Background MUM-LM are resistant to ICIs for several reasons including the prevalence of myeloid-derived suppressor cells (MDSCs). PFS has been limited, even with approved therapies such as tebentafusp (median 3.3 months) with grade 3/4 AE rates typically >30%. TLR9 agonists are capable of MDSC polarization but drug delivery has historically been limited using an intra-tumoral approach. Pressure-enabled drug delivery (PEDDTM) of SD-101, a TLR9 agonist, has the potential to overcome these barriers to improve outcomes.
Methods PERIO-01 is a phase 1 trial of hepatic arterial SD-101 via PEDD in MUM-LM (NCT04935229), with dose-escalation cohorts as monotherapy (Cohort A), with nivolumab (Cohort B), or nivolumab + ipilimumab (Cohort C). SD-101 is delivered over 2 outpatient cycles, with 3 weekly doses/cycle.
Results 53 patients received at least one dose of SD-101: 13 in Cohort A, 25 in Cohort B, and 15 in Cohort C. Median age was 65 and 45% were female. 70% received prior MUM-LM treatment, and 8 (15%) received tebentafusp. Fifteen participants (28%) had LM >5cm and 18 (44%) had >10 LMs. One patient experienced partial response (Cohort B 4 mg) that is ongoing at 258 days. Six additional patients had decreases in target lesion size (SD), 3 ongoing at a median follow-up of 168 days. Across dose levels, median PFS was highest in Cohort B (2 mg) at 11.7 months, and disease control rate of 86% (6/7 SD). Serious grade 3/4 treatment-related AEs (TRAEs) to SD-101 or ICI were documented in 8% of subjects: 0% in Cohort A, 4% in Cohort B, and 20% in Cohort C, with an overall Grade 3/4 TRAE rate of 21%. PEDD of SD-101 resulted in reductions in LM monocytic MDSC (mMDSC) by immunofluorescence, along with decreased expression of ARG1, CD163, and FASN. We also observed evidence of immune activation in LM with increased CD4+ and CD8+ T cells, decreased Treg, and increased IFNg and IFNa2 gene expression. These were associated with evidence of systemic immune activation peripherally characterized by increased proliferating CD8+ T and NK cells, and increased IP-10, TNFa, IFNg, IL-2R, and IL-18. Among 25 patients with evaluable ctDNA data, 68% had a decrease relative to peak, with complete clearance in 28%.
Conclusions Delivery of SD-101 by PEDD plus systemic ICI in MUM-LM patients results in clinical activity with median PFS of 11.7 months, MDSC re-programming, and evidence of peripheral and intra-tumoral immune activation. Phase 2 of PERIO-01 is planned for expansion of the optimal dose.
Trial Registration NCT04935229
Ethics Approval The study was IRB approved at all sites and participants signed written informed consent
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