Non-responder Group Research Articles

Predictors of response to Radioactive Iodine Therapy in Intermediate and high risk patients with papillary thyroid carcinoma

BackgroundRadioactive iodine (RAI) therapy is the standard treatment approach after total thyroidectomy in patients with papillary thyroid carcinoma (PTC). We aimed to identify predictive factors of response to the treatment in intermediate and high-risk patients with PTC. In addition, the impact of multiple RAI treatments was explored.MethodsIn a 3-year retrospective study, data from intermediate and high-risk patients with PTC who received RAI therapy following total thyroidectomy, were analyzed by the end of year-one and year-three. Demographic data, tumor size, capsular/vascular invasion, extrathyroidal extension, local or distant metastasis, initial dose and cumulative dose of RAI, serum thyroglobulin(Tg), antithyroglobulin antibody(TgAb), and imaging findings were investigated. Patients with an excellent response to a single dose of RAI treatment, after three years of follow-up were classified as the “Responder group”. Excellent response was defined as stimulated serum Tg less than 1 ng/ml, or unstimulated serum Tg less than 0.2 ng/ml in TgAb-negative patients with negative imaging scans.Results333 patient records with a complete data set were analyzed in this study. After three years of initial treatment, 271 patients were non-responders (NR) and 62 were responders (R). At baseline, the median pre-ablation serum Tg level was 5.7 ng/ml in the NR group, and 1.25 ng/ml in the R group (P < 0.001). TSH-Stimulated serum Tg greater than 15.7 ng/ml, was associated with response failure even after multiple RAI therapy, AUC: 0.717(0.660–0.774), sensitivity: 52.5%, specificity: 89.47%, P < 0.001. On the other hand, multiple RAI therapy was associated with excellent response in 16.2% of the patients. The chance of ER was decreased by 74% if initial post-operation ultrasound imaging confirmed the presence of locoregional involvement, OR 0.26, (95% CI: 0.12–0.55), P < 0.001.ConclusionStimulated serum Tg and locoregional involvement after total thyroidectomy are predictive factors of non-response to RAI therapy in intermediate and high-risk patients with PTC. In addition, a minority of patients achieve excellent response after multiple RAI therapy.

Phase 2 trial of the farnesyltransferase inhibitor tipifarnib for relapsed/refractory peripheral T-cell lymphoma

AbstractA phase 2, international, open-label, nonrandomized, single-arm trial was conducted to evaluate the efficacy and safety of tipifarnib, a farnesyltransferase inhibitor, as monotherapy for relapsed/refractory peripheral T-cell lymphoma (PTCL) and to evaluate tumor mutation profile as a biomarker of response. Adults with relapsed/refractory PTCL received tipifarnib 300 mg orally twice daily for 21 days in a 28-day cycle. The primary end point was objective response rate (ORR); secondary end points included ORR, progression-free survival (PFS), duration of response (DOR), and adverse events (AEs) in specific subtypes. Sixty-five patients with PTCL were enrolled: n = 38 angioimmunoblastic T-cell lymphoma (AITL), n = 25 PTCL not otherwise specified, and n = 2 other T-cell lymphomas. The ORR was 39.7% (95% confidence interval [CI], 28.1-52.5) in all patients and 56.3% (95% CI, 39.3-71.8) for AITL. Median PFS was 3.5 months overall (954% CI, 2.1-4.4), and 3.6 months (95% CI, 1.9-8.3) for AITL. Median DOR was 3.7 months (95% CI, 2.0-15.3), and greatest in patients with AITL (7.8 months; 95% CI, 2.0-16.3). The median overall survival was 32.8 months (95% CI, 14.4 to not applicable). Tipifarnib-related hematologic AEs were manageable and included neutropenia (43.1%), thrombocytopenia (36.9%), and anemia (30.8%); other tipifarnib-related AEs included nausea (29.2%) and diarrhea (27.7%). One treatment-related death occurred. Mutations in RhoA, DNMT3A, and IDH2 were seen in 60%, 33%, and 27%, respectively, in the AITL tipifarnib responder group vs 36%, 9%, and 9% in the nonresponder group. Tipifarnib monotherapy demonstrated encouraging clinical activity in heavily pretreated relapsed/refractory PTCL, especially in AITL, with a manageable safety profile. This trial was registered at www.ClinicalTrials.gov as #NCT02464228.

