biostudies-literatureUnknown12(4)Pegna GJLMB-100 is a novel immune-conjugate (immunotoxin) that targets mesothelin. A phase 1/2 clinical trial was conducted (NCT02810418) with primary objectives assessing the safety and efficacy of LMB-100 ± nab-paclitaxel. Participant blood samples were analyzed for changes in serum cytokines and circulating immune cell subsets associated with response or toxicity. On Arm A, participants (n = 20) received standard 30-minute LMB-100 infusion with nab-paclitaxel. Although clinical efficacy was observed, the combination caused intolerable capillary leak syndrome (CLS), a major toxicity of unclear etiology that affects many immunotoxin drugs. Participants developing CLS experienced rapid elevations in IFNγ and IL-8 compared to those without significant CLS, along with midcycle increases in Ki-67- CD4 T cells that were CD38, HLA-DR, or TIM3 positive. Additionally, a strong increase in activated CD4 and CD8 T cells and a concurrent decrease in Tregs were seen in the single Arm A patient achieving a partial response. In Arm B, administration of single agent LMB-100 to participants (n = 20) as a long infusion given over 24-48 h was investigated based on pre-clinical data that this format could reduce CLS. An optimal dose and schedule of long infusion LMB-100 were identified, but no clinical efficacy was observed even in patients receiving LMB-100 in combination with nab-paclitaxel. Despite this, both Arm A and B participants experienced increases in specific subsets of proliferating CD4 and CD8 T cells following Cycle 1 treatment. In summary, LMB-100 treatment causes systemic immune activation. Inflammatory and immune changes that accompany drug associated CLS were characterized for the first time.Cancer medicine4236-4249https://www.ebi.ac.uk/biostudies/studies/S-EPMC9972172biostudies-literatureSystemic immune changes accompany combination treatment with immunotoxin LMB-100 and nab-paclitaxel.PMC9972172Cao LPastan IDonahue RNAlewine CTrepel JBHassan RPeer CJAhmad MISteinberg SMPegna GJFigg WDVenzon DJYuno ALee MJYu YfalseSystemic immune changes accompany combination treatment with immunotoxin LMB-100 and nab-paclitaxel.LMB-100 is a novel immune-conjugate (immunotoxin) that targets mesothelin. A phase 1/2 clinical trial was conducted (NCT02810418) with primary objectives assessing the safety and efficacy of LMB-100 ± nab-paclitaxel. Participant blood samples were analyzed for changes in serum cytokines and circulating immune cell subsets associated with response or toxicity. On Arm A, participants (n = 20) received standard 30-minute LMB-100 infusion with nab-paclitaxel. Although clinical efficacy was observed, the combination caused intolerable capillary leak syndrome (CLS), a major toxicity of unclear etiology that affects many immunotoxin drugs. Participants developing CLS experienced rapid elevations in IFNγ and IL-8 compared to those without significant CLS, along with midcycle increases in Ki-67- CD4 T cells that were CD38, HLA-DR, or TIM3 positive. Additionally, a strong increase in activated CD4 and CD8 T cells and a concurrent decrease in Tregs were seen in the single Arm A patient achieving a partial response. In Arm B, administration of single agent LMB-100 to participants (n = 20) as a long infusion given over 24-48 h was investigated based on pre-clinical data that this format could reduce CLS. An optimal dose and schedule of long infusion LMB-100 were identified, but no clinical efficacy was observed even in patients receiving LMB-100 in combination with nab-paclitaxel. Despite this, both Arm A and B participants experienced increases in specific subsets of proliferating CD4 and CD8 T cells following Cycle 1 treatment. In summary, LMB-100 treatment causes systemic immune activation. Inflammatory and immune changes that accompany drug associated CLS were characterized for the first time.2023-01-01T00:00:00Z2023 Feb2026-05-28T08:10:54.506Z2025-04-21T13:40:25.066ZS-EPMC99721723620801710.1002/cam4.5290