Background: Preclinical trial has demonstrated that sequential use of Selinexor and Anti-CD19 directed chimeric antigen receptor modified T-Cell therapy (CART19) cells might improve the anti-tumor efficacy of CART 19 cells against lymphoma cells. However, the efficacy and safety of CART19 combined with Selinexor in lymphoma patients is unknown. We report preliminary data from a phase 2 trial of sequential use of Selinexor and CART19 in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (R/R B-NHL). Methods: We performed a multicenter, prospective, phase II, open-label clinical study of sequential use of Selinexor and CART19 in R/R B-NHL. Patients received Selinexor as a bridging therapy (40–60 mg) with a weekly for three weeks prior to CART19 infusion. Over all response (ORR), duration of response (DOR) and safety were evaluated as primary objectives. This study is registered with ClinicalTrials.gov, NCT05322330. Results: Between February 10, 2022, and February 10, 2023, 6 patients were enrolled. Four patients with diffuse large B-cell lymphoma, one mantle cell lymphoma and one Burkitt lymphoma received Selinexor 40mg and CART19 treatment. The median age was 55.5 years (range 34–77), 3 (50.0%) of 6 patients had refractory disease, 5 (83.3%) of 6 patients had extranodal involvement and the median prior systemic therapy was 2 (range 2–5), 5 (83.3%) of 6 patients had evaluated LDH prior to Selinexor administration. Median on-study follow-up was 9.68 months (range 2.53–12.17). 4 (66.7%) of 6 patients had an overall response. Cytokine release syndrome (CRS) was the most common adverse event, occurring in all 6 (100.0%) patients [66.7% was grade 1–2 and 33.3% was grade 3]. No neurotoxicity was observed. The most common grade 3–4 adverse events were neutropenia (5 [83.3%] of 6 patients), thrombocytopenia (4 [66.7%]), and anemia (3 [50.0%]). No treatment-related grade 5 adverse event occurred. Furthermore, our data showed that the use of Selinexor resulted in a higher proportion of CD8+central memory T cell phenotypes (P = 0.04) while having no effect on CD4+ central memory T cell phenotypes (Figure 1). Encore Abstract - previously submitted to ASCO 2023 Keywords: Cellular therapies, Combination Therapies, Ongoing Trials No conflicts of interests pertinent to the abstract.

Combinations of immunotherapy with chemotherapy as a first-line treatment for ES-SCLC have generated mixed results. The EXTENTORCH trial assessed toripalimab in combination with chemotherapy as a first-line treatment for patients with ES-SCLC (NCT04012606). Patients with histologically or cytologically confirmed ES-SCLC, stratified by gender and baseline ECOG PS (0 vs. 1) were randomized in a 1:1 ratio to receive 240 mg toripalimab or placebo plus etoposide and cisplatin/carboplatin Q3W for 4-6 cycles, followed by single-agent toripalimab or placebo until progressive disease, intolerable toxicity or up to 2-year treatment. The primary endpoints were PFS as assessed by the investigator per RECIST v1.1 and OS. Tumor mutational burden (TMB) and genomic alterations were assessed by whole-exome sequencing (WES) of tumor tissues. From Sep 2019 to May 2021, 442 patients were enrolled from 48 participating sites in China. 223 and 219 patients were randomized to the toripalimab and the placebo arms, respectively. At data cut off (28 Feb 2022), median follow-up was 11.8 months, a significant improvement in PFS was observed for toripalimab over placebo (5.8 vs. 5.6 months, HR = 0.667 [95% CI: 0.539-0.824], P = 0.0002). Despite 59.4% of patients in the placebo arm received ≥3 additional lines of therapy and 25.6% received a PD-(L)1 inhibitor after the study treatments, OS was significantly improved in the toripalimab arm (14.6 vs. 13.3 months, HR = 0.798 [95% CI: 0.648-0.982], P = 0.0327) at the final OS analysis at data cut off (20 Apr 2023). WES results from 300 patients showed that improvements in PFS and OS were similar irrespective of TMB status. Genomic alterations in integrin-mediated focal adhesion complex were associated with poor prognosis for both PFS and OS in the toripalimab arm. Toripalimab plus chemotherapy had a manageable safety profile, with no new safety signals observed. The addition of toripalimab to chemotherapy provided significant improvements in PFS and OS for patients with ES-SCLC with an acceptable safety profile.

