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.

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

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

P1, N=160, Recruiting, Zymeworks BC Inc. | Not yet recruiting --> Recruiting

P1, N=12, Recruiting, Shantou University Medical College | Not yet recruiting --> Recruiting

P1, N=260, Recruiting, Amgen | Trial completion date: Jan 2027 --> Aug 2027 | Trial primary completion date: May 2026 --> Dec 2026

P1, N=160, Not yet recruiting, Zymeworks BC Inc.

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

P1, N=40, Recruiting, Second Affiliated Hospital of Guangzhou Medical University | Trial primary completion date: Dec 2025 --> Dec 2029

P1, N=95, Completed, Harpoon Therapeutics | Phase classification: P1/2 --> P1

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

P2, N=17, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Recruiting --> Active, not recruiting | Trial completion date: Dec 2024 --> Apr 2025 | Trial primary completion date: Dec 2024 --> Apr 2024

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, N=260, Recruiting, Amgen | Trial completion date: Oct 2026 --> Jan 2027 | Trial primary completion date: Feb 2026 --> May 2026

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

P1, N=260, Recruiting, Amgen | Trial primary completion date: Apr 2025 --> Feb 2026

P1, N=2, Terminated, National Cancer Institute (NCI) | Completed --> Terminated; Study was closed early due to slow accrual.

P1, N=120, Recruiting, Janssen Research & Development, LLC

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

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

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.

P1, N=2, Completed, National Cancer Institute (NCI) | Recruiting --> Completed | N=20 --> 2

Moreover, HK013-G1 is well tolerated in cynomolgus monkeys. These results show that this bsAb has the potential to develop into a new clinical therapy for cancer types with high-level MSLN expression.

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

In the MSLN-expressing ST206B ovarian cancer patient-derived xenograft model, MSLN-TTC accumulated specifically in the tumor, which combined with pegylated liposomal doxorubicin (Doxil), docetaxel, bevacizumab, or regorafenib treatment induced additive-to-synergistic antitumor efficacy and substantially increased response rates compared with respective monotherapies. The combination treatments were well tolerated and only transient decreases in white and red blood cells were observed. In summary, we demonstrate that MSLN-TTC treatment shows efficacy in p-gp-expressing models of chemoresistance and has combination potential with chemo- and antiangiogenic therapies.

In 30 evaluable patients, the overall response rate and disease control rate were 20% (13% confirmed) and 77%, respectively, and the 6-month overall survival rate was 70%. Gavo-cel warrants further study in patients with mesothelin-expressing cancers given its encouraging anti-tumor activity, but it may have a narrow therapeutic window.

P1, N=19, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed

In xenograft models, NM28-2746 exhibited significant tumor suppressing activity, which was significantly enhanced by combination therapy with NM21-1480. NM28-2746, alone or in combination with NM21-1480, may overcome shortcomings of previous MSLN-targeted immuno-oncology drugs, exhibiting enhanced discrimination of high MSLN-expressing cell activity in the presence of sMSLN.

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

P1, N=12, Not yet recruiting, Shantou University Medical College

P1/2, N=95, Completed, Harpoon Therapeutics | Active, not recruiting --> Completed | N=200 --> 95 | Trial completion date: May 2023 --> Jan 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.

A single IV gavo-cel infusion at the RP2D was associated with a manageable toxicity profile and high rates of disease control, including objective responses in pts with refractory MPM and OvC. A phase 2 study is underway testing the safety and efficacy of gavo-cel in combination with checkpoint inhibitors in pts with mesothelin-expressing solid tumors. Clinical trial information: NCT03907852.

Importantly, TriKE triggered NK cell responses from patients at all stages of disease and treatment, suggesting TriKE can enhance current therapies. These pre-clinical studies suggest mesothelin-targeted TriKE has the potential to overcome the immunosuppressive environment of NSCLC to treat disease.

We developed a fusion protein (GrB-Fc-SD1) composed of human GrB and containing SD1, a novel human single-domain antibody that uniquely targets Region III of the glycoprotein, mesothelin...In addition, screening of an expanded panel of tumor cell lines for in vitro cytotoxicity is currently in progress and will be reported. In vivo efficacy studies against nude mice bearing Capan-2 xenograft models are currently underway and will also be reported.

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.

These data highlight TC-210 T cells as a promising cell therapy for treating MSLN-expressing cancers. The differentiated profile from CAR-T cells may translate into better efficacy and safety of TRuC-T cells for solid tumors.