Non-responder Group Research Articles

Relationship between mitral valve echocardiographic parameters and interventional septal reduction therapy success in patients with hypertrophic obstructive cardiomyopathy - a pilot study

Abstract Funding Acknowledgements Type of funding sources: None. Background The mitral valve (MV) has an important contribution to left ventricular outflow tract obstruction (LVOTO) in patients with hypertrophic obstructive cardiomyopathy (HOCM). Several parameters were described to be significantly different between obstructive and non-obstructive forms of HCM, like the aortomitral angle, anterior mitral leaflet (AML) and LVOT size, anterior displacement of the coaptation line, annular related parameters, etc. The redundant length of the AML beyond the coaptation point and the entire AML length are important in the decision to also approach the mitral valve when surgical septal reduction therapy (SRT) is considered, to increase the success rate. Data is scarce regarding mitral valve related predictors of interventional SRT response. This is important as certain patients have a suboptimal response regardless of the proper coronary anatomy and branch targeting. Purpose To evaluate the possible differences in certain mitral valve parameters in interventional SRT responders versus non-responders. Methods We retrospectively included in the study a number of 21 consecutive HOCM patients treated with alcohol septal ablation (ASA). All the procedures were guided with contrast echocardiography besides fluoroscopy and all patients had a proper distribution of at least 1 septal branch. They were divided in two groups- responder group (15 patients) with a non-significant residual LVOT PG (<50mmHg/>50% reduction) and non-responder group (6 patients) with a significant residual LVOT PG (>50mmHg/<50% reduction) and/or early rebound. We accounted for the residual LVOT PG evaluated by continuous Doppler at least 6 months after SRT. The groups were compared regarding LV dimensions and ejection fraction and mitral valve annulus/ leaflet size and displacement of the coaptation line, evaluated by bidimensional transthoracic echocardiography, before the intervention. Results The most hypertrophied part of the LV was the basal interventricular septum (IVS). The two groups were similar regarding age, comorbidities, LV dimensions and ejection fraction and baseline LVOT PG. Also, there was no significant difference between AML length, posterior mitral leaflet (PML) length, AML/PML, MV annulus. The redundant length of the AML was significantly lower in responders whereas anterior displacement of the coaptation point (projection of AML/projection of PML on the MV annulus) was less intense in responders and almost reached statistical significance. (Table) Interestingly, we found a baseline AML/PML projection <1 in all non-responder patients and only in 2 responder patients (13.33%) (p<0.001). Conclusion So far, significant anterior displacement of the coaptation point and the residual AML length may have an important impact on the response to ASA in HOCM patients. This pilot study could be an important start point for larger prospective studies to confirm and evaluated the prediction value of these parameters among others.

Consumer response to wine made from smoke-affected grapes

When vineyards and grapes are exposed to smoke from wildfires or controlled burns, this can result in wines with smoky, burnt or ashy attributes that have been linked to the presence of elevated concentrations of volatile phenols and phenolic glycosides. These smoky flavours are considered undesirable by winemakers, but there is little information about how consumers respond to smoke-affected wines. To investigate whether consumers respond negatively to smoky attributes when wine is tasted blind, three studies assessing sets of Pinot noir rosé, Chardonnay and unoaked Shiraz wines with varied smoke flavour were conducted. Overall, wines rated high in smoke flavour were less liked compared to non-smoke-affected wines. Independent of wine type, there was a strong negative correlation between smoky flavour and overall consumer liking. Detailed data analysis revealed that consumers who are wine drinkers fell into one of three categories: highly responsive to smoke, moderately responsive, or a smaller group of non-responders. This consumer-based information is essential for guiding the assessment of risk from smoke exposure of grapes and potential for quality defects in wine, as well as identifying and benchmarking management options for wine producers, not only in Australia, but globally.

Predictors of a weak antibody response to COVID-19 mRNA vaccine in systemic lupus erythematosus.

To characterize the antibody response to COVID-19 mRNA vaccination in patients with Systemic Lupus Erythematosus (SLE) and identify predictors of poor response. SLE patients who are followed at the Beth Israel Deaconess Medical Center Lupus Cohort (BID-LC) were enrolled. SARS-CoV-2 IgG Spike antibody was measured in patients who received two doses of either the BNT162b2 (Pfizer-BioNTech) or the mRNA-1273 (Moderna) COVID-19 vaccine (n = 62). We defined non-responders as patients with an IgG Spike antibody titer less than two-fold (< 2) the index value of the test and responders as patients with antibody levels greater or equal to two-fold (≥ 2). A web-based survey was used to collect information regarding immunosuppressive medication use and SLE flares after vaccination. In our cohort of lupus patients, 76% were vaccine responders. The use of two or more immunosuppressive drugs was associated with being a non-responder (Odds Ratio 5.26; 95% CI 1.23-22.34, p = 0.02). Both Belimumab use and higher Prednisone dose were associated with vaccine non-response (p = 0.04 and p = 0.04). The non-responder group had higher mean levels of serum IL-18 than the responder group (p = 0.04) as well as lower C3 levels (p = 0.01). Lupus flares and breakthrough infections were uncommon post-vaccination. Immunosuppressive medications have a negative impact on vaccine humoral response in SLE individuals. We observed a trend towards vaccine no-response in BNT162b2 recipients and a relationship between IL-18 and impaired antibody response that merits further investigation.

