Cancer-associated fibroblasts (CAFs) are a critical component of the tumor microenvironment and play a central role in tumor progression. Previously, we reported that CAFs might induce tumor immunosuppression via interleukin-6 (IL-6) and promote tumor progression by blocking local IL-6 in the tumor microenvironment with neutralizing antibody. Here, we explore whether an anti-IL-6 receptor antibody could be used as systemic therapy to treat cancer, and further investigate the mechanisms by which IL-6 induces tumor immunosuppression. In clinical samples, IL-6 expression was significantly correlated with α-smooth muscle actin expression, and high IL-6 cases showed tumor immunosuppression. Multivariate analysis showed that IL-6 expression was an independent prognostic factor. In vitro, IL-6 contributed to cell proliferation and differentiation into CAFs. Moreover, IL-6 increased hypoxia-inducible factor 1α (HIF1α) expression and induced tumor immunosuppression by enhancing glucose uptake by cancer cells and competing for glucose with immune cells. MR16-1, a rodent analog of anti-IL-6 receptor antibody, overcame CAF-induced immunosuppression and suppressed tumor progression in immunocompetent murine cancer models by regulating HIF1α activation in vivo. The anti-IL-6 receptor antibody could be systemically employed to overcome tumor immunosuppression and improve patient survival with various cancers. Furthermore, the tumor immunosuppression was suggested to be induced by IL-6 via HIF1α activation.

Background: The postoperative survival rate of patients with esophageal squamous cell carcinoma (ESCC) remains poor compared with other gastrointestinal cancers. We hypothesized that skeletal muscle loss (SML) in the postoperative acute phase might be a new predictor for long-term prognosis after highly invasive surgery such as ESCC surgery.Methods: The following items were retrospectively investigated. First, whether SML occurred in the postoperative acute phase of ESCC was verified. Second, the preoperative and intraoperative factors involved in SML in the postoperative acute phase of ESCC were investigated. Then, whether SML in the postoperative acute phase affected long-term prognosis was examined. The medical records of consecutive patients who underwent radical esophagectomy for ESCC were retrospectively reviewed; 72 cases were eligible for this study.Results: There was already a significant difference between the total psoas major muscle mass index (TPI) of the acute phase up to 3 days after surgery and the preoperative baseline TPI. The psoas muscle loss index (PMLI) was significantly milder in cases with less blood loss during surgery and in cases that underwent thoracoscopic esophagectomy than in cases that underwent open esophagectomy. The three-year overall survival rate was significantly different between the PMLI severe group and the PMLI mild group.Conclusion: SML occurred even in the postoperative acute phase. Furthermore, it is very significant that SML in the postoperative acute phase of ESCC surgery is involved in the long-term prognosis.

Background: The postoperative survival rate of patients with esophageal squamous cell carcinoma (ESCC) remains poor compared with other gastrointestinal cancers. We hypothesized that skeletal muscle loss in the postoperative acute phase might be a new predictor for long-term prognosis after highly invasive surgery such as ESCC surgery.Methods: The following items were retrospectively investigated. First, whether skeletal muscle loss occurred in the postoperative acute phase of ESCC was verified. Second, the preoperative and intraoperative factors involved in skeletal muscle loss in the postoperative acute phase of ESCC were investigated. Then, whether skeletal muscle loss in the postoperative acute phase affected long-term prognosis was examined. The medical records of consecutive patients who underwent radical esophagectomy for ESCC between January 2010 and June 2015 were retrospectively reviewed; 72 cases were eligible for this study. The total psoas major muscle mass index (TPI) at the level of the third lumbar vertebra (L3) was measured using computed tomography (CT) before surgery and three days after surgery. The long-term prognosis was estimated by the Kaplan-Meier method and the multivariate logistic regression model.Results: There was already a significant reduction of TPI in the acute phase up to POD 3 after ESCC surgery in comparison with the preoperative baseline TPI (P < 0.001). The TPI reduction rate was significantly milder in cases with less blood loss during surgery and in cases that underwent thoracoscopic esophagectomy than in cases that underwent open esophagectomy. The three-year overall survival rate was significantly different between the TPI reduction rate severe group and the TPI reduction rate mild group.Conclusion: skeletal muscle loss occurred even in the postoperative acute phase. Furthermore, it is very significant that skeletal muscle loss in the postoperative acute phase of ESCC surgery is involved in the long-term prognosis.

