Tofacitinib to prevent anti-drug antibody formation against LMB-100 immunotoxin in patients with advanced mesothelin-expressing cancers

Nebojsa Skorupan; Cody J Peer; Xianyu Zhang; Hyoyoung Choo-Wosoba; Mehwish I Ahmad; Min-Jung Lee; Shraddha Rastogi; Nahoko Sato; Yunkai Yu; Guillaume Joe Pegna; Seth M Steinberg; Shelley S Kalsi; Liang Cao; William D Figg; Jane B Trepel; Ira Pastan; David FitzGerald; Christine Alewine

doi:10.3389/fonc.2024.1386190

Tofacitinib to prevent anti-drug antibody formation against LMB-100 immunotoxin in patients with advanced mesothelin-expressing cancers

Front Oncol. 2024 Apr 19:14:1386190. doi: 10.3389/fonc.2024.1386190. eCollection 2024.

Authors

Nebojsa Skorupan¹, Cody J Peer², Xianyu Zhang¹, Hyoyoung Choo-Wosoba³, Mehwish I Ahmad⁴, Min-Jung Lee⁵, Shraddha Rastogi⁵, Nahoko Sato⁵, Yunkai Yu⁶, Guillaume Joe Pegna⁷, Seth M Steinberg³, Shelley S Kalsi⁸, Liang Cao⁶, William D Figg², Jane B Trepel⁵, Ira Pastan¹, David FitzGerald¹, Christine Alewine¹

Affiliations

¹ Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
² Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
³ Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
⁴ Office of Research Nursing, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
⁵ Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
⁶ Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
⁷ Medical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
⁸ Hematology Consult and Graduate Medical Section, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, United States.

Abstract

Background: LMB-100 is a mesothelin (MSLN)-targeting recombinant immunotoxin (iTox) carrying a Pseudomonas exotoxin A payload that has shown promise against solid tumors, however, efficacy is limited by the development of neutralizing anti-drug antibodies (ADAs). Tofacitinib is an oral Janus Kinase (JAK) inhibitor that prevented ADA formation against iTox in preclinical studies.

Methods: A phase 1 trial testing LMB-100 and tofacitinib in patients with MSLN-expressing cancers (pancreatic adenocarcinoma, n=13; cholangiocarcinoma, n=1; appendiceal carcinoma, n=1; cystadenocarcinoma, n=1) was performed to assess safety and to determine if tofacitinib impacted ADA formation. Participants were treated for up to 3 cycles with LMB-100 as a 30-minute infusion on days 4, 6, and 8 at two dose levels (100 and 140 µg/kg) while oral tofacitinib was administered for the first 10 days of the cycle (10 mg BID). Peripheral blood was collected for analysis of ADA levels, serum cytokines and circulating immune subsets.

Results: The study was closed early due to occurrence of drug-induced pericarditis in 2 patients. Pericarditis with the combination was not reproducible in a transgenic murine model containing human MSLN. Two of 4 patients receiving all 3 cycles of treatment maintained effective LMB-100 levels, an unusual occurrence. Sustained increases in systemic IL-10 and TNF-α were seen, a phenomenon not observed in prior LMB-100 studies. A decrease in activated T cell subsets and an increase in circulating immunosuppressive myeloid populations occurred. No radiologic decreases in tumor volume were observed.

Discussion: Further testing of tofacitinib to prevent ADA formation is recommended in applicable non-malignant disease settings.

Clinical trial registration: https://www.clinicaltrials.gov/study/NCT04034238.

Keywords: JAK inhibition; anti-drug antibodies; immunotoxin; mesothelin; pericarditis.

Associated data

ClinicalTrials.gov/NCT04034238

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was also supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (Project No.’s ZIA BC, 011652 to CA, and ZIC SC, 006537 to WF).