Radiological Factors Associated with Bisphosphonate Treatment Failure and Their Impact on Fracture Healing in Postmenopausal Women with Osteoporotic Vertebral Fractures.

(1) Background: Bisphosphonate treatment failure is one of the most difficult clinical problems for patients with osteoporosis. This study aimed to analyze the incidence of bisphosphonate treatment failure, associated radiological factors, and effect of fracture healing in postmenopausal women with osteoporotic vertebral fractures (OVFs). (2) Methods: A total of 300 postmenopausal patients with OVFs who were prescribed bisphosphonate were retrospectively analyzed and divided into two groups according to the treatment response: response (n = 116) and non-response (n = 184) groups. The radiological factors and the morphological patterns of OVFs were included in this study. (3) Results: The initial BMD values of the spine and femur in the non-response group were significantly lower than those in the response group (all Ps < 0.001). The initial BMD value of the spine (odd ratio = 1.962) and the fracture risk assessment tool (FRAX) hip (odd ratio = 1.32) showed statistical significance in logistic regression analysis, respectively (all Ps < 0.001). (4) Conclusions: The bisphosphonate non-responder group showed a greater decrease in BMD over time than the responder group. The initial BMD value of the spine and the FRAX hip could be considered radiological factors influencing bisphosphonate non-response in the postmenopausal patients with OVFs. The failure of bisphosphonate treatment for osteoporosis has a possible negative on the fracture healing process in OVFs.

Il-6 and UGT1A1 variations may related to furosemide resistance in heart failure patients.

Furosemide is a diuretic and is used for the treatment of patients with heart failure (HF). It has been found that in some HF patients, the drug does not treat patients efficiently. This condition is named as furosemide resistance. In this study, it is aimed to investigate the relationship between UDP-glucuronosyltransferase 1 (UGT1A1) and interleukine-6 (IL-6) variations with furosemide resistance in HF patients. Sixty HF patients using furosemide (patient group) and 30 healthy individuals (control group) were enrolled in this study. Patients were divided into two subgroups as non-responders (furosemide resistant) group (n = 30) and the responders (non-resistant) group (n = 30) according to the presence of furosemide resistance (n = 30). Variations in the first exon of UGT1A1 and rs1800795 and rs1800796 variations in IL-6 were analyzed by direct sequencing and real-time polymerase chain reaction (RT-PCR), respectively. The effects of newly detected mutations on 3-D protein structure were analyzed by in silico analysis. At the end of the study, 11 variations were detected in UGT1A1, of which nine of them are novel and eight of them cause amino acid change. Also, rs1800795 and rs1800796 variations were detected in all the groups. When patient and control groups were compared with each other, rs1800796 mutation in IL-6 was found statistically high in the patient group (p = 0.027). When the three groups were compared with each other, similarly, rs1800796 mutation in IL-6 was found statistically high in the non-responders group (p = 0.043). When allele distributions were compared between the patient and control groups, the C allele of rs1800795 mutation in IL-6 was found statistically high in the patient group (p = 0.032). When allele distributions were compared between the three groups, 55T-insertion in UGT1A1 was found statistically high in the non-responders group (p = 0.017). According to in silico analysis results, two variations were found deleterious and six variations were detected as probably damaging to protein functions. Our study may contribute to the elucidation of pharmacogenetic features (drug response-gene relationship) and the development of individual-specific treatment strategies in HF patients using furosemide.

Understanding resistance in V600E BRAF advanced colon cancer treated with BRAF inhibitors plus anti-EGFR antibodies +/- MEK inhibitors: The URBAN study.

