Immune checkpoint inhibitor (ICI) therapy has demonstrated limited survival advantages in patients with advanced hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Nelitolimod (SD-101), a class C toll-like receptor 9 (TLR9 agonist), reduces myeloid-derived suppressor cells (MDSCs) while broadly activating the tumor microenvironment. Due to safety concerns with intravenous infusion and limitations in the distribution of needle injection, hepatic arterial infusion (HAI) of nelitolimod with Pressure-Enabled Drug Delivery to improve ICI responsiveness was investigated in the phase 1b regional immuno-oncology trial, PERIO-02, presented at ASCO 2024.
PERIO-02 is an open-label, phase 1 trial of nelitolimod given by HAI in patients with advanced HCC or iCCA (NCT05220722). Nelitolimod was administered in escalating doses in 3 different cohorts: without ICI in cohort A, with pembrolizumab in cohort B, and with nivolumab plus ipilimumab in cohort C. Nelitolimod was delivered over 2 cycles, with 3 weekly doses per cycle. The primary objective of the study included determining the optimal dosage and ensuring safety of the treatment. Blood, liver tumor, and normal liver biopsies were used for immune monitoring.
A total of 23 patients were administered at least 1 dose of nelitolimod with 70% having iCCA and 30% having HCC. No patients were treatment-naïve, whereas 4 had received 1 line of therapy (1L; 17%), 5 had received 2 lines of therapy (2L; 22%), and 14 had received ≥3 lines of therapy (>3L; 61%). Approximately 26% of the patients had >10 liver tumors. Three (13%) patients experienced serious adverse events related to treatment, with 1 patient experiencing a dose-limiting toxicity. The most common adverse events among all cohorts were fever (n=5; 22%), abdominal pain (n=6; 26%), decrease in appetite (n=2; 9%), chills (n=3; 13%), and fatigue (n=3; 13%). Within cohort B, 1 of 4 of the evaluable patients achieved stable disease as their best on-treatment response, whereas the rest experienced progressive disease according to RECIST v1.1 criteria. In cohort C, at a 4-mg dose of nelitolimod, all 3 patients achieved disease control, with 1 complete response in the liver (5L iCCA), 1 with partial response, and 1 with stable disease. Reductions in the size of the target liver lesion (from 31.3 to 17.5 mm), non-target liver lesion, and extrahepatic lymph nodes were observed in 1 patient on days 53 and 84, with complete response in the target liver lesions and stability in extrahepatic nodal lesions reported on day 154. The median progression-free survival in the cohort C 4-mg dose level exceeds 120 days. The median overall survival for this group has not yet been reached, with a range of 120 to 170 days. Immune effects observed in cohort C 4-mg patients included elevated levels of liver tumor CD4 and CD8 T cells, as well as an increase in the CD8 T cell:MDSC ratio. Gene expression alterations in cohort C 4-mg patients indicated enhanced Th1 programming in tumor tissue, accompanied by heightened Th1, interferon, granzyme A, and CXCL 10 activation signals in the surrounding normal liver. Changes in blood immune cells comprised increased expression of CXCL10 and IL2-R, whereas IL17A, IDO, and NT5E (CD73) levels decreased.
The HAI treatment with nelitolimod has been well tolerated and has shown encouraging immunologic activity in HCC and iCCA. The clinical and biologic activity observed in cohort C at 4 mg provides support for further enrollment in this cohort.
Lee SS, Almhanna K, Sheth R, et al. PERIO-02: phase 1b pressure enabled regional immuno-oncology trial of nelitolimod (SD-101), a class C TLR9 agonist, delivered via hepatic artery infusion +/- checkpoint inhibition in intrahepatic cholangiocarcinoma and hepatocellular carcinoma. Chicago, IL, & online: presented at 2024 ASCO Annual Meeting; abstract 4622.
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