Exploring genotypic variations in cotton associated with growth and nitrogen use efficiency

Low nitrogen (N) is a major limitation of cotton sustainability and productivity. N-efficient genotype cultivation can enhance productivity under the economical N usage. This study was conducted to characterize 15 cotton genotypes for N use efficiency (NUE) under differential N (0.0125 and 0.125 g kg−1 of sand) supply. All studied traits significantly responded to genotypes and N treatments. Under low N conditions, plants experienced reduced seedling height, root weight, shoot weight and total biomass (TDM) production, chlorophyll content, photosynthetic efficiency, NPK content, and N uptake efficiency (NUpE). Thus, intercellular CO2 concentration, photosynthetic N use efficiency (PNUE), and NUtE enhanced in low N supply, although these changes varied in magnitude. Based on variations in TDM production (14.6–33.1%) and NUtE (3.3–20.4%), GH-Uhad, FH-Anmol, FH-Super, GH-Haadi, and SLH-Chandani were categorized as efficient and responsive (ER), while J-7, CIM-343, FH-155, FH-492, FH-444 found as inefficient and non-responsive. The efficient and non-responsive group contained FH-142, GH-Baghdadi, and FH-490 whereas FH-152 and Cyto-179 were classified as inefficient and responsive. The scoring method provided further insight into genotypic NUE related to biomass distribution, photosynthetic rate (Pn), NUpE, and NUtE under low N. The highest cumulative score (15-18) of ER genotypes for these attributes indicated selected traits orchestrated to determine the NUE. Moreover, agronomical and NUE-related traits were positively associated with Pn, suggesting that photosynthesis is a primary manipulator of plant growth which coordinates biomass production and NUE. Overall, cultivars exhibited greater genotypic variation for NUE, providing a scientific basis to evaluate the existing germplasm and proposing that cultivation of N-efficient genotypes can decrease N application and help cotton breeding for sustainable production.

Can Ultrasound Evaluation of Lymph Node Size and Necrosis Rate Predict Chemotherapy Response in Cervical Tuberculous Lymphadenitis?

To explore the relationship between the initial size and the necrotic rate of lymph nodes evaluated by ultrasound in patients with cervical tuberculous lymphadenitis (CTL) and therapeutic response. Overall, 55 patients were included in this study. Conventional ultrasound and contrast-enhanced ultrasound examination were performed before anti-tuberculosis chemotherapy. Based on the different therapeutic outcomes, they were divided into responder groups (n = 39) and non-responder groups (n = 16). The relationship between the initial size (maximum area, length diameter, short diameter), rate of necrosis, and therapeutic response were compared and analyzed between two groups. There was a significant difference in maximum area, short diameter and rate of necrosis of lymph nodes between the responder groups and the non-responder groups (P < 0.05). The receiver-operating-characteristic (ROC) curve analysis was used to differentiate the two groups, it showed that the area under the curve was 0.746 for maximum area and 0.721 for short diameter, respectively. The cut-off value for the lymph node maximum area and short diameter based on ROC curve analysis was determined as 3.94cm2 (sensitivity 76.9%, specificity 68.7%) and 1.15cm (sensitivity 59.0%, specificity 93.7%), respectively. A negative correlation was observed between maximum area, short diameter, and therapeutic response. The initial maximum area and short diameter of lymph nodes were found to have a negative correlation with chemotherapy response in patients with CTL. The treatment outcomes are typically unsatisfactory for lymph nodes exhibiting an initial necrosis rate of 50% or higher. These findings may be helpful for evaluating therapeutic response.

Nutritional Status Is Associated With Physical Improvement of Palliative Cancer Patients During Cancer Rehabilitation.

Physical decline is accompanied with malnutrition in advanced cancer patients, thus nutritional care is often provided with cancer rehabilitation. However, a limited number of studies have focused on which nutritional index serves as an important marker to provide more intensive nutritional support for patients. We retrospectively reviewed advanced cancer patients who received chemotherapy and rehabilitation during hospitalization. In analysis 1, patients were divided into two groups: a Well group with caloric intake ≥ basal metabolism, calculated by the Harris-Benedict equation, and a Poor group with caloric intake less than their basal energy expenditure. The primary endpoint was the ratio of patients whose Eastern Cooperative Oncology Group Performance Status (ECOG PS) or Barthel index (BI) was maintained during rehabilitation. In analysis 2, the cohort was restratified into Responders, whose ECOG PS and BI improved, and Non-responders, comprising the remaining patients. Several nutritional indices were compared between the groups. Eighty-four patients were evaluated in analysis 1, namely 51 Well patients and 33 Poor patients. The ECOG PS-maintained rate was 98% and 91% (p=0.29), and the BI-maintained rate was 100% and 88% (p=0.02) in the Well and Poor groups, respectively. In analysis 2, 72 patients were evaluated after excluding 12 patients who lacked nutritional data after rehabilitation. Compared with the Responders group, caloric intake appeared worse in the Non-responders group, although their nutritional background tended to be better. Insufficient caloric intake might be a predictive marker of poor outcomes after rehabilitation in advanced cancer patients.

Integrated 68 Ga-FAPI-04 PET/MR in Pancreatic Cancer : Prediction of Tumor Response and Tumor Resectability After Neoadjuvant Therapy.