3587 Background: The combination of BRAF inhibitors (BRAFi) plus anti-EGFR antibodies is a new standard of care in V600E BRAF mutated (mut) metastatic colorectal cancer (mCRC). Nevertheless, resistance develops during the target therapy (TT). We designed the URBAN study, a translational prospective project, in order to identify possible primary and acquired resistance mechanisms. Methods: Patients (pts) with V600E BRAF mut mCRC treated with BRAFi + anti-EGFR +/- MEK inhibitors at Veneto Institute of Oncology were enrolled. Clinical data and liquid biopsy at baseline and progression were collected. The ctDNA derived from plasma was analyzed by the AVENIO expanded kit, a hybridization capture sequencing-based 77 genes pan-cancer assay contained in NCCN Guidelines. Survival outcomes were calculated using Kaplan–Meier curves, log-rank tests and univariate Cox regression models were also performed. The study is exploratory and no formal hypothesis has been postulated. Results: Forty consecutive V600E BRAF mut mCRC pts were enrolled. Median age was 63 years (42-77), 47.5% of pts were males. Right CRC were 65% and 20% were MSI-H. Only 5% of pts received TT after second line; doublet regimen was administered in 60% of pts while triplet in 40%. According to the mPFS of doublet arm in the BEACON trial (4.2 months, mo), our population was divided in responder (R), 24 (60%), and non-responder (NR), 16 (40%). In R vs NR group, mPFS was 9 vs 3.2 mo while mOS was 21.6 vs 10.7 mo, respectively. The V600E BRAF mut was detected in 85% of the pre-treatment plasma samples without statistically significant differences in the genomic alterations between R and NR groups, but there was a higher frequency of MET and EGFR amplification in NR group. At progression, the mutation of BRAF was lost in 2 cases in R group. After receiving TT, the most common acquired mutations involved RAS genes: 16 pts (40%) acquired at least one activating mutation in KRAS and/or NRAS. Among these, 9 pts showed multiple mutations of the same RAS gene probably due to both intra- and inter-lesional heterogeneities; none of these pts had MSI-H mCRC. We found a higher number of RAS and MAP2K1 acquired mutations in NR and a trend to acquire EGFR amplification in R group. Inactivating mutations in RFN43 gene was observed in 2 cases in R group. These data did not reach statistical significance, probably due to the low number of cases. Interestingly, 37% of NR pts acquired three or more molecular alterations vs 13% in R group. Furthermore, a higher number of genetic alterations was acquired in pts treated with doublet vs triplet regimen. Conclusions: This prospective, observational molecular profiling study provided further evidences to support the use of ctDNA in capturing the dynamic somatic mutational spectrum in V600E BRAF mut mCRC and to identify potential mechanisms of resistance to TT. An expansion of study population is ongoing.

Can the apparent transverse relaxation rate (R2*) evaluate the efficacy of concurrent chemoradiotherapy in locally advanced nasopharyngeal carcinoma? a preliminary experience

BackgroundThe use of the apparent transverse relaxation rate (R2*) in nasopharyngeal carcinoma (NPC) has not been previously reported in the literature. The aim of this study was to investigate the role of the R2* value in evaluating response to concurrent chemoradiotherapy (CCRT) in patients with NPC.MethodsForty-one patients with locoregionally advanced NPC confirmed by pathology were examined by blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) before and after CCRT, and conventional MRI was performed 3 months after the completion of CCRT. All patients were divided into a responding group (RG) and a nonresponding group (NRG), according to MRI findings 3 months after the end of treatment. The R2* values before (R2*preT) and after (R2*postT) CCRT and the ΔR2* (ΔR2*=R2*postT – R2*preT) were calculated in the tumor.ResultsAmong the 41 patients, 26 were in the RG and 15 were in the NRG. There was no statistical difference in the R2*preT between RG and NRG (P = 0.307); however, there were significant differences in R2*postT and ΔR2* (P < 0.001). The area under the curve of R2*postT and ΔR2* for predicting the therapeutic response of NPC was 0.897 and 0.954, respectively, with cutoff values of 40.95 and 5.50 Hz, respectively.ConclusionThe R2* value can be used as a potential imaging indicator to evaluate the therapeutic response of locoregionally advanced NPC.

Alteration of gut microbiota composition in patients with cholangiocarcinoma with non-responsiveness to first-line chemotherapy: A pilot study.

4104 Background: Gut microbiota established crucial roles in host metabolism and several diseases, particularly cancers. Distinct bacterial profiles from intestine are found to be a potential factor in carcinogenesis, while some of those are associated with detrimental treatment to the responsiveness in various types of cancer. Association of gut microbiota and treatment outcome has been thoroughly investigated in intrahepatic cholangiocarcinoma (ICCA). The present study aimed to compare gut microbiota profiles between chemotherapy responder and non-responder in ICCA patients. Methods: Unresectable or metastatic ICCA patients were recruited in the study. The criteria of all patients were naïve to chemotherapy. All patients received first line combination of cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 at day1 and day 8 in every 21-day cycle and were given up to 8 cycles. The primary endpoint was to evaluate the association between gut microbiota and the objective response rate. Bacterial genomic DNA samples were extracted from the stool using a commercial genomic DNA isolation kit (Qiagen, Hilden, Germany) and then underwent next-generation sequencing. Data analyses were conducted by using QIIME2 and Analysis of Compositions of Microbiomes with Bias Correction (ANCOM-BC). Results: Seventeen ICCA patients were recruited. The objective response rate was 23.5% comparable to historical study. Chemotherapy responder group was defined as partial response patients (N = 4) and chemotherapy non-responder group included stable of disease and progressive disease (N = 13). Baseline characteristics were similar including age, sex, ECOG performance status, numbers of metastatic organ and CA 19-9 in two groups. Median Age were 63 years old (60-70) and 61 (45-73), respectively. Alpha-diversity and beta-diversity were not different between two groups. In chemotherapy non-responder group, some taxa were dominantly observed including Ruminococcaceae, Oribacterium, Oxalobacter, Peptostreptococcus, Aggregabacter, which had been previously reported increasing in ICCA patients. Interestingly, Ruminococcaceae, which was previously documented to be correlated with vascular invasion, was significantly increased abundance in non-responder group. Moreover, the median progression-free survival (PFS) was improved in chemotherapy responder group compared to non-responder group 11.8 and 6.6 month, respectively. Large sample sizes study to confirm this study result should be developed. Conclusions: Distinct bacteria from gut microbiota such as Ruminococcaceae has inversely associated with chemotherapy response in ICCA patients receiving first line cisplatin and gemcitabine combination, suggesting the possibility of the poorer PFS.