AIM: To predict progression within 6 months after chimeric antigen receptor-modified (CAR) T-cell therapy for relapsed/refractory (R/R) B-cell non-Hodgkin's lymphoma (B-NHL) patients by radiomic indexes derived from contrast-enhanced computed tomography (CECT) examinations.MATERIALS AND METHODS: Seventy R/R B-NHL patients who underwent CECT before treatment with CAR T-cells were examined retrospectively. In total, 297 volumes of interest for lesions were segmented from CECT images. Patients without and with disease progression were assigned to groups 1 and 2, respectively. Radiomic and combined predictive models were constructed by three machine-learning algorithms using features from the training set, respectively. Furthermore, predictive models were constructed based on multilesion-based and largest-lesion-based radiomic features, respectively.RESULTS: In the test set, no marked differences were observed between the areas under the curves (AUCs) of the combined and radiomic models for all three machine-learning algorithms (all p>0.05). Differences in machine-learning algorithms did not significantly affect the predictive performances of the models. Radiomics and combined models constructed with multi-lesion-based radiomic features showed better predictive performances than those applying largest-lesion-based radiomic features (all p<0.05 for comparisons between combined models).CONCLUSION: CECT-based radiomic features may be applied to predict disease progression in R/R B-NHL patients within 6 months after CAR T-cell treatment, and radiomic features from multiple lesions may have better predictive efficacy. Different machine-learning algorithms may not show significant differences in prediction performance.(c) 2023 Published by Elsevier Ltd on behalf of The Royal College of Radiologists.

Background: Approximately one-third of Diffuse large B-cell lymphoma(DLBCL) arises primarily from extranodal sites,less than 70% showed extranodal involvement in at least 1 site.Patients with multiple extranodal involvement indicates adverse clinical outcomes,and non-GCB subtype is another poor prognostic factor.Study shows that the rates of complete remission(CR),five-year OS,five-year PFS were significantly lower for the non-GCB subtype(77.5% vs 52.6%,78% vs 54%,76% vs 48%).Patients who failed in initial treatment had poor prognosis and short overall survival.In the genetic taxonomy, with non-GCB tumors enriched for MCD and BN2 subtype are suitable for the treatment of BTK inhibitor.Zanubrutinib has shown very promising future in newly diagnosed and relapsed/refractory B-cell lymphoma. Aims: We conducted a single-arm,phase II trial for newly diagnosed non-GCB DLBCL with extranodal involvement to evaluate the efficacy and safety of the zanubrutinib combined with R-CHOP(number NCT 04835870). Methods: 20 patients enrolled in this prospective single-center study with newly diagnosed non-GCB DLBCL from October 2020 to February 2022.Patients received therapies:R-CHOP(intravenously rituximab(375mg/m2 on Day0), cyclophosphamide(750mg/m2on Day1),doxorubicin(50mg/m2 on Day1),vincristine(1.4mg/m2 on Day1),and oral prednisone(50mg/day Day1-5) with Zanubrutinib(160mg bis in die orally) regimen. Particularly,patients with a weak constitution or older than 70 years old were administered ZR-miniCHOP. Results: 20 patients received ZR-CHOP regimen treatments, Patients had a median age of 60 years(31~83years) and 4 patients were over 70 years old,11 patients (55%) had IPI-PS ≥3 score,16 patients (80%) had stage III/IV disease,13 patients (65%) had ≥2 extranodal organs involved,2 patients (10%) had bulky disease and 9 patients (45%) were double-expression lymphoma confirmed by immunohistochemistry and FISH (Table 1). The median follow-up time of all patients was 8.7 months(0.4~16.1months) and there are 12 patients received 6 ~ 8 cycles of treatment who can evaluate the efficacy. The objective response rate(ORR) of 12 patients was 91.67%(11/12),11 patients(91.67%) reached complete remission(CR),of which 9 achieved CR at the interim evaluation, and 1 patient(8.3%) reached progression disease(PD).The median OS and PFS of the 12 patients who finished treatment were 10.7months(5.6~16.1months) and 10.2months(5.6~16.1months).One patient relapsed(Figure 1).13(65%) patients reduced the dose during treatment, the most common AEs were hematological toxicity, fatigue and apositia. all-grade and grade 3 or higher hematological toxicity were 100% and 65%,11 patient observed grade 3 or higher neutropenia and 3 patients had severe pneumonia during treatment. Hemorrhage were observed in 3 patients,2 patients developed atrial fibrillation after the first medication.No patient had fatal adverse events(Table2). Image:Summary/Conclusion: Our results showed that Zanubrutinib plus R-CHOP(ZR-CHOP) is a safe and effective scheme for this part of non-GCB DLBCL patients with extranodal involvement.It indicate that the addition of zanubrutinib to the standard first-line treatment can enable these patients to achieve remission in the early stage of treatment and without significantly increasing toxicity.