This study aimed to investigate the value of 68 Ga-fibroblast activation protein inhibitor (FAPI) PET/MR semiquantitative parameters in the prediction of tumor response and resectability after neoadjuvant therapy in patients with pancreatic cancer. This study was performed retrospectively in patients with borderline resectable or locally advanced pancreatic cancer who underwent 68 Ga-FAPI PET/MRI from June 2020 to June 2022. The SUV max , SUV mean , SUV peak , uptake tumor volume (UTV), and total lesion FAP expression (TLF) of the primary tumor were recorded. The target-to-background ratios (TBRs) of the primary tumor to normal tissue muscle (TBR muscle ) and blood (TBR blood ) were also calculated. In addition, the minimum apparent diffusion coefficient value of the tumor was measured. After 3-4 cycles of gemcitabine + nab-paclitaxel chemotherapy, patients were divided into responders and nonresponders groups according to RECIST criteria (v.1.1). They were also divided into resectable and unresectable groups according to the surgical outcome. The variables were compared separately between groups. A total of 18 patients who met the criteria were included in this study. The UTV and TLF were significantly higher in nonresponders than in responders ( P < 0.05). The SUV max , SUV mean , and TBR muscle were significantly higher in unresectable patients than in resectable ones ( P < 0.05). Receiver operating characteristic curve analysis identified UTV (area under the curve [AUC] = 0.840, P = 0.015) and TLF (AUC = 0.877, P = 0.007) as significant predictors for the response to gemcitabine + nab-paclitaxel chemotherapy, with cutoff values of 25.05 and 167.38, respectively. In addition, SUV max (AUC = 0.838, P = 0.016), SUV mean (AUC = 0.812, P = 0.026), and TBR muscle (AUC = 0.787, P = 0.041) were significant predictors of the resectability post-NCT, with cutoff values of 14.0, 6.0, and 13.9, respectively. According to logistic regression analysis, TLF was found to be significantly associated with tumor response ( P = 0.032) and was an independent predictor of tumor response ( P = 0.032). In addition, apparent diffusion coefficient value was an independent predictor of tumor resectability ( P = 0.043). This pilot study demonstrates the value of 68 Ga-FAPI PET/MR for the prediction of tumor response and resectability after neoadjuvant therapy. It may aid in individualized patient management by guiding the treatment regimens.

Predicting Acupuncture Efficacy in Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Study on Model Development and Result Visualization.

Acupuncture is one of primary treatment options for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), but its efficacy varies among patients. This study aimed to develop and validate a nomogram for predicting the efficacy of acupuncture in CP/CPPS. This study enrolled 220 patients with CP/CPPS who received acupuncture. Patients were divided into a responder group and nonresponder group based on the reduction in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI). Potential variables were selected using the least absolute shrinkage and selection operator regression, and a nomogram was established using the multivariable logistic regression model. The performance of the nomogram was assessed by the receiver operating characteristic curves and calibration curves. Two Hundred Twenty men were randomly assigned to the training cohort (n = 154) and the internal test cohort (n = 66). The developed nomogram included age, current drinking status, sedentary lifestyle, habit of staying up late, expectations for acupuncture, comorbidities, NIH-CPSI pain subscale and total scores. The area under the curve of the prediction model was 0.777 (95% CI: 0.702-0.851) in the training cohort, 0.752 (95% CI: 0.616-0.888) in the internal test cohort, demonstrating satisfactory discriminative ability as indicated by the calibration curve. The nomogram accurately identified CP/CPPS patients who would benefit from acupuncture. Factors such as youth, abstention from alcohol, avoiding sedentary habits and staying up late, having high expectations for acupuncture, being free from comorbidities, and baseline high scores on both the NIH-CPSI pain subscale and total scores may positively affect the efficacy of acupuncture. Further validation of our findings requires multicenter and large-sample prospective studies.

Comprehensive analysis of single cell and bulk RNA sequencing reveals the heterogeneity of melanoma tumor microenvironment and predicts the response of immunotherapy.

Tumor microenvironment (TME) heterogeneity is an important factor affecting the treatment response of immune checkpoint inhibitors (ICI). However, the TME heterogeneity of melanoma is still widely characterized. We downloaded the single-cell sequencing data sets of two melanoma patients from the GEO database, and used the "Scissor" algorithm and the "BayesPrism" algorithm to comprehensively analyze the characteristics of microenvironment cells based on single-cell and bulk RNA-seq data. The prediction model of immunotherapy response was constructed by machine learning and verified in three cohorts of GEO database. We identified seven cell types. In the Scissor+ subtype cell population, the top three were T cells, B cells and melanoma cells. In the Scissor- subtype, there are more macrophages. By quantifying the characteristics of TME, significant differences in B cells between responders and non-responders were observed. The higher the proportion of B cells, the better the prognosis. At the same time, macrophages in the non-responsive group increased significantly. Finally, nine gene features for predicting ICI response were constructed, and their predictive performance was superior in three external validation groups. Our study revealed the heterogeneity of melanoma TME and found a new predictive biomarker, which provided theoretical support and new insights for precise immunotherapy of melanoma patients.