Myeloid-derived suppressor cells as biomarkers of the effectiveness of therapy with new biological agents in axial spondyloarthritis

Innate immune cells, including myeloid cells — myeloid derived suppressor cells (MDSCs) — are supposed to play an important role in the pathogenesis of axial spondyloarthritis (AxSp). Myeloid derived suppressor cells represent a heterogeneous population of immature cells capable of suppressing innate and adaptive immune responses with the most pronounced suppressor activity against T cells. Biological disease-modifying antirheumatic drugs (bDMARDs) can reduce the clinical and laboratory disease activity, but their effectiveness varies widely in different patients with AxSp. The present study is aimed at studying MDSCs subpopulations and their suppressive function depending on the response to bDMARD therapy in AxSp. The study included AxSp patients with a disease duration of 16.5 years (median); HLA-B27 (+) status was detected in 79% of cases. All patients received bDMARDs at least the past 12 weeks, including TNF inhibitors (etanercept, certolizumab pegol, adalimumab, or golimumab) or IL-17 inhibitors (secukinumab, ixekizumab, or netakimab). Percentage of granulocytic MDSCs (G-MDSCs, Lin-HLA-DR-CD33+CD66b+), monocytic MDSCs (M-MDSCs, HLA-DRlow/-CD14+), MDSCs of early stage differentiation (E-MDSCs, Lin-HLA-DR- CD33+CD66b-), as well as intracellular expression of arginase-1 was assessed by flow cytometry. Frequency of circulating MDSC subpopulations of patients with a stable response to bDMARDs (responders) did not differ significantly compared to healthy donors. Patients not responding to bDMARDs therapy showed increased relative and absolute number of E-MDSCs compared to healthy donors (pU = 0.01 and pU = 0.02, respectively) and the responders (pU = 0.03 and pU = 0.07, respectively). Increased percentage of E-MDSCs was positively correlated to disease activity — ESR (Rs = 0.821; p = 0.023), CRP (Rs = 0.714; p = 0.07) and ASDASCRP (Rs = 0.829; p = 0.042) in the non-responder group. Responder patients exhibited no correlation between disease activity and circulating MDSCs. The suppressor potential of MDSCs was analyzed by the intracellular expression of arginase-1 molecule which is involved in the inhibition of T cell response. Patients with the stable response were characterized by increased expression of arginase-1 in E-MDSCs compared to donors (pU = 0.02). Non-responders did not demonstrate significant changes in Arg-1 expression, however, the percentage of arginase-1-expressing G-MDSCs was positively correlated to indexes ASDASESR (Rs = 0.857; p = 0.014) and BASDAI (Rs = 0.785; p = 0.036). Thus, E-MDSCs as well as arginase-1 expression in MDSCs may serve as biomarkers of effectiveness bDMARD therapy, and act as potential candidate predictors of response to therapy in AxSp.

Clinical-grade natural killer cells expanded from donor peripheral blood and anti-leukemia effect against myeloid leukemia.

e19018 Background: Natural killer (NK) cells play a crucial role in immune surveillance and tumor clearance. It has been reported that allogeneic NK cell therapy has good safety and curative effect in patients with refractory and relapsed acute myeloid leukemia (AML). However, the clinical application of adoptive NK infusion is limited due to the lower number of human NK cells. We established a feeder-free NK cell expansion system from peripheral blood (PB) and explore the anti-leukemia potential in preclinical and clinical studies. Methods: The killing capacity of ex vivo-expanded NK cells were detected by Flow cytometry. The in vivo expansion, survival and anti-leukemia activity of the expanded NK cells were detected in K562-bearing NSG mice. Six AML patients with hematological/extra medullary relapsed (n = 3) or persistent positive minimal residual disease (n = 3) after consolidation and maintenance therapy were enrolled in Peking University Institute of Hematology from 2021 to 2022. The patients were treated with high-dose cyclophosphamide and fludarabine, then combined with adoptive infusion of donor-derived expanded NK cells. The chimerism, the number and function of NK cells were analyzed, and the safety and clinical efficacy were evaluated. Results: The ex vivo-expanded NK cells exhibit highly anti-leukemia activity. NK cells proliferate in mice and the CD56+ cells to reach the peak time in each organ is 3-7 days and drop to the level before infusion after 14 days. NK cell infusion significantly improve the survival of leukemia mice, and the anti-leukemia effect is NK cell dose-dependent. In the clinical trial, six patients received a total of 7 cases of NK cell infusion, including 3 cases in low-dose group and 4 cases in middle-dose group, among which 1 patient received 2 dose (1 low-dose and 1 middle-dose). In the low-dose group, 1 patient got response (1/3), with the minimal residual disease turned negative. In the middle-dose group, 3 patients responded (3/4), of which 1 patient had the fusion gene CBFB /ABL decreased from 0.99% to 0.13%, 1 case of extramedullary recurrence of AML turned negative, and NK cells could be detected in cerebrospinal fluid, 1 case of hematological recurrence got hematological remission after treatment. The survival time of NK cells in vivo was 7d-30d, with longer time in middle dose group than those in low dose group. The proportion and number of NK cells in responding cases were significantly higher than those in non-responsive group. Conclusions: Clinical grade expanded NK cells has strong anti-leukemia activity in patients with relapse or minimal residual positive AML patients. NK cells can survive for 2 weeks and can enter the central nervous system without obvious adverse reactions. The response rate in middle-dose group is higher than that in low-dose group. However, the efficacy of NK cells still needs to be further confirmed in a large sample size. Clinical trial information: NCT04221971 .

