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Background Extranodal natural killer/T (NK/T) cell lymphoma, nasal type (ENKTL), represents a rare subtype of T-cell lymphomas with aggressive clinical behavior and is relatively resistant to chemotherapy. However, there is relatively poor understanding of molecular pathogenesis of multidrug resistance in ENKTL. Here, we aimed to explore the biological roles and potential mechanism of IL-13 and ABCC4 in multidrug resistance of NK/T-cell lymphoma. Methods ELISA analysis was used to determine the level of serum IL-13 and immunohistochemical analysis was applied to detect the ABCC4 expression level in patients with human NK/T-cell lymphoma. Western blot assay was employed to measure the expression of ABCC4 in cells. Lenti-sh-ABCC4 viruses were constructed to knock down ABCC4 in YTS cells. CCK-8 assay and flow cytometric analysis were performed to detect the effects of IL-13 and ABCC4 on cell proliferation and apoptosis. CCK-8 assay was conducted to detect the effect of IL-13 and ABCC4 on cell sensitivity to adriamycin (ADM) in YTS cells. Results Levels of serum IL-13 and ABCC4 expression were observed to be upregulated in patients with human NK/T-cell lymphoma. Moreover, ABCC4 protein expression was also increased in NK/T-cell lymphoma YTS cells compared to the normal NK cells. Interestingly, IL-13 promoted ABCC4 expression in YTS cells. IL-13 promoted proliferation and suppressed apoptosis of YTS cells and reversed the effects of ABCC4 knockdown on promotive proliferation and inhibitory apoptosis. In addition, IL-13 enhanced YTS cell chemotherapy resistance to ADM by promoting ABCC4 expression. Conclusion Our findings concluded that IL-13 inhibited chemotherapy sensitivity of NK/T-cell lymphoma cells by regulating ABCC4, disrupting which may effectively improve the therapy protocols against resistant NK/T-cell lymphoma.

The aberrant activation of the Wnt/β-catenin signal has an important role in the progression of cancers. Herein, we investigated β-catenin mutation and the activation of the Wnt pathway in association with the clinical-pathological characteristics, chemo-resistance and prognosis of NK/T-cell lymphoma (NKTCL). Real-time quantitative PCR, immunocytochemistry and immunohistochemistry SP methods detected the levels of β-catenin, c-myc and cyclin D1 in human NKTCL cell lines (SNK-6 and YTS) and NKTCL tissues. Mutation analysis was detected in exon 3 of β-catenin gene; and we analyzed cell viability after histone deacetylase inhibitor (HDACi) treatment. As a result, 19 (38%) of NK/T-cell lymphoma displayed nuclear β-catenin and 16 (32%) contained mutations in exon 3; while no mutations were detected in lymphomas negative for β-catenin nuclear staining (p<0.05). Most mutations affecting β-catenin were adjacent to regulatory phosphorylation sites. β-catenin, c-myc and cyclin D1 were significantly elevated in SNK-6 and YTS cell lines compared to normal NK/T cells (p<0.05). Furthermore, the high expression of β-catenin, c-myc and cyclin D1 significantly correlated with the III/IV Ann Arbor stage. Additionally, the expression of β-catenin in the SNK-6 cell line decreased significantly after treatment with HDACi, and Kaplan-Meier survival analysis revealed that the elevated expression of β-catenin correlated with poor prognosis in NKTCL patients (23.66±2.77 months vs 31.65±1.78 months, p=0.023). In conclusion: mutations in exon 3 of β-catenin and the activated Wnt pathway are common in NK/T-cell lymphoma that has nuclear β-catenin, and it is closely correlated with the Ann Arbor stage and prognosis in NKTCL patients.