Clinical significance of the maximum standardized uptake value on positron emission tomography to predict treatment response and outcomes in patients with rectal cancer undergoing neoadjuvant chemoradiotherapy.

The association between the reduction rate of the maximum standardized uptake value (SUVmax) on positron emission tomography (PET) during neoadjuvant chemoradiotherapy (NACRT) and the prognosis in patients with locally advanced rectal cancer is unknown. We retrospectively analyzed 62 patients with locally advanced rectal cancer who underwent curative surgery after NACRT at Kobe University between 2008 and 2021. The SUVmax reduction rate was calculated from preoperative and postoperative PET scans, and its association with the prognosis was investigated. The cutoff value for SUVmax reduction rate was 61.5%. Twenty patients had an SUVmax reduction rate > 61.5% (SUV responder group) and 38 patients had an SUVmax reduction rate ≤ 61.5% (SUV nonresponder group). Regarding pathological outcomes, the rate of a good histological response was significantly higher in the SUV responder group than in the SUV nonresponder group (80.0% vs. 21.1%, p < 0.001). Both the overall (OS) and relapse-free survival (RFS) rates were significantly better in the SUV responder group than in the SUV nonresponder group (OS, p = 0.035; RFS, p = 0.019). In the SUV responder group, only 1 case of recurrence was observed, with a median follow-up period of 56months. The rate of SUVmax reduction during NACRT might predict the long-term prognosis of patients with locally advanced rectal cancer.

Histogram analysis of multiple diffusion models for predicting advanced non-small cell lung cancer response to chemoimmunotherapy

BackgroundThere is an urgent need to find a reliable and effective imaging method to evaluate the therapeutic efficacy of immunochemotherapy in advanced non-small cell lung cancer (NSCLC). This study aimed to investigate the capability of intravoxel incoherent motion (IVIM) and diffusion kurtosis imaging (DKI) histogram analysis based on different region of interest (ROI) selection methods for predicting treatment response to chemoimmunotherapy in advanced NSCLC.MethodsSeventy-two stage III or IV NSCLC patients who received chemoimmunotherapy were enrolled in this study. IVIM and DKI were performed before treatment. The patients were classified as responders group and non-responders group according to the Response Evaluation Criteria in Solid Tumors 1.1. The histogram parameters of ADC, Dslow, Dfast, f, Dk and K were measured using whole tumor volume ROI and single slice ROI analysis methods. Variables with statistical differences would be included in stepwise logistic regression analysis to determine independent parameters, by which the combined model was also established. And the receiver operating characteristic curve (ROC) were used to evaluate the prediction performance of histogram parameters and the combined model.ResultsADC, Dslow, Dk histogram metrics were significantly lower in the responders group than in the non-responders group, while the histogram parameters of f were significantly higher in the responders group than in the non-responders group (all P < 0.05). The mean value of each parameter was better than or equivalent to other histogram metrics, where the mean value of f obtained from whole tumor and single slice both had the highest AUC (AUC = 0.886 and 0.812, respectively) compared to other single parameters. The combined model improved the diagnostic efficiency with an AUC of 0.968 (whole tumor) and 0.893 (single slice), respectively.ConclusionsWhole tumor volume ROI demonstrated better diagnostic ability than single slice ROI analysis, which indicated whole tumor histogram analysis of IVIM and DKI hold greater potential than single slice ROI analysis to be a promising tool of predicting therapeutic response to chemoimmunotherapy in advanced NSCLC at initial state.

A computed tomography-based nomogram for neoadjuvant chemotherapy plus immunotherapy response prediction in patients with advanced esophageal squamous cell carcinoma.

To develop a CT-based nomogram to predict the response of advanced esophageal squamous cell carcinoma (ESCC) to neoadjuvant chemotherapy plus immunotherapy. In this retrospective study, 158 consecutive patients with advanced ESCC receiving contrast-enhanced CT before neoadjuvant chemotherapy plus immunotherapy were randomized to a training cohort (TC, n = 121) and a validation cohort (VC, n = 37). Response to treatment was assessed with response evaluation criteria in solid tumors. Patients in the TC were divided into the responder (n = 69) and non-responder (n = 52) groups. For the TC, univariate analyses were performed to confirm factors associated with response prediction, and binary analyses were performed to identify independent variables to develop a nomogram. In both the TC and VC, the nomogram performance was assessed by area under the receiver operating characteristic curve (AUC), calibration slope, and decision curve analysis (DCA). In the TC, univariate analysis showed that cT stage, cN stage, gross tumor volume, gross volume of all enlarged lymph nodes, and tumor length were associated with the response (all P < 0.05). Binary analysis demonstrated that cT stage, cN stage, and tumor length were independent predictors. The independent factors were imported into the R software to construct a nomogram, showing the discriminatory ability with an AUC of 0.813 (95% confidence interval: 0.735-0.890), and the calibration curve and DCA showed that the predictive ability of the nomogram was in good agreement with the actual observation. This study provides an accurate nomogram to predict the response of advanced ESCC to neoadjuvant chemotherapy plus immunotherapy.