Peripheral immunological response to treatment with a novel bifunctional anti-PD-L1/TGFβRII agent in recurrent/metastatic nasopharyngeal carcinoma.

e14622 Background: Anti-programmed cell death protein-ligand 1 (PD-L1) monotherapy has not shown promising anti-tumor effects in recurrent/metastatic nasopharyngeal carcinoma (R/M NPC) in first-line settings. Consequently, second-generation checkpoint inhibitors via targeting multiple pathways are urgently needed. Bintrafusp alfa (also known as M7824) is one of such agents that targets both the transforming-growth factor beta (TGF-β) and PD-L1 pathways. As T cells are the major immune cell subset responsible for tumor destruction, we focus on the peripheral memory T-cell subsets. Through the evaluation of peripheral biomarker analysis and their correlation with clinical outcomes, we have characterized blood-based dynamic phenotypes that predict responses to M7824 in NPC. Methods: Biomarker analysis was performed as part of a phase II clinical trial (NCT04396886) in patients with treatment-refractory histologically confirmed recurrent NPC (n=32) who received M7824. Peripheral blood samples were obtained at baseline before treatment (D0) and every 2 weeks during treatment. Samples collected at D0 and at time of best response assessment (DR) were analysed using multicolor flow cytometry. Patients with complete/partial response or stable disease for at least 6 months were considered responders (R), those with stable disease less than 6 months or progressive disease were considered non-responders (NR). Results: Peripheral T cells between R (n=10) and NR (n=22) patients were compared. While the overall percentage of memory T-cell subsets was similar in both groups after treatment, R patients displayed a significantly lower amount of prototype cell death receptor, CD95, among terminally differentiated effector memory (TEMRA; CD45RA+CD62L+) T cells (CD45+CD3+and CD45+ CD3+CD4+: p&lt;0.0001; CD45+CD3+CD8+: p=0.0047) (CD95DR/RvsNR) as compared to patient in NR group. Besides, reduced expression of CD95DR on TEMRA CD4 T cells was significantly associated with longer overall survival (OS), regardless of response status (median OS: 16.26 months for patients with lower CD95 levels; median OS: 5.29 months for patients with higher CD95 levels [p &lt; 0.0001]). Notably, we noticed that R patients displayed a lower frequency of CD95-expressing TEMRA at the baseline (CD95D0/Rvs NR) as compared to NR group. Conclusions: The apoptotic response of peripheral blood TEMRA CD4 T cells (CD95DR/R vsNR) may be a useful surrogate biomarker for predicting prognosis to M7824 therapy in NPC. The finding of a lower frequency of CD95D0TEMRA in R patients suggesting that CD95 may potentially act as a biomarker for predicting treatment response as well as reveal a possible target for guiding therapeutic strategy for R/M NPC.[Table: see text]

IFABP2 as a new prognostic biomarker for secondary non-response in rheumatoid arthritis

