MSLN positive

P2, N=96, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2024 --> Oct 2025 | Trial primary completion date: Oct 2024 --> Oct 2025

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.

P1/2, N=20, Recruiting, Xinqiao Hospital of Chongqing | Suspended --> Recruiting

P1/2, N=20, Suspended, Xinqiao Hospital of Chongqing | Recruiting --> Suspended

IL12R54 also upregulated CXCR6 expression in the T cells through the NF-κB pathway, which facilitated T cell infiltration and persistence in the tumor tissues. In summary, the studies provide a good therapeutic option for the clinical treatment of solid tumors.

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.

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

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

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

P1/2, N=82, Recruiting, RemeGen Co., Ltd. | Not yet recruiting --> Recruiting | Initiation date: Apr 2023 --> Jul 2023

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.

CAR-UNKT cells also demonstrated strong antitumor activity in mouse models of ovarian cancer, with the ability to migrate and infiltrate the tumor without inducing immune memory. The fast-in and -out, enhanced and prolonged tumor killing properties of CAR-UNKT suggested a novel cure option of cellular immunotherapy in the treatment of MSLN-positive solid tumors.

MSLN expression is widely observed in gynecological carcinosarcomas. Moreover, high-MSLN expression is a favorable prognostic factor for UCS. MSLN could be a promising therapeutic target for UCS, even in the era of anti-HER2 therapy.

Contrary to the conclusions of prior studies with MSLN-targeted CARs, membrane distal epitopes were superior to membrane proximal epitopes when binders were paired with the correct spacer, and shed MSLN and MUC16 were not inhibitory for the best-performing CARs, regardless of target epitope. Furthermore, regulated expression enhanced the potency and durability of response compared to constitutive expression. This approach may improve CAR activity in patients with MSLN+ solid tumors or leukemia.

Our results suggest that irinotecan can enhance the antitumor activity of MSLN-targeted CAR T cells, and offer a promising combination therapy strategy for MSLN-positive solid tumors.

P2, N=96, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2023 --> Oct 2024 | Trial primary completion date: Oct 2023 --> Oct 2024

P=N/A, N=371, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Sep 2023 --> Sep 2024 | Trial primary completion date: Sep 2023 --> Sep 2024

The X-ray crystal structure of full-length MSLN in complex with 3C9 reveals interaction of the 3C9 domains with two distinctive residue patches on the MSLN surface. This newly discovered VH antibody domain has a high potential as a therapeutic candidate for MSLN-expressing cancers.

P1/2, N=74, Active, not recruiting, National Cancer Institute (NCI) | Phase classification: P1 --> P1/2

These data support further clinical development of SynKIR-110 in patients with advanced solid tumors. SynKIR-110 is currently being investigated in a Phase I clinical trial STAR-101 (NCT05568680).

P1, N=11, Completed, Amgen | Active, not recruiting --> Completed | Trial completion date: Sep 2023 --> Jun 2023

Paclitaxel (PTX)-based chemotherapy remains the main approach to treating lung cancer but systemic toxicity limits its use...Furthermore, Lip-CExo@PTX prolonged the survival time of tumor-bearing mice in a CT-26 metastatic lung cancer model. Therefore, Lip-CExo@PTX may deliver PTX to tumor cells through sequential targeted delivery and enhance the antitumor effects, providing a promising strategy for immunochemotherapy of lung cancer.

P1, N=74, Active, not recruiting, National Cancer Institute (NCI) | Phase classification: P1/2 --> P1

P1, N=11, Active, not recruiting, Amgen | Trial completion date: Aug 2024 --> Sep 2023 | Trial primary completion date: Feb 2024 --> Jun 2023

Moreover, NAV-003 demonstrated good tolerability in mice and efficacy against patient-derived mesothelioma xenografts co-engrafted with human peripheral blood mononuclear cells. Together these data support the potential for NAV-003 clinical development and human proof-of-concept studies in patients with MSLN-expressing cancers.

MSLN expression was more heterogenous in epithelioid mesothelioma than reported previously. Therefore, it would be appropriate to perform an immunohistochemical assessment of MSLN expression to stratify and assess patient suitability for mesothelin-targeted personalised therapies, such as chimeric antigen receptor T cells.

P1/2, N=82, Not yet recruiting, RemeGen Co., Ltd.

It was found that 7×19 CAR-T cells showed enhanced antitumor potential by the maintenance of their effector functions. These data support the foresight of this therapy as a treatment option for patients with mesothelin-positive renal cell carcinoma.

P1, N=30, Recruiting, Second Affiliated Hospital of Guangzhou Medical University

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.

This study constitutes a first attempt to establish an immunocompetent pre-clinical model for the study of mesothelin-targeting, nanobody-based CAR T cells in unprimed hosts. This model will facilitate the study of the dynamic changes occurring in the tumor microenvironment following nanobody-based CAR T cell therapy while also providing valuable insight into the tumor resistance mechanisms and methods to overcome them.

P1, N=42, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

P1/2, N=74, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

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.

P1, N=12, Not yet recruiting, First Affiliated Hospital of Shantou University Medical College

MSLN was highly expressed in patients with cervical cancer, especially in those with non-SCC. High MSLN expression in the primary lesion was significantly associated with poor OS, and its expression was maintained in metastatic lesions. Our findings indicate that MSLN may be an attractive therapeutic target for cervical cancer.