Details

Autor(en) / Beteiligte

• Pegna, Guillaume Joe
• Lee, Min‐Jung
• Peer, Cody J.
• Ahmad, Mehwish I.
• Venzon, David J.
• Yu, Yunkai
• Yuno, Akira
• Steinberg, Seth M.
• Cao, Liang
• Figg, William D.
• Donahue, Renee N.
• Hassan, Raffit
• Pastan, Ira
• Trepel, Jane B.
• Alewine, Christine

Titel

Systemic immune changes accompany combination treatment with immunotoxin LMB‐100 and nab‐paclitaxel

Ist Teil von

• Cancer medicine (Malden, MA), 2023-02, Vol.12 (4), p.4236-4249

Ort / Verlag

United States: John Wiley & Sons, Inc

Erscheinungsjahr

2023

Link zum Volltext

Quelle

Wiley Online Library All Journals

Beschreibungen/Notizen

• 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. LMB‐100 is an immunotoxin directed against mesothelin, a surface protein expressed by over 85% of pancreatic adenocarcinomas as well as an estimated 30% of all solid tumors. Immunotoxin therapies, while potentially promising, are limited by their side effect profiles, most notably capillary leak syndrome (CLS). This study provides the most detailed assessment to date of the systemic immune and inflammatory changes occurring in patients following LMB‐100 treatment and identifies those specific to patients who develop CLS. These findings illuminate the systemic effects of immunotoxin treatment in patients and could ultimately lay the groundwork for new combinations capable of harnessing the immune activating effects of immunotoxin therapy while avoiding dangerous toxicities such as CLS.