Increased intestinal permeability promotes the translocation of bacterial products from the local microbiome to the circulation, inducing inflammation and increasing clinical activity in rheumatoid arthritis (RA). This study evaluates whether intestinal fatty acid binding protein 2 (IFABP2) serum levels are prognostic biomarkers of non-response to conventional synthetic disease-modifying antirheumatic drug therapy (csDMARDs) in RA. The therapeutic schemes administered to 60 women with RA for at least 18months were assessed retrospectively, and the treatment response was classified according to the change in DAS28-ESR over time. Serum levels of IFABP2 and TNF-α were determined by ELISA. Receiver operating characteristics (ROC) curve analysis and logistic regression models were used to assess the predictive value and the association of IFABP2 with the non-responder phenotype in RA patients. Eleven women had a responder phenotype, 23 had a primary non-responder phenotype, and 26 had a secondary non-responder phenotype. Secondary non-responders showed higher DAS28-ESR (P=0.009) and higher IFABP2 serum levels compared to the responder group (P=0.023) and the primary non-responder group (P=0.018). IFABP2 serum levels were positively correlated with chloroquine dose (r=0.581, P=0.007) and negatively correlated with total cholesterol (r=-0.456, P=0.019) in secondary non-responders. The area under the curve (AUC) value of IFABP2 for predicting secondary non-response was 0.736, and IFABP2 serum levels>9.311ng/mL were associated with secondary non-response to csDMARDs (OR=6.00, P=0.003). IFABP2 serum levels are potentially a new biomarker predictive of secondary non-response to csDMARDs in RA, although our findings should be validated externally and in a larger cohort.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Anbal-cel is a novel autologous anti-CD19 CAR-T cell therapy which has been knocked-down for PD-1 and TIGIT expression using OVIS platform. It demonstrated superior T-cell functionality compared to other marketed CD19 CAR-T cells at preclinical studies. Phase 1 dose escalation study confirmed anbal-cel is safe and potentially effective. Methods: Patients with relapsed or refractory LBCL were enrolled from six Korean investigator sites to receive anbal-cel at a dose of 2 × 106 CAR-T cells/kg. Primary endpoint is objective response rate (ORR) assessed by Independent Review Committee (IRC). Secondary endpoints are progression-free survival (PFS), duration of response (DOR), pharmacokinetics (PK) and safety profiles. Results: As of 28 February 2023, a total of 41 patients were infused and 34 patients completed at least one tumor response evaluation at day 28. With the median age of 63 (range 37–82), 66% of the patients (27/41) were double expressor. Non-GCB type was 76% (31/41) and 42% (17/41) were primary refractory patients. Median follow-up period was 4.6 months. ORR (CR/PR) assessed by investigators was 85.3% and CR rate at day 28 & month 3 were 73.5% (25/34) and 71.4% (22/31) respectively. IRC assessment result was similar and will be presented at the meeting. Among the 41 patients, grade 3 CRS and ICANS were reported from 6 patients (14.6%) and 2 patients (4.9%) respectively. No grade 4 CRS and ICANS was observed. Prolonged neutropenia was observed in 11 patients (26.8%) and thrombocytopenia was observed in 12 patients (29.3%). Three (7.3%) serious infections (1 bacteria and 2 COVID-19 infections) were reported during primary follow-up period. Responder group (CR) reported higher incidence and severity of CRS compared to non-responder group (Non-CR), but it was insignificant. Incidence rate, severity of ICANS and prolonged cytopenia were comparable between the two groups. Among CAR+ T-cells in the anbal-cel product, median CD4:CD8 ratio was 3.6 and CCR7+ memory phenotype CAR T-cells account for 65.8% of CAR-T cells. Median knock-down rates of PD-1 and TIGIT were 65% and 96% respectively. The responder group showed a significantly increased level of CCR7+ memory phenotype (68.6% vs. 44.9%) and PD-1 knock-down rate (71.8% vs. 59.3%) compared to the non-responder group, which showed correlation with increased levels of AUC0-28days and Cmax. Anbal-cel expansion was not correlated to tumor volume measured by SPD and TMTV. In addition, the responder group had notable changes in cytokine levels of IL-2, IL-10, IFN-γ, granzyme, GM-CSF and peak levels of various cytokines were proportional to severity of CRS. Patients with higher levels of IL-15 and MCP-1 at baseline had tendency to experience ICANS. Conclusions: Anbal-cel demonstrated unique characteristics in product profile which demonstrated potential to correlate with treatment outcomes and warrant to confirm with more data. The research was funded by: Curocell Inc. Keywords: aggressive B-cell non-Hodgkin lymphoma, cellular therapies, immunotherapy No conflicts of interests pertinent to the abstract.

Single cell transcriptomics to identify immunological ACKR1+ DCs and their effect on clinical outcomes in left-sided CRC.

e15550 Background: Myeloid cells play critical roles in the growth and metastasis of malignant tumors with both protumor and antitumor capabilities. Plenty of studies have reported they participated in modulating tumor inflammation and angiogenesis, and therapeutic strategies targeting myeloid cells are ongoing in pre-clinical and clinical trials. The functions of myeloid cells and their subtypes in left-sided and right-side CRC remain unclear. Methods: A published scRNA-seq dataset (Pelka et al., 2021) with 21 samples from left-sided CRC and 79 from right-sided CRC (colorectal cancer) was obtained. Seurat (Stuart et al., 2019) was used to perform dimensionality reduction and differential expression analysis, and the cell subtypes in the myeloid cells were identified to study the associations between clinical outcomes and different tumor tissue sites of CRC. We also obtained an immunotherapy dataset from TISMO to identify associations between cell subtypes and immunotherapy outcomes. Results: Systematic comparisons of myeloid cells (n = 39,167) from left-sided and right-sided CRC revealed that highly expressed genes from right-sided CRC showed protumor capability and those from left-sided CRC showed antitumor activity. Specifically, left-sided CRC harbored a significant (p = 0.018) higher proportion of ACKR1+ DCs compared to right-sided CRC. ACKR1+ DCs might be immunological as its marker genes were significantly positively correlated with CD8+T cells and highly enriched in APC(antigen processing presentation)-related pathways. TCGA survival analysis revealed that the higher expression of the marker genes in ACKR1+ DC was associated with better overall survival (OS, p = 0.0088). Furthermore, immunotherapy biopsy showed ACKR1+ DCs subtype significantly enriched in immunotherapy responsive group compared to non-responsive group in colon cancer (p = 0.019), melanoma (p = 0.0058) and renal adenocarcinoma (p = 3.3e-06) among the obtained TISMO dataset. Conclusions: We identified an immunological ACKR1+ DCs subtype, which was highly enriched in left-sided CRC and was correlated with better clinical outcomes and immunotherapy responses. Those findings might provide potential therapeutic target and help better understand the mechanism of treatment strategies in CRC.