Long-term survival outcomes in patients with relapsed/refractory large B-cell lymphoma after treatment of relma-cel: 4-year follow-up in RELIANCE study.

e19001 Background: RELIANCE study (NCT04089215) demonstrated the efficacy and safety of relma-cel, a CD19-targeted chimeric antigen receptor T-cell product, in patients with heavily pre-treated relapsed/refractory large B-cell lymphoma (r/r LBCL). We previously reported efficacy of relma-cel, noting objective response rate (ORR) in 77.59% of patients (CRR 53.45%), 2-year progression-free survival (PFS) rate and overall survival (OS) rate were 38.8% and 69.3%, respectively. Herein, we aimed to update the long-term survival results for 4-year follow-up (FU). Methods: Study design was previously published. Eligible patients were adults with histologically confirmed r/r LBCL and had failed at least two prior lines of therapy, including an anti-CD20 monoclonal antibody and an anthracycline-based regimen. Patients were enrolled at 10 clinical sites in China and underwent lymphodepletion prior to receiving relma-cel at a single dose of 100 × 106 (n=27) or 150 × 106 (n=32) CAR+ T cells. The primary endpoint was ORR at 3-month, as assessed by investigators. Secondary endpoints were duration of response (DOR), PFS, OS and safety profiles. For this abstract, we collected the survival status and updated the survival outcomes. Results: From Nov 2017 to Dec 2019, a total of 68 patients were enrolled, and 59 received relma-cel infusion. Among 58 evaluable efficacy patients with 2-year FU, 31 achieved CR (CR group), 14 achieved PR (PR group) and 13 had no response (Non-responder group). As of Dec 18, 2023, with 48.1 months (95% CI, 37.75 to 49.38) of median FU, 25 patients were still alive, 18 were died (5 deaths in CR group, 5 in PR group and 8 in Non-responder group), and 15 patients were censored due to lost to FU including 7 lost within 2 years and 8 after 2 years. The median OS were not reached (NR), and 1-year and 2-year OS rate were reported previously. The update estimated landmark OS rates were 69.3% at 3-year and 66.7% at 4-year. The OS rates of CR group at each year were numerically higher than those of PR group and Non-responder group (87.1% v.s. 59.3% v.s. 30.8% at 3-year and 82.5% v.s. 59.3% v.s. 30.8% at 4-year; Table). Conclusions: Four-year FU results in RELIANCE Study suggested that, although heavily pretreated, the patients who had response, especially who achieved CR, may experience greater survival benefits, from relma-cel therapy. Clinical trial information: NCT04089215 . [Table: see text]

Relationship between prehabilitation responsiveness and postoperative physical functional recovery in cardiovascular surgery

BackgroundThe purpose of this study was to examine the relationship between responsiveness to prehabilitation and postoperative recovery of physical function in cardiac surgery patients. MethodsNinety-three cardiac surgery patients (mean age: 76.4 years) were included in this retrospective cohort study. Preoperative physical function was measured using the Short Physical Performance Battery (SPPB), and a prehabilitation exercise program was implemented for the SPPB domains with low scores. Among the patients, those whose SPPB score was over 11 from the start of prehabilitation and remained over 11 on the day before surgery were defined as the high-functioning group, and those whose SPPB score improved by 2 points or more from the start of prehabilitation and exceeded 11 points were defined as the responder group. Those whose SPPB score did not exceed 11 immediately before surgery were classified as non-responders. The characteristics of each group and postoperative recovery of physical function were investigated. ResultsThere were no serious adverse events during prehabilitation. Mean days of prehabilitation was 5.4 days. The responder group showed faster improvement in postoperative physical function and shorter time to ambulatory independence than the non-responder group. The non-responder group had lower preoperative skeletal muscle index, more severe preoperative New York Heart Association classification, and a history of musculoskeletal disease or stroke. ConclusionThere were responders and non-responders to prehabilitation among cardiac surgery patients. Cardiac surgery patients who respond to prehabilitation had faster recovery of physical function. Further research is needed to determine what type of prehabilitation is more effective in postoperative recovery of physical function in cardiac surgery patients.

Pan-cancer B- and T-cell transcriptome analysis of CXCL13 as a predictive marker for immune checkpoint inhibitor response.

