^
    8d
    Tofacitinib to prevent anti-drug antibody formation against LMB-100 immunotoxin in patients with advanced mesothelin-expressing cancers. (PubMed, Front Oncol)
    Further testing of tofacitinib to prevent ADA formation is recommended in applicable non-malignant disease settings. https://www.clinicaltrials.gov/study/NCT04034238.
    Journal • Metastases
    |
    MSLN (Mesothelin) • TNFA (Tumor Necrosis Factor-Alpha) • IL10 (Interleukin 10)
    |
    MSLN expression
    |
    tofacitinib • LMB-100
    2ms
    LMB-100 Followed by Pembrolizumab in the Treatment of Adults With Mesothelin-Expressing Non-Squamous Non-Small Cell Lung Cancer (NSCLC) (clinicaltrials.gov)
    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.
    Trial completion date • Trial termination
    |
    EGFR (Epidermal growth factor receptor) • PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • MSLN (Mesothelin) • CTLA4 (Cytotoxic T-Lymphocyte Associated Protein 4)
    |
    KRAS mutation • EGFR mutation • MSLN expression
    |
    Keytruda (pembrolizumab) • LMB-100
    3ms
    Intratumor Injection of Anti-Mesothelin Immunotoxin LMB-100 With Ipilimumab in Malignant Mesothelioma (clinicaltrials.gov)
    P1, N=2, Terminated, National Cancer Institute (NCI) | Completed --> Terminated; Study was closed early due to slow accrual.
    Trial termination
    |
    Yervoy (ipilimumab) • LMB-100
    5ms
    Phase I Evaluation of Immunotoxin LMB-100 Administered by Normothermic, Intrapleural Perfusion Following Cytoreductive Surgery in Participants With Pleural Mesotheliomas, or Pleural Effusions From Cancers Expressing Mesothelin (clinicaltrials.gov)
    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
    Trial completion date • Trial primary completion date • Surgery
    |
    MSLN (Mesothelin)
    |
    MSLN expression • MSLN positive
    |
    LMB-100
    5ms
    Intratumor Injection of Anti-Mesothelin Immunotoxin LMB-100 With Ipilimumab in Malignant Mesothelioma (clinicaltrials.gov)
    P1, N=2, Completed, National Cancer Institute (NCI) | Recruiting --> Completed | N=20 --> 2
    Trial completion • Enrollment change
    |
    Yervoy (ipilimumab) • LMB-100
    10ms
    Mesothelin-Targeted Immunotoxin LMB-100 in Combination With Tofacitinib in Persons With Previously Treated Pancreatic Adenocarcinoma, Cholangiocarcinoma and Other Mesothelin Expressing Solid Tumors (clinicaltrials.gov)
    P1, N=19, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed
    Trial completion • Combination therapy
    |
    MSLN (Mesothelin)
    |
    MSLN expression
    |
    tofacitinib • LMB-100
    1year
    Phase I Evaluation of Immunotoxin LMB-100 Administered by Normothermic, Intrapleural Perfusion Following Cytoreductive Surgery in Participants With Pleural Mesotheliomas, or Pleural Effusions From Cancers Expressing Mesothelin (clinicaltrials.gov)
    P1, N=42, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting
    Enrollment open • Surgery
    |
    MSLN (Mesothelin)
    |
    MSLN expression • MSLN positive
    |
    LMB-100
    over1year
    Anti-mesothelin immunotoxin induces mesothelioma eradication, anti-tumor immunity, and the development of tertiary lymphoid structures. (PubMed, Proc Natl Acad Sci U S A)
    LMB-100 treatment upregulates genes associated with tertiary lymphoid structures (TLS) development and induces TLS formation in tumors. In sum, immunotoxin-mediated cell death induces anti-tumor immunity and the development of TLS, which provides insights into how immunotoxins cause tumor regressions.
    Journal
    |
    CD8 (cluster of differentiation 8) • MSLN (Mesothelin) • CD4 (CD4 Molecule)
    |
    MSLN expression
    |
    LMB-100
    over1year
    Systemic immune changes accompany combination treatment with immunotoxin LMB-100 and nab-paclitaxel. (PubMed, Cancer Med)
    In summary, LMB-100 treatment causes systemic immune activation. Inflammatory and immune changes that accompany drug associated CLS were characterized for the first time.