Evaluation of the Relationship between Vitamin D Receptor Gene Polymorphisms and Multiple Sclerosis Patients Who Responsive or non-Responsive to Treatment with Beta Interferon

Introduction: Multiple Sclerosis is a chronic, inflammatory disorder of the central nervous system, which leads to demyelination of nerves. Treatment with interferon beta is one of the best approaches to reduce recurrence and progression of the disease. The aim of this study is to search for the relationship between 4 polymorphisms FokIrs10735810, TaqIrs731236, ApaIrs797532 and BsmIrs1544410 located in the vitamin D receptor in MS patients responsive and non-responsive to interferon beta treatment and pave the way for the correct and fast administration of the appropriate drug, as well as reducing time, cost and lack of success in treatment.&#x0D; Methods: The type of study is observational and the study method is case-control. Blood samples were taken from 200 MS patients who were treated with interferon (100 responders and 100 non-responders). Using PCR-RFLP technique, the samples were subjected to enzymatic digestion with restriction enzymes ApaI, FokI, TaqI and BsmI. The data were evaluated using SPSS version 16, SNP Analyzer and Prism software, and K-tests and logistic regression.&#x0D; Results: A significant difference in the genotypic and allelic frequencies of ApaI (p=0.68), BsmI (p=0.65), FokI (p=0.57) and TaqI (p=0.50) polymorphisms in the patients between the two responsive and non-responsive groups to treatment was not observed.&#x0D; Conclusion According to our findings, there was no significant correlation between ApaI, FokI, TaqI and BsmI polymorphisms located in vitamin D receptor gene and response to treatment.

Time-related factors predicting a positive response to cardiac resynchronisation therapy in patients with heart failure

This study aimed to identify time parameters predicting favourable CRT response. A total of 38 patients with ischemic cardiomyopathy, qualified for CRT implantation, were enrolled in the study. A 15% reduction in indexed end-systolic volume after 6 months was a criterion for a positive response to CRT. We evaluated QRS duration, measured from a standard ECG before and after CRT implantation and obtained from mapping with NOGA XP system (AEMM); and the delay, measured with the implanted device algorithm (DCD) and its change after 6 months (ΔDCD); and selected delay parameters between the left and right ventricles based on AEMM data. A total of 24 patients presented with a positive response to CRT versus 9 non-responders. After CRT implantation, we observed differences between responders and non-responders group in the reduction of QRS duration (31 ms vs. 16 ms), duration of paced QRS (123 ms vs. 142 ms), and the change of ΔDCDMaximum (4.9 ms vs. 0.44 ms) and ΔDCDMean (7.7 ms vs. 0.9 ms). The difference in selected parameters obtained during AEMM in both groups was related to interventricular delay (40.3 ms vs. 18.6 ms). Concerning local activation time and left ventricular activation time, we analysed the delays in individual left ventricular segments. Predominant activation delay of the posterior wall middle segment was associated with a better response to CRT. Some AEMM parameters, paced QRS time of less than 120 ms and reduction of QRS duration greater than 20 ms predict the response to CRT. ΔDCD is associated with favourable electrical and structural remodelling.Clinical trial registration: SUM No. KNW/0022/KB1/17/15.

The Trend of Serum Creatinine Does Not Predict Follow-Up Biopsy Findings Among Kidney Transplant Recipients With Antibody-Mediated Rejection.

We included all cases of AMR at our program between March 2016 and July 2020 who had a follow-up biopsy after the index biopsy, with initial diagnosis of AMR. We trended the Scr and change in Scr (delta Scr) and its association with being a responder (microvascular inflammation, MVI ≤1) or nonresponder (MVI >1), as well as graft failure. A total of 183 kidney transplant recipients were included, 66 in the responder group and 177 in the nonresponder group. The MVI scores and sum chronicity scores, along with transplant glomerulopathy scores, were higher in the nonresponder group. However, Scr at index biopsy was similar in responders (1.74 ± 0.70) versus nonresponders (1.83 ± 0.65; P = 0.39), as were the delta Scr at various time points. After adjustment for multiple variables, delta Scr was not associated with being a nonresponder. Also, delta Scr value at follow-up biopsy compared with index biopsy among responders was 0 ± 0.67 (P = 0.99) and among nonresponders was -0.01 ± 0.61 (P = 0.89). Being a nonresponder was significantly associated with an increased risk of graft failure at the last follow-up in univariate analysis but was not in multivariate analysis (hazard ratio 1.35; 95% confidence interval, 0.58-3.17; P = 0.49). We found that Scr is not a good predictor of the resolution of MVI, supporting the utility of follow-up biopsies after treatment of AMR.