2626 Background: Maturation of lymphoid structures and tumor-antigen presentation via B cells in the tumor microenvironment (TME) have been recognized as factors in tumor immunity. The presence of B cells and tertiary lymphoid structures appears to result in better prognosis in patients with cancer but their role in response to immunotherapy remains subject to research. This study aimed to leverage the transcriptome expression of B and T cell markers and elucidate their impact on response to immune checkpoint inhibitors (ICIs). Methods: Among 514 patients with cancer included in the Profile-Related Evidence determining Individualized Cancer therapy study (NCT02478931), 208 with advanced cancer and available date treated with ICIs were analyzed. Patients were divided into responders (progression-free survival [PFS] after initiation of ICI therapy: 6 or more months) and non-responders (PFS: less than 6 months). Transcriptome expression of 34 immunoregulatory markers associated with B and T cells was compared between these groups using odds ratios (ORs) of “High” transcriptome expression [“High” (75-100 percentile), “Intermediate” (25-74), and “Low” (0-24), rank compared to 735 controls] of each immune marker for immunotherapy responders. A logistic regression model was used to perform a multivariable analysis of ORs. Clinical characteristics between responders and non-responders were summarized, and rate of “High” transcriptome expression of identified markers contributing to immunotherapy response was summarized by cancer type. Results: In total, 82 and 126 patients were classified into responder and non-responder groups. Median age was 65.0 and 61.0, and women were 58.5% (48/82) and 54.8% (69/126) in each group, respectively. Cancer type in both groups was well balanced. In univariate analysis, “High” transcriptome expression of CXCL13, CD3, BTLA, CTLA-4, and PD-1 was significantly more frequent in the responder than non-responder group. Cluster heatmaps in both groups revealed more B and T cell enriched population in the responder group. In multivariable analysis, patients with “High” CXCL13 expression were more likely to be immunotherapy responders (OR: 3.91, 95% confidence interval [CI]=1.02-15.04, p=0.044). High CXCL13 transcriptome expression was most common in head and neck (25%, 3/12), breast (22.4%, 11/49), neuroendocrine (20%, 3/15), and lung (20%, 4/20) tumors. Conclusions: This pan-cancer analysis found an association between high CXCL13 mRNA expression and better response to ICI therapy. CXCL13 role in promoting a lymphoid structure in the TME by facilitating B-cell recruitment could enable anti-tumor immunity, resulting in better response to immunotherapy. This indicates that dissection of not only T cell but also B cell regulatory factors is necessary to cancer immunotherapy response and resistance mechanisms. Clinical trial information: NCT02478931 .

Associations of T-cell fitness prior to B-cell maturation antigen (BCMA)–targeted chimeric antigen receptor T-cell (CART) and bispecific T-cell engager (BiTE) therapies and efficacy/toxicity in relapsed/refractory multiple myeloma (RRMM).

7549 Background: While CART and BiTE have led to unprecedented responses in RRMM, some patients (pts) do not respond or have short-lived responses. Currently no predictive markers exist to identify these pts. This study explored pretreatment T-cell fitness and efficacy/toxicity in RRMM using a novel single-cell secretome analysis. We hypothesized that pretreatment Polyfunctional Strength Index (PSI) may predict efficacy to BCMA-directed T-cell therapies. Methods: We included 14 RRMM pts treated with idecabtagene vicleucel or teclistamab at Yale Cancer Center with ≥6 mos post-treatment follow-up. Peripheral blood prior to treatment was frozen and then PBMC’s thawed for analysis. PSI, a metric for T-cell fitness combining polyfunctional T-cells % with the intensity of secreted cytokines, was obtained using the IsoPlexis’ Single-Cell Secretome Platform. The overall PSI was an average of CD4+ and CD8+ PSIs. Response was assessed by the International Myeloma Working Group criteria and response duration was defined as time from response to disease progression. Responder (R) was defined as ≥very good partial response for ≥6 mos. Non-responder (NR) was defined as stable or progressive disease ≤3 mos. Cytokine release syndrome (CRS) and immune-effector cell associated neurotoxicity syndrome (ICANS) were graded using the American Society for Transplantation &amp; Cellular Therapy system. Statistics were performed with Mann-Whitney U test using GraphPad PRISM v.9. Results: There were 7 pts in R group (2 BiTE &amp; 5 CART) and 7 pts in NR group (3 BiTE &amp; 4 CART). Median follow-up time was 13.5 mos(range, 7-27). Median age at treatment was 64 yrs in R and 63 yrs in NR. Extramedullary disease (EM) was present in 14.3%(n=1) in R and 71.4%(n=5) in NR. High-risk cytogenetics, defined as del17p, t(4;14), t(14;16), t(14;20), 1q gain/amplification and del1p, were seen in 42.9%(n=3) in R and 85.7%(n=6) in NR. Median prior lines of therapy was 6(range, 4-9) in R and 8(range, 4-10) in NR. CRS/ICANS occurred 85.7%(n=6) in R and 28.6%(n=2) in NR. Overall PSI was 184 in R and 91 in NR(p=0.1649). CD4+ PSI was 160 in R and 75 in NR(p=0.1649). CD8+ PSI was 207 in R and 108 in NR(p=0.1981). Overall PSI was 143 in CRS/ICANS and 130 in no CRS/ICANS(p=0.7546). Conclusions: Overall PSI, CD4+ PSI and CD8+ PSI were 1.9-2.1 times higher in R compared to NR and overall PSI was slightly higher in CRS/ICANS compared to no CRS/ICANS though the difference was not statistically significant. One limitation was a small sample size and thus testing PSI in a larger cohort might yield statistically significant results. The NR group had more high-risk cytogenetics and higher EM. One confounder could be that measuring peripheral T-cell fitness may not be sufficient to predict response in EM where spatial determinants of T-cell influx play a role.

