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LOCOREGIONAL INJECTION OF THE RNA OLIGONUCLEOTIDE TARGETING CARBOHYDRATE SULFOTRANSFERASE 15 IS ABLE TO ACCELERATE TUMOR-INFILTRATING T CELLS IN PATIENTS WITH UNRESECTABLE PANCREATIC CANCER, REFRACTORY TO FIRST-LINE CHEMOTHERAPY
DDW ePoster Library. Tanisaka Y. 05/21/22; 352839; EP1146
Dr. Yuki Tanisaka
Dr. Yuki Tanisaka
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Number: EP1146
LOCOREGIONAL INJECTION OF THE RNA OLIGONUCLEOTIDE TARGETING CARBOHYDRATE SULFOTRANSFERASE 15 IS ABLE TO ACCELERATE TUMOR-INFILTRATING T CELLS IN PATIENTS WITH UNRESECTABLE PANCREATIC CANCER, REFRACTORY TO FIRST-LINE CHEMOTHERAPY

Society: AGA
Track: Pancreatic Diseases

Author(s): Yuki Tanisaka1, Toshio Fujisawa2, Takayoshi Tsuchiya3, Motohiko Kato4, Yuichi Torisu5, Makoto Nishimura6, Hiromu Kutsumi7, Yoko Matsuda8, Tomio Arai9, Hidyuki Saya4, Masafumi Mizuide1, Yusuke Takasaki2, Yoshiya Yamauchi3, Shigeo Koido5, Shomei Ryozawa1, Takao Itoi3, Hiroyuki Isayama2, Naohisa Yahagi4

Institution(s): 1. Gastroenterology, Saitama Medical University International Medical Center, Saitama, Japan. 2. Juntendo Daigaku, Bunkyo-ku, Tokyo, Japan. 3. Tokyo Ika Daigaku, Shinjuku-ku, Tokyo, Japan. 4. Keio Gijuku Daigaku Byoin, Shinjuku-ku, Tokyo, Japan. 5. Tokyo Jikeikai Ika Daigaku, Minato-ku, Tokyo, Japan. 6. Memorial Sloan Kettering Cancer Center, New York, NY, United States. 7. Shiga Ika Daigaku, Otsu, Shiga, Japan. 8. Kagawa Daigaku Igakubu Daigakuin Igakukei Kenkyuka, Kita-gun, Kagawa, Japan. 9. Tokyo-to Kenko Choju Iryo Center, Itabashi-ku, Tokyo, Japan.

BACKGROUND: Limited T cell infiltration in tumor is still a hurdle for immunotherapies in pancreatic ductal adenocarcinoma (PDAC). In this respect, locoregional drug delivery is recently shown to induce effective anti-tumor immunity, suggesting one of the new promising approaches to promote T cell infiltration into tumor microenvironment. Carbohydrate sulfotransferase 15 (CHST15) is a proteoglycan biosynthetic enzyme and responsible for tumor matrix remodeling. As stromal-depleting agents are also expected to allow T cell entry, we investigated if blockade of CHST15 by locoregional injection with the double stranded RNA oligonucleotide STNM01, which inhibits the expression of the CHST15 gene, alters tumor immune microenvironment in patients with unresectable PDAC who failed to respond to first-line chemotherapy.
METHODS: We conducted a Phase 1/2a, open-label, dose escalation study to evaluate the safety and efficacy of STNM01 in patients with unresectable PDAC as a second-line therapy in combination with systemic chemotherapy. One cycle consists of endoscopic ultrasound (EUS)-guided locoregional injection with 250, 1,000, 2,500 or 10,000 nM of STNM01 three times at 2 week-interval in 4 weeks. The primary outcome was incidence of dose-liming toxicity. The secondary outcomes included overall survival, local tumor response, immunohistology for tumor microenvironmental components and safety. This study was registered with jRCT (jRCT2031190055).
RESULTS: A total of 22 patients across 4 doses were enrolled and 3 cycles were repeated at maximum. As the primary outcome, no dose-limiting toxicity was observed. As the secondary outcomes, the median overall survival was 7.8 months in the entire population (n=22) and 7.9 months in the maximum tolerated dose (MTD: 10,000 nM) population (n=13). Notably, the 6-month and 1-year survival rate of the MTD population was 84.6% and 38.6%, respectively. Local tumor response evaluated was mostly stable (71.4%), and one patient showed complete disappearance of visible lesions in the pancreas and tumor draining lymph node. Changes of tumor microenvironmental components were analyzed by immunohistochemical staining. At baseline, higher expression of CHST15 significantly correlated with poor CD3+ and CD8+ T cell infiltration. At the end of cycle one, STNM01 led to a significant reduction in CHST15, while significantly increased the tumor-infiltrating CD3+ and CD8+ T cells. Patients who survived over 1 year exhibited a significantly higher fold increase of T cells at the end of cycle 1, when compared to patient group showing survival of 1 year or less. STNM01 application showed a good tolerability and safety profile.
CONCLUSION: EUS-guided locoregional injection of STNM01 was well tolerated and able to prolong prognosis by enhancing T cell infiltration in patients with refractory, unresectable pancreatic cancer.
Number: EP1146
LOCOREGIONAL INJECTION OF THE RNA OLIGONUCLEOTIDE TARGETING CARBOHYDRATE SULFOTRANSFERASE 15 IS ABLE TO ACCELERATE TUMOR-INFILTRATING T CELLS IN PATIENTS WITH UNRESECTABLE PANCREATIC CANCER, REFRACTORY TO FIRST-LINE CHEMOTHERAPY