12126 Background: The study was to evaluate the equivalence of LY01011 to the reference product denosumab in terms of reduction of bone metabolism markers. Methods: Eligible patients were randomized at 1:1 ratio to receive 120 mg LY01011 injection or 120 mg denosumab every four weeks subcutaneously. Following the completion of three doses of 120 mg LY01011 or denosumab in a 12-week double-blind treatment period (DBTP), all enrolled patients would continue to receive LY01011 administration until the week 53 of follow-up period. The primary end point was the natural logarithm change at week 13 from baseline in urinary cross-linked N terminal telopeptide of type I collagen, corrected for urine creatinine (uNTx/uCr). The equivalence between LY01011 and denosumab would be concluded if the 90% CI was completely inside the pre-defined equivalence boundary between -0.135 and 0.135. A formal blinded sample-size re-estimation (BSSR) was planned to take place once 60% of the planned participants had completed the Week 13 assessments. After BSSR, the sample size increased from 560 to 850 according to prespecified procedure based on pooled standard deviationfrom the blinded data, which was set as a cap to ensure a feasible sample size for the study and no need to do any multiplicity adjustment. Results: All eligible 850 patients, included in the full analysis set, were randomized into the LY01011 group (n = 424) and denosumab group (n = 426). The samples from the 12-week DBTP were collected for analysis in both groups. The least square mean (LSM) (SE) of the natural logarithm change of uNTX/uCr at week 13 from baseline was -1.740 (0.0420) in the LY01011 group and -1.745 (0.0421) in denosumab group. The LSM difference was 0.005 between LY01011 and denosumab groups with 90% CI of [-0.088, 0.097] (p > 0.05). Skeletal related events occurring in the LY01011 and denosumab groups were 3.5% and 2.8%, respectively. The mean (SD) percentage changes of serum bone-specific alkaline phosphatase (s-BALP) from baseline to week 13 were -31.154% (39.6790) and -33.021% (37.3826) in the LY01011 and denosumab groups, respectively. The median was -36.866% and -37.457% (p > 0.05). The incidence of treatment-emergent adverse events (TEAEs) of any grade was 91.7% and 90.8% in LY01011 and denosumab groups(p > 0.05). Both groups had 38.4% of Grade ≥3 TEAEs, of which 5.4% (LY01011) and 4.5% (denosumab) were judged to be related to the study drug. Immunogenicity analysis showed that no participant (0/399) had a positive ADA test in denosumab group and only one participant (0.2%, 1/401) was tested ADA positive in LY01011 group. Conclusions: The study demonstrated the equivalent efficacy of LY01011 in the reduction of bone metabolism biomarker NTX to reference product, denosumab, which met the primary endpoint. It had a good safety profile with no unexpected adverse reactions in the study. Clinical trial information: NCT04859569 .

Except breast cancer and gastric cancer, HER2 gene amplification or overexpression is also expressed in other solid tumors, including but not limited to colorectal cancer (CRC), non-small cell lung cancer (NSCLC), gallbladder cancer, renal pelvis cancer and pancreatic cancer. The reports of immunotherapy combined with HER2-targeted therapy are limited. KN046 is a novel bispecific antibody that blocks both PD-L1 interaction with PD-1 and CTLA4 interaction with CD80/CD86. KN026 is a novel bispecific antibody that simultaneously binds to two distinct HER2 epitopes. Here the preliminary safety and efficacy results of KN046 in combination KN026 were reported in patients with locally advanced unresectable or metastatic other solid tumors who received ≥ 1 line prior systemic therapy. Methods: HER2-positive locally advanced unresectable or metastatic other solid tumors with progression after ≥ 1 line of prior systemic therapy were recruited, including 14 CRC patients, 4 NSCLC patients, 4 gallbladder cancer patients, 1 renal pelvis cancer patient and 1 pancreatic cancer patient. These patients were by KN046 (iv. 5 mg/kg Q3W) plus KN026 (iv. 30 mg/kg Q3W, loading on C1D1, D8) until progression, unacceptable toxicity, or patient withdrawal. Efficacy was assessed according to RECIST 1.1 Q6W. The primary endpoint was objective response rate (ORR). Results: As of the August 10th, 2021, 24 non-breast or non-gastric cancer patients with the median age of 56 years (range: 37-66) were enrolled. 20 and 24 patients were evaluable for overall response and safety, respectively. The ORR was 55.0% (11 of 20, 95% CI: 31.5-76.9). And the disease control rate (DCR) was 85.0% (17 of 20, 95% CI 62.1-96.8). The 6-month progression-free survival (PFS) rate was 84.1%. 11 CRC patients were evaluable for overall response. The ORR and DCR in CRC was 45.5% (5 of 11, 95% CI: 16.7-76.6) and 90.9% (10 of 11, 95% CI 58.7-99.8), respectively. Twenty of total 24(87.9%) patients suffered from treatment-related adverse events (TRAEs) of any grade. Total 4 of 24 (16.7%) patients had experienced ≥grade 3 TRAEs, including 4 cases related to KN046 and 3 cases related to KN026. The most common (≥10%) TRAEs were infusion related reaction (29.2%), diarrhea (19.4%), alanine aminotransferase increased (16.7%), aspartate aminotransferase increased (16.7%), vomiting(12.5%) and decreased appetite (12.5%). No treatment-related deaths were observed. Conclusion: This chemotherapy-free regimen of KN046 in combination with KN026 has shown promising clinical efficacy and manageable toxicity in HER2-positive non-breast and non-gastric solid tumors with ≥ 1 line prior systemic therapy. The trial is currently ongoing. ClinicalTrials.gov Number, NCT04521179 Citation Format: Jifang Gong, Lei Chen, Meili Sun, Yanming Zhang, Jieer Ying, Xiangcai Wang, Mingli Ni, Zhixiang Zhuang, Baohong Guo, Long Xiao, Summer Xia, Lin Shen. Preliminary safety and efficacy results of KN046 in combination with KN026 in patients with locally advanced unresectable or metastatic HER2-positive solid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT542.