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Background: PD-1 blockade showed promising efficacy for broad type of cancer patients (pts), though objective response rates are very limited. In addition to the specific killing of cancer cells via oncolytic adenovirus, these agents prompt the immune system to stimulate an antitumor immune response. OBP-301 is an oncolytic adenovirus in which gene is modified to be able to selectively replicate in cancer cells by introducing hTERT promotor. Further antitumor effect might be expected with an active activation of two different antitumor immunity by OBP-301 in combination with pembrolizumab. Therefore, we conducted phase I study to evaluate the safety and efficacy of OBP-301 with pembrolizumab. Methods: The major eligibility criteria are pts with advanced or metastatic solid tumor not responded to or intolerant of standard chemotherapies, and with possibility of intratumoral injection. Phase Ia part was designed to determine the recommended dose in a “3+3” cohort-based dose escalation design of OBP-301 (1 × 1010VP on cohort 1, 1 × 1011VP on cohort 2 and 1 × 1012VP on cohort 3) with pembrolizumab (200mg/body q3w). OBP-301 is administered at day1, 15, and 29 by intratumoral injection and pembrolizumab is administered at day 8 and thereafter every 3 weeks. Primary endpoint is DLT. Secondary endpoints are response rate, progression free survival, and incidence of adverse event. Phase Ib part was designated to evaluate the safety and efficacy of the recommended dose OBP-301 selected in phase Ia part in combination with pembrolizumab. Biomarker study was planned to use paired samples of both tumor biopsy and blood. Clinical trial information: NCT03172819. Results: A total 22 pts (phase Ia part: 11 pts, phase Ib part: 11 pts) were enrolled in the study from Dec 2017 to Feb 2021. Median age was 65. Among the pts, 18 had esophageal squamous cell carcinoma, 2 had gastric cancer, one EGJ cancer, and one had colon cancer. No DLT was observed and the recommended dose for phase Ib part was 1 × 1012VP (cohort 3). Eighteen pts was injected to primary site, and 5 pts injected to metastatic site (Lymph node:1, Liver:3). Common grade 3 or 4 adverse events were fever (4.5%), and abnormal hepatic function (4.5%). Objective tumour responses were documented in 2(9.1%) of 22 pts. Tumor samples were subjected to multiplex immunohistochemistry (17 pts) and showed that tumor-infiltrating PD-1+CD8+ T cells prior to the treatment were significantly higher in 5 responders who experienced PR or &gt;6 months SD, compared with 12 non-responders (P=0.0365). Conclusion: The combination of OBP-301 with pembrolizumab was well tolerated and showed limited response. The result of biomarker analyses using paired samples of both tumor biopsy and blood will be presented. Tumor-infiltrating PD-1+CD8+ T cells could be a biomarker for this combinatory therapy. Citation Format: Takashi Kojima, Toshiyoshi Fujiwara, Shunsuke Tanabe, Tomoyuki Kadota, Hiromi Ono, Kazuko Tsukamoto, Takashi Ikeno, Masashi Wakabayashi, Akihiro Sato, Masanori Kondo, Shogo Kumagai, Shohei Koyama, Hiroyoshi Nishikawa, Toshihiko Doi. Final results from a phase I study to evaluate the safety and efficacy of a telomerase-specific oncolytic adenovirus (OBP-301) with pembrolizumab in patients with advanced solid tumors (EPOC1505) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT193.