Society: AGA
Track: Pancreatic Diseases

Author(s): Yuki Tanisaka1, Toshio Fujisawa2, Takayoshi Tsuchiya3, Motohiko Kato4, Yuichi Torisu5, Makoto Nishimura6, Hiromu Kutsumi7, Yoko Matsuda8, Tomio Arai9, Hidyuki Saya4, Masafumi Mizuide1, Yusuke Takasaki2, Yoshiya Yamauchi3, Shigeo Koido5, Shomei Ryozawa1, Takao Itoi3, Hiroyuki Isayama2, Naohisa Yahagi4

Institution(s): 1. Gastroenterology, Saitama Medical University International Medical Center, Saitama, Japan. 2. Juntendo Daigaku, Bunkyo-ku, Tokyo, Japan. 3. Tokyo Ika Daigaku, Shinjuku-ku, Tokyo, Japan. 4. Keio Gijuku Daigaku Byoin, Shinjuku-ku, Tokyo, Japan. 5. Tokyo Jikeikai Ika Daigaku, Minato-ku, Tokyo, Japan. 6. Memorial Sloan Kettering Cancer Center, New York, NY, United States. 7. Shiga Ika Daigaku, Otsu, Shiga, Japan. 8. Kagawa Daigaku Igakubu Daigakuin Igakukei Kenkyuka, Kita-gun, Kagawa, Japan. 9. Tokyo-to Kenko Choju Iryo Center, Itabashi-ku, Tokyo, Japan.

BACKGROUND: Limited T cell infiltration in tumor is still a hurdle for immunotherapies in pancreatic ductal adenocarcinoma (PDAC). In this respect, locoregional drug delivery is recently shown to induce effective anti-tumor immunity, suggesting one of the new promising approaches to promote T cell infiltration into tumor microenvironment. Carbohydrate sulfotransferase 15 (CHST15) is a proteoglycan biosynthetic enzyme and responsible for tumor matrix remodeling. As stromal-depleting agents are also expected to allow T cell entry, we investigated if blockade of CHST15 by locoregional injection with the double stranded RNA oligonucleotide STNM01, which inhibits the expression of the CHST15 gene, alters tumor immune microenvironment in patients with unresectable PDAC who failed to respond to first-line chemotherapy.
METHODS: We conducted a Phase 1/2a, open-label, dose escalation study to evaluate the safety and efficacy of STNM01 in patients with unresectable PDAC as a second-line therapy in combination with systemic chemotherapy. One cycle consists of endoscopic ultrasound (EUS)-guided locoregional injection with 250, 1,000, 2,500 or 10,000 nM of STNM01 three times at 2 week-interval in 4 weeks. The primary outcome was incidence of dose-liming toxicity. The secondary outcomes included overall survival, local tumor response, immunohistology for tumor microenvironmental components and safety. This study was registered with jRCT (jRCT2031190055).
RESULTS: A total of 22 patients across 4 doses were enrolled and 3 cycles were repeated at maximum. As the primary outcome, no dose-limiting toxicity was observed. As the secondary outcomes, the median overall survival was 7.8 months in the entire population (n=22) and 7.9 months in the maximum tolerated dose (MTD: 10,000 nM) population (n=13). Notably, the 6-month and 1-year survival rate of the MTD population was 84.6% and 38.6%, respectively. Local tumor response evaluated was mostly stable (71.4%), and one patient showed complete disappearance of visible lesions in the pancreas and tumor draining lymph node. Changes of tumor microenvironmental components were analyzed by immunohistochemical staining. At baseline, higher expression of CHST15 significantly correlated with poor CD3+ and CD8+ T cell infiltration. At the end of cycle one, STNM01 led to a significant reduction in CHST15, while significantly increased the tumor-infiltrating CD3+ and CD8+ T cells. Patients who survived over 1 year exhibited a significantly higher fold increase of T cells at the end of cycle 1, when compared to patient group showing survival of 1 year or less. STNM01 application showed a good tolerability and safety profile.
CONCLUSION: EUS-guided locoregional injection of STNM01 was well tolerated and able to prolong prognosis by enhancing T cell infiltration in patients with refractory, unresectable pancreatic cancer.

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