    Journal
    |
    CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma) • MSLN (Mesothelin) • CXCL8 (Chemokine (C-X-C motif) ligand 8) • HAVCR2 (Hepatitis A Virus Cellular Receptor 2) • CD4 (CD4 Molecule)
    |
    CXCL8 elevation
    |
    albumin-bound paclitaxel • LMB-100
    over1year
    LMB-100 Followed by Pembrolizumab in the Treatment of Adults With Mesothelin-Expressing Non-Squamous Non-Small Cell Lung Cancer (NSCLC) (clinicaltrials.gov)
    P2, N=6, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting | N=100 --> 6
    Enrollment closed • Enrollment change
    |
    EGFR (Epidermal growth factor receptor) • PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • MSLN (Mesothelin)
    |
    KRAS mutation • EGFR mutation • ALK rearrangement • MSLN expression
    |
    Keytruda (pembrolizumab) • LMB-100
    almost2years
    Phase I Evaluation of Immunotoxin LMB-100 Administered by Normothermic, Intrapleural Perfusion Following Cytoreductive Surgery in Participants With Pleural Mesotheliomas, or Pleural Effusions From Cancers Expressing Mesothelin (clinicaltrials.gov)
    P1, N=42, Not yet recruiting, National Cancer Institute (NCI)
    New P1 trial
    |
    MSLN (Mesothelin)
    |
    MSLN expression • MSLN positive
    |
    LMB-100
    over2years
    Mesothelin-Targeted Immunotoxin LMB-100 in Combination With Tofacitinib in Persons With Previously Treated Pancreatic Adenocarcinoma, Cholangiocarcinoma and Other Mesothelin Expressing Solid Tumors (clinicaltrials.gov)
    P1, N=16, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting | N=45 --> 16
    Enrollment closed • Enrollment change • Combination therapy
    |
    MSLN (Mesothelin)
    |
    MSLN expression
    |
    tofacitinib • LMB-100
    almost3years
    LMB-100 Followed by Pembrolizumab in the Treatment of Adults With Mesothelin-Expressing Non-Squamous Non-Small Cell Lung Cancer (NSCLC) (clinicaltrials.gov)
    P2, N=100, Recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2022 --> Mar 2024 | Trial primary completion date: Mar 2022 --> Apr 2023
    Clinical • Trial completion date • Trial primary completion date
    |
    EGFR (Epidermal growth factor receptor) • PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • MSLN (Mesothelin)
    |
    KRAS mutation • EGFR mutation • ALK rearrangement • MSLN expression
    |
    Keytruda (pembrolizumab) • LMB-100
    3years
    LMB-100 Followed by Pembrolizumab in the Treatment of Adults With Mesothelin-Expressing Non-Squamous Non-Small Cell Lung Cancer (NSCLC) (clinicaltrials.gov)
    P2, N=100, Recruiting, National Cancer Institute (NCI) | Trial primary completion date: Apr 2021 --> Mar 2022
    Clinical • Trial primary completion date
    |
    EGFR (Epidermal growth factor receptor) • PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • MSLN (Mesothelin)
    |
    KRAS mutation • EGFR mutation • ALK rearrangement • MSLN expression
    |
    Keytruda (pembrolizumab) • LMB-100
    3years
    [VIRTUAL] Phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with tofacitinib in patients with advanced pancreatobiliary cancer. (ASCO 2021)
    LMB-100 was unable to be co-administered safely with tofacitinib . ADA formation was prevented in 2 patients through 3 cycles, a rare occurrence.
    Clinical • P1 data • Combination therapy
    |
    MSLN (Mesothelin)
    |
    MSLN expression
    |
    tofacitinib • LMB-100
    over3years
    Mesothelin-Targeted Immunotoxin LMB-100 in People With Malignant Mesothelioma (clinicaltrials.gov)
    Active, not recruiting --> Completed | Trial completion date: Aug 2021 --> Jan 2021
    Clinical • Trial completion • Trial completion date
    |
    ALB (Albumin)
    |
    cisplatin • albumin-bound paclitaxel • LMB-100
    over3years
    [VIRTUAL] Phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with tofacitinib in persons with pancreatobiliary cancer or other mesothelin expressing solid tumors. (ASCO-GI 2021)
    Participants will receive tofacitinib 10 mg twice daily on days 1-10 and LMB-100 at 65, 100, or 140 mcg/kg on days 4, 6 and 8 of a 21-day cycle. The dose escalation phase has been completed and enrollment onto dose expansion phase is ongoing.
