LMB-100

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

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

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

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

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

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.

In summary, LMB-100 treatment causes systemic immune activation. Inflammatory and immune changes that accompany drug associated CLS were characterized for the first time.

P2, N=6, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting | N=100 --> 6

P1, N=42, Not yet recruiting, National Cancer Institute (NCI)

P1, N=16, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting | N=45 --> 16

P2, N=100, Recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2022 --> Mar 2024 | Trial primary completion date: Mar 2022 --> Apr 2023

P2, N=100, Recruiting, National Cancer Institute (NCI) | Trial primary completion date: Apr 2021 --> Mar 2022

LMB-100 was unable to be co-administered safely with tofacitinib . ADA formation was prevented in 2 patients through 3 cycles, a rare occurrence.

Active, not recruiting --> Completed | Trial completion date: Aug 2021 --> Jan 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.

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.

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.

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.

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.

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