Analysis of systemic immune changes in patients with advanced cancer treated with immunotoxin LMB-100 and tofacitinib.

Abstract

e15017 Background: LMB-100 recombinant immunotoxin delivers a modified Pseudomonas exotoxin A payload to mesothelin-expressing tumors. Almost all patients receiving LMB-100 develop anti-drug antibodies (ADAs) after 2 cycles/ 6 doses of the drug, therefore reducing peak serum drug concentrations to near the lower limit of detection. Tofacitinib is an oral JAK inhibitor that had been shown to prevent ADA formation in pre-clinical studies. Apart from assessing safety and tolerability, this trial sought to determine whether co-administration of tofacitinib with LMB-100 delays the formation of neutralizing ADAs so more patients could achieve the peak LMB-100 concentration of > 600 ng/mL during treatment cycle 2. Correlative data examining circulating immune cell subsets and cytokines pre- and on-treatment are presented here. Methods: Patients with pancreatic adenocarcinoma (n = 13) and other mesothelin-expressing solid tumors (n = 3; cholangiocarcinoma, appendix, cystadenocarcinoma) were treated for up to 3 cycles (21 days) with LMB-100 given on days 4, 6, and 8 at 2 dose levels (100 and 140 mcg/kg), accompanied by oral tofacitinib for the first 10 days of the cycle (10 mg BID). Adverse events were assessed as per CTCAE 5.0. Analysis of the cytokine data was performed using a Wilcoxon signed-rank test. Results: DLTs of grade 3 cardiac toxicity (n = 1) and grade 4 hyponatremia (n = 1) were seen at the 140mcg/kg dose of LMB-100. One patient treated at 100 mcg/kg developed a grade 4 pericardial effusion, resulting in early closure of the study for safety. The two patients who experienced cardiac toxicity had lower baseline CD4+ cells and increased CD19+ cells post-LMB-100 treatment. Four out of 8 evaluable patients achieved LMB-100 concentration above the threshold during cycle 2, and 2 out of 3 did so during cycle 3. Analysis of peripheral blood cytokine levels showed sustained increases in TNF-α, IL-8, and IL-10 following LMB-100 administration through to the start of cycle 2. Percentage of Tregs increased through cycle 1 in patients who developed drug-neutralizing ADAs and was significantly higher than in patients with LMB-100 levels above threshold at the start of cycle 2. Conclusions: Combination of LMB-100 with tofacitinib is not safe. An insufficient number of patients was treated to conclusively assess the ability of tofacitinib to stop or delay ADA formation. Increases in circulating Tregs were observed in patients with early neutralizing ADA formation. Clinical trial information: NCT04034238 .