    P1 data • Combination therapy
    |
    MSLN (Mesothelin) • JAK1 (Janus Kinase 1)
    |
    MSLN expression
    |
    LMB-100
    over3years
    Phase 1 study of the immunotoxin LMB-100 in patients with mesothelioma and other solid tumors expressing mesothelin. (PubMed, Cancer)
    The MTD for single-agent LMB-100 was found to be 140 µg/kg given on a schedule of every other day for 3 doses every 3 weeks. Although less immunogenic than the first-generation antimesothelin immunotoxin SS1P, the majority of patients developed antidrug antibodies after 2 cycles, indicating that LMB-100 has limited antitumor efficacy as a single agent. Phase 2 studies of LMB-100 plus pembrolizumab currently are ongoing for patients with mesothelioma and lung cancer.
    Clinical • P1 data • Journal • PD(L)-1 Biomarker
    |
    MSLN (Mesothelin)
    |
    Keytruda (pembrolizumab) • LMB-100 • SS1(dsFv)-PE38
    almost4years
    Immunogenicity of Immunotoxins Containing Pseudomonas Exotoxin A: Causes, Consequences, and Mitigation. (PubMed, Front Immunol)
    Moxetumomab Pasudotox (Lumoxiti) contains an anti-CD22 Fv and a 38 kDa portion of PE...LMB-100 is a de-immunized variant of the toxin with a humanized antibody that targets mesothelin and a PE toxin that was rationally designed for diminished reactivity with antibodies and B cell receptors...Here we review the immunogenicity of the original and de-immunized PE immunotoxins in mice and patients, the development of anti-drug antibodies (ADAs), their impact on drug availability and their effect on clinical efficacy. Efforts to mitigate the immunogenicity of immunotoxins and its impact on immunogenicity will be described including rational design to identify, remove, or suppress B cell or T cell epitopes, and combination of immunotoxins with immune modulating drugs.
    Review • Journal
    |
    MSLN (Mesothelin)
    |
    Lumoxiti (moxetumomab pasudotox) • LMB-100
    almost4years
    Mesothelin-Targeted Recombinant Immunotoxins for Solid Tumors. (PubMed, Biomolecules)
    This has led to multiple clinical trials, testing the safety and efficacy of the clinical leads SS1P and LMB-100. This review summarizes existing pre-clinical and clinical data on MSLN-targeted iTox's. In addition, we address the potential future directions of research to enhance the activity of these anti-tumor agents.
    Review • Journal
    |
    MSLN (Mesothelin)
    |
    LMB-100 • SS1(dsFv)-PE38
    almost4years
    Enhanced efficacy of mesothelin-targeted immunotoxin LMB-100 and anti-PD-1 antibody in patients with mesothelioma and mouse tumor models. (PubMed, Sci Transl Med)
    The overall objective tumor response in the 10 patients who received PD-1 inhibitor (pembrolizumab, 9; nivolumab, 1) after progression on LMB-100 was 40%, and the median overall survival was 11.9 months. The enhanced antitumor effects with LMB-100 plus anti-PD-1 antibody were also observed in a human peripheral blood mononuclear cell-engrafted mesothelioma mouse model and a human mesothelin-expressing syngeneic lung adenocarcinoma mouse model. LMB-100 plus pembrolizumab is now being evaluated in a prospective clinical trial for patients with mesothelioma.
    Journal • PD(L)-1 Biomarker
    |
    PD-L1 (Programmed death ligand 1) • CD8 (cluster of differentiation 8) • MSLN (Mesothelin)
    |
    PD-L1 expression
    |
    Keytruda (pembrolizumab) • Opdivo (nivolumab) • LMB-100
    4years
    [VIRTUAL] Phase I study of mesothelin-targeted immunotoxin LMB-100 given as a long infusion with or without nab-paclitaxel. (ASCO 2020)
    Long infusion format LMB-100 is generally well tolerated but immunogenicity limits treatment to 1 effective cycle. No anti-tumor efficacy of the single agent was observed. Research Funding: U.S. National Institutes of Health
    P1 data
    |
    IL6 (Interleukin 6) • MSLN (Mesothelin)
    |
    albumin-bound paclitaxel • LMB-100