Long-term effectiveness and safety of lacosamide as adjunctive therapy in children and adolescents with refractory epilepsy: a real-world study

PurposeThe effectiveness and tolerability of lacosamide (LCM) among Chinese children and adolescents with refractory epilepsy has not yet been established. Therefore, the objective of this study was to assess the effectiveness and tolerability of LCM among children and adolescents with refractory epilepsy in Xinjiang, Northwest China.MethodsEffectiveness was assessed by measuring changes in seizure frequency at 3, 6 and 12 months compared with baseline. Patients that achieved ≥ 50% reduction in the frequency of all seizures per month, relative to baseline, were considered to be responders.Results105 children and adolescents with refractory epilepsy were enrolled in the study. The responder rates were 47.6%, 39.2%, and 31.9%, respectively at 3, 6, and 12 months. Seizure freedom rates were 32.4%, 28.9%, and 23.6% at 3, 6, and 12 months, respectively. The retention rates at 3, 6, and 12 months were 92.4%, 78.1%, and 69.5%, respectively. The maintenance dose of LCM within the responder group (8.2 ± 4.5 mg·kg− 1·d− 1) was significantly higher compared to the non-responder group (7.3 ± 2.3 mg·kg− 1·d− 1) (p < 0.05). At first follow-up, 44 patients (41.9%) reported experiencing at least one treatment-emergent adverse events.ConclusionThis real-world study of children and adolescents validated that LCM was both an effective and well-tolerated treatment option for the treatment of refractory epilepsy.

Gut Microbiota and B Cell Receptor (BCR) Inhibitors for the Treatment of Chronic Lymphocytic Leukemia: Is Biodiversity Correlated with Clinical Response or Immune-Related Adverse Event Occurrence? A Cross-Sectional Study

Several studies have strengthened the link between the gut microbiota (GM) and the response to immunotherapy in patients with tumors, highlighting the potential role of GM as a biomarker of response. Targeted therapies including B-cell receptor (BCR) inhibitors (BCRi) represent the newest approach to the treatment of chronic lymphocytic leukemia (CLL); however, not all patients achieve a satisfactory response, and immune-related adverse events (irAEs) can also impact the efficacy. The aim of the study was to compare GM biodiversity in patients with CLL, treated with BCRi for at least 12 months. Twelve patients were enrolled: 10 patients in the responder group (R) and 2 patients in the non-responder group (NR). We identified seven patients (58.3%) who experienced adverse reactions (AE). Although we did not observe a significant difference across the study population in terms of relative abundance and alpha and beta diversity, we found a differing distribution of bacterial taxa between the analyzed groups. We noted a higher level of the class Bacteroidia and the order Bacteroidales in the R group, and an inversion in the Firmicutes and Bacteroidetes ratio in the AE group. No prior studies have focused on linking GM and response to BCRi in these patients. Although the analyses are preliminary, they provide suggestions to guide future research.

Predictive value of bone marrow megakaryocyte count for immunotherapeutic response in primary Sjögren's syndrome patients with severe immune thrombocytopenia: A single-center case-control study in China.

To investigate potential predictors of treatment response in primary Sjögren's syndrome (pSS) patients with severe immune thrombocytopenia (ITP), with a focus on bone marrow megakaryocyte (MK) count. This case-control study included patients with pSS and severe ITP who were admitted to Peking Union Medical College Hospital and met the 2002 AECG or 2016 American College of Rheumatology / European League Against Rheumatism criteria for SS. Patients who had overlap other connective tissue diseases and with thrombocytopenia that could be explained by other causes were excluded. Severe ITP was defined as platelet count <20 × 109 /L. Response was evaluated at 3 months after treatment. Sixty-eight eligible patients were included: 34 (50%) achieved complete remission (CR), 18 (26%) partial remission (PR) and 16 (24%) were non-responders (NRs). Fewer infections were found in the CR group (24%) than in the PR (50%) and NR (56%) groups (P = 0.04). The MK count (CR 32 vs PR 36 vs NR 4 per slide, P < 0.001) in the NR group was significantly lower than in the other groups. MK count >6.5 per slide predicted good treatment response, with 85.7% sensitivity, 88.1% specificity and 0.866 area under the curve. Logistic regression indicated that patients with more MKs were more likely to respond to immunotherapy (crude odds ratio [OR] 1.45, 95% CI 1.2-2.0, adjusted OR 1.68, 95% CI 1.2-2.7). MK count predicted response to immunosuppressive treatment in pSS patients with severe ITP. These patients are recommended to have bone marrow aspiration before treatment initiation. Clinicians should be aware of screening for infections during clinical practice.