Programmed cell death 1 (PD-L1) is the first FDA-approved predictive biomarker for non-small cell lung cancer (NSCLC) patients treated with PD-(L)1 blockade therapy. However, many clinical patients are not subject to PD-L1 testing due to different reasons such as limited sample source and tumor heterogeneity. Therefore, this study aimed to understand the association between multimodal genomic alterations and PD-L1 expression, and further explore whether genomic alterations can be leveraged to stratify patients who may benefit from immunotherapy.

OBJECTIVE: To explore the role of T-box 2 (TBX2) in esophageal squamous cell carcinomas (ESCC). PATIENTS AND METHODS: Quantitative real-time polymerase chain reaction (PCR) and Western blot (WB) assays were used to detect the expression level of TBX2 in tissues and cells. Transwell assays were conducted for determination of cell invasion and migration. RESULTS: The results suggested that the TBX2 was upregulated in ESCC tissues. Further, high expression of TBX2 expression was associated with tumor size, differentiation, distant metastasis, and TNM stage. In our in-vitro study, we decreased the expression of TBX2 in ESCC cells by transfection using LipofectamineTM 3000. The results from the transwell assay suggested that the downregulation of TBX2 could significantly suppress cell migration and invasion. Besides, WB results indicated that epithelial-mesenchymal transition (EMT)-related protein expressions were also changed after transfection. CONCLUSIONS: TBX2, as an oncogene, could promote the progress of ESCC by affecting the transfer ability in tumor cells.

TIF1γ is a novel regulator of transforming growth factor (TGF)-β/Smad signaling. Our previous studies show that dysregulated expression of transcriptional intermediary factor 1 γ (TIF1γ) and abnormal TGF-β/Smad signaling are implicated in non-small-cell lung cancer (NSCLC) separately. However, how TIF1γ contributes to NSCLC by controlling TGF-β/Smad signaling is poorly understood. Here, we investigated the mechanistic role of TIF1γ in TGF-β-induced epithelial–mesenchymal transition (EMT), as well as a link between TIF1γ and SOX2 in NSCLC. We show that TIF1γ is a downstream target of SOX2 in NSCLC cells. SOX2 overexpression negatively regulated TIF1γ promoter activity and thereby attenuated TIF1γ mRNA and protein expression levels; SOX2 knockdown significantly enhanced TIF1γ promoter activity and augmented TIF1γ expression. Moreover, TIF1γ mRNA expression was downregulated in human NSCLC tissues and negatively correlated with SOX2 protein, which was upregulated in NSCLC tissues. Importantly, knockdown of TIF1γ or SOX2 overexpression augmented SMAD4 (human Mad (mothers against decapentaplegic)-related homologous protein 4)-dependent transcriptional responses, and enhanced TGF-β-induced EMT and human NSCLC cell invasion; knockdown of SOX2 impaired TGF-β-induced EMT and NSCLC cell invasion. In an in vivo model of metastasis, knockdown of TIF1γ promotes NSCLC cell metastasis. In addition, our data suggested that TIF1γ inhibited TGF-β-induced EMT through competing with SMAD4 in NSCLC cells. Taken together, our findings reveal a new mechanism by which SOX2-mediated transcription repression of TIF1γ promotes TGF-β-induced EMT in NSCLC.