A single-arm exploratory clinical study of β-glucan combined with camrelizumab and SOX chemotherapy as first-line treatment for advanced gastric adenocarcinoma.

e16008 Background:The combination of immunotherapy plus chemotherapy has revolutionized the therapy pattern of advanced gastric adenocarcinoma, but the efficacy is still unsatisfactory. β-glucan has been reported to be a potential natural immune modulator for tumor growth inhibition. Therefore, we aimed to evalute the efficacy and safety of β-glucan plus immunotherapy and chemotherapy in the first-line treatment of advanced gastric adenocarcinoma. Methods:This is a prospective, single-arm, investigator-initiated trail. All included patients are adults with advanced gastric adenocarcinoma, and with an Eastern Cooperative Oncology Group (ECOG) score ≤ 2. Eligible patients received WGP β-glucan (500 mg; twice daily on days 1-14) + camrelizumab (day 2; fixed-dose 200 mg) + oxaliplatin (day 1; 130 mg/m2)+ oral S-1 (twice daily on days 1-14; body surface area &lt; 1.25 m2: 40 mg; body surface area 1.25-1.5 m2: 50 mg; body surface area &gt; 1.5 m2: 60 mg) every 3 weeks. The curative effect is evaluated (RECIST 1.1) every 2 cycles. Safety evaluation indicators include vital signs, laboratory indicators and treatment-related adverse events (TRAEs). The primary endpoints were objective response rate (ORR) and safety; the secondary endpoints were median progression-free survival (mPFS) and median overall survival (mOS); the exploratory endpoint treatment-related biomarker changes from liquid biopsies. Results:From April 2021 to October 2022, a total of 30 patients with average of 67.5 years old had been enrolled, incuding 20 (66.7%) males and 8 (26.7%) patients with an ECOG PS score of 2. The ORR was 60%; the mPFS was 10.4 months (95% confidence interval [CI], 9.52-11.27); the mOS was 14.0 months (95% CI, 11.09-16.91). A total of 19 patients (63.3%) had TRAEs, with 9 patients (30%) with grade ≥ 3. The most common treatment-related adverse events were nausea (53.3%) and hemangioma (33.3%). No TRAEs associated with β-glucan were observed. After 2 cycles of treatment, the levels of IL-2 and IFN-γ significantly increased ( P &lt; 0.05), and the number of CD4+ T cells also significantly increased ( P &lt; 0.05). Furthermore, the protein expressions of GZMA, GZMH, and CD244 were significantly lower in the responding group (CR+ PR) than in the non-responding group (SD + PD) (P &lt; 0.05). Conclusions: This preliminary study demonstrates that β-glucan plus camrelizumab and SOX chemotherapy offers favorable efficacy and a manageable safety profile in patients with advanced gastric adenocarcinoma, and further studies are needed to verify its efficacy and safety. Clinical trial information: ChiCTR2100044088.

First-line immunochemotherapy modulates peripheral immune landscape in advanced gastric cancer and gastroesophageal junction cancer (GC/GEJC): Prediction of response to combination therapy.

