A clinical study following phase I/IIa trial of STNM01 to investigate the overall survival and tumor microenvironment in patients with unresectable pancreatic cancer.
Authors: Tsuchiya Takayoshi , Fujisawa Toshio , Kato Motohiko , Mizuide Masafumi , Torisu Yuichi , Nishimura Makoto , Kurosawa Takashi , Tomishima Ko , Kutsumi Hiromu , Matsuda Yoko , Arai Tomio , Saya Hideyuki , Ryozawa Shomei , Isayama Hiroyuki , Itoi Takao , Yahagi Naohisa 
Published: June 2022

4144 Background: Carbohydrate sulfotransferase 15 (CHST15) is a proteoglycan biosynthetic enzyme and responsible for tumor matrix remodeling. We reported last year the top-line clinical results of Phase I/IIa (PI/IIa) trial of STNM01, a synthetic RNA oligonucleotide to CHST15, as a second-line (2L) therapy in patients with progressive, unresectable pancreatic ductal adenocarcinoma (PDAC). Here we report the final PI/IIa results and follow-up clinical results investigating the changes of tumor microenvironmental parameters and the correlation with overall survival (OS). Methods: An additional clinical study was followed by PI/IIa trial (jRCT2031190055), which was a multicenter, open-label study of locoregional injections with STNM01 three times at 2 week-interval in 4 weeks as one cycle. A total of 3 cycles were repeated at maximum in combination with systemic 2L chemotherapy, oral fluoropyrimidine S-1 in the PI/IIa trial. The primary objective of this additional clinical study was OS. The secondary objectives were relations of tumor microenvironmental parameters evaluated by immunohistochemistry with OS. For comparison analyses, two-tailed unpaired t-test was performed. For correlation analyses, the Pearson coefficient analyses were performed. Results: A total of 22 patients were enrolled in the study. The average number of tumor-infiltrating CD3+ (13.8/mm2) and CD8+ T cells (8.0/mm2) at baseline in the evaluable population (n = 20) was at most one tenth or less, compared to historical data, indicating 2L population contained more T cell-immune suppressive patients. Baseline CD3+ and CD8+ T cells negatively correlated with tumoral CHST15 expression (p = 0.0051, p = 0.0478, respectively). As the final PI/IIa results, the median OS was 7.8 months with 6 and 12 months-survival rates of 68.2% and 31.8%, respectively. Disease control rate was 76.2% including 1 complete response. STNM01 led to a significant reduction in CHST15 at the end of cycle 1 compared to baseline (p = 0.0095, n = 19), and this was associated with increased CD3+ (p = 0.0331) and CD8+ T cells (p = 0.0146) and reduced CD33+ myeloid-derived suppressor cells (MDSCs) (p = 0.0281) in the tumor. Patient subpopulation who survived over 1 year (n = 5) showed a significant fold increase of CD3+ (p = 0.0033) and CD8+ T cells (p = 0.0147) and decrease of CD33+ MDSCs (p = 0.0403) at the end of cycle 1 compared to another subpopulation who survived less than 1 year (n = 13-14). Higher fold increase of CD3+ T cells (p = 0.0035, n = 19) or fold decrease of CD33+ MDSCs (p = 0.0212, n = 15) at the end of cycle 1 significantly correlated with longer OS. Conclusions: Locoregional injection of STNM01 was able to reactivate and augment tumor-infiltrating T cells while repress MDSCs. These changes in tumor immune cell profiles correlate with prolong prognosis in patients with first-line refractory, unresectable PDAC. Clinical trial information: jRCT2031190055.