and in complete tumor rejection in the majority of cases. This data reveals the potential of CXCR6 to direct CAR T cells to the tumor site and this approach may therefore be an attractive strategy to target a major pitfall in the translation of CAR T cell therapy to solid tumors.

P1, N=18, Terminated, Janssen Research & Development, LLC | Trial completion date: Mar 2020 --> Oct 2018 | Active, not recruiting --> Terminated | Trial primary completion date: Mar 2020 --> Aug 2018; Development of JNJ-64041757 discontinued due to lack of efficacy. No further follow up data will be collected after October 22, 2018.

P1, N=18, Active, not recruiting, Janssen Research & Development, LLC | Recruiting --> Active, not recruiting | N=42 --> 18