e14540 Background: The use of immunochemotherapy has brought about a change in the treatment of advanced or metastatic GC/GEJC, but only a subset of patients could benefit substantially. Therefore, seeking efficacious biomarkers to identify favorable populations for the regimen is imperative. This study aims to explore predictive markers and potential mechanism of combination therapy for GC/GEJC in real-world settings based on blood proteomic biopsy. Methods: This is a prospective, single-center trial in which all patients are adults with advanced or metastatic GC/GEJC confirmed by pathology or imaging. 30 eligible patients will receive PD-1 mab (sintilimab/nivolumab (NIVO) Q3W) and chemotherapy (SOX/XELOX Q3W) regardless of programmed death ligand-1 status. Blood samples were collected before treatment and after every two treatment cycles for Olink Target 96 IO analysis. CT scans were performed after every two cycles and will be categorized as responding (complete response plus primary response) or non-responding (progress disease plus stable disease) according to RECIST 1.1. Results: As of January 17, 2024, a total of 21 patients were enrolled. Eight of these patients received 16 samples before and after treatment, with 4 each of the 8 patients responding and non-responding. By analyzing the baseline samples comparing the responding and non-responding groups, it was found that patients in the responding group had lower expression of serum PD-L1 (sPD-L1) ( p=0.015). In the post-treatment samples, angiopoietin 1 was found to be poorly expressed in the responding patients ( p&lt;0.001). In contrast, high expression of angiopoietin 2 in post-treatment blood samples was more pronounced in non-responders compared to pre-treatment ( p=0.020). Additionally, we observed that immunotherapy can modify the immune microenvironment by up-regulating the T cell receptor signaling and NK cell-mediated toxic effects pathways. These pathways may be potential targets for treatment. Conclusions: In summary, low sPD-L1 level before treatment may be a predictive biomarker for better efficacy of immuno-combination chemotherapy in advanced GC/GEJC; whereas elevation of angiopoietin after treatment predicts poor efficacy and suggests that antiangiogenic therapy may subsequently be added in non-responding patients. We are further recruiting more patients to obtain more accurate conclusions. Clinical trial information: ChiCTR2300078000 .

Landscape of genomic alterations in patients with chemoradiation resistant cervical cancer using whole-genome sequencing.

e17531 Background: Cervical cancer is a pressing global health concern and ranks as the second most prevalent female malignancy in India. Unfortunately, 80% of cases are diagnosed at locally advanced stages, leading to significant morbidity and mortality. Standard treatment for locally advanced cervical cancer involves concurrent pelvic radiotherapy and chemotherapy (CCRT). However, a substantial 30%-40% of patients experience CCRT treatment failure. The genomic alterations owing to CCRT resistance are largely unknown. This pilot study aims to identify genomic alterations associated with differential responses to concurrent chemoradiotherapy in cervical cancer patients. Methods: We collected 36 fresh tissue biopsies along with 5 ml of blood from stage IIIB cervical cancer patients. From the total of 36 cervical cancer patients, based on RECIST (Response evaluation criteria in solid tumors) criteria 19 patients were classified as responders and 17 patients were categorized as non-responders to CCRT. Genomic DNA was extracted from both tumor tissue and paired blood samples. Subsequently, whole genome sequencing was performed using the Novaseq 6000 platform, achieving a sequencing depth of 30x-50x coverage with 2x150bp paired reads. The data was further analyzed for Single Nucleotide Variants (SNVs), Copy Number Alterations (CNAs), Structural Variants (SVs), and mutational signatures. Results: In our study, we identified several notable mutated genes, with MUC12 (35%), MUC4 (31%), MACF1 (27%), and OBSCN (27%) being the most prominent. The mutational spectrum encompassed well-known significantly mutated genes such as FBXW7, SPEN, PIK3CA, KMT2C, KMT2D, ARID1A, and STK11, as well as potential novel candidates, genes not previously associated with cervical cancer, such as PKHD1L1, PLEC, and LRP1B. Pathway analysis revealed that several signaling pathways were enriched in cervical cancer, including Notch signaling, Hippo signaling, and RTK/RAS signaling pathways. Mutational signature analysis revealed a prevalence of APOBEC mutagenesis pattern. Copy number alterations displayed amplifications in regions such as 3q, 9p, 14q, and 11p which encompass genes like PIK3CA, JAK2, CD274, and AKT1. Comparative analysis of genomic alterations between chemoradiation resistant and sensitive patients identified mutations in genes related to Notch signaling and TNF signaling, which were exclusively present in the non-responder group. Conclusions: This study represents an initial attempt to understand the genomic landscape of cervical cancer in Indian population using whole genome sequencing approach and its association with responses to CCRT. These findings not only pave the way for further research but also hold promise for the development of targeted therapies, offering potential enhancements in the management of chemoradiation-resistant cervical cancer patients.

Exploring gut microbiome markers in predicting efficacy of immunotherapy against lung cancer.

8525 Background: Immunotherapy has profoundly changed the treatment landscape for lung cancer (LC) due to its tolerable safety profile and longer sustained therapeutic response. However, only about 20% of patients with locally advanced and metastatic disease can derive long-term clinical benefit from ICIs. Previous studies have suggested that the microbiome is involved in the development of LC in some way. We aimed to use the gut microbiome (GM) to model the benefit of immunotherapy and to mine the biomarkers with a global impact on immune response. Methods: We performed human gut metagenomic analysis on the responder patients and non-responder patients with immunotherapy. A total of 296 fecal samples, including baseline samples (71 responders, 98 non-responders and 72 healthy controls), and 55 samples during treatment were enrolled in our study, the taxonomic and functional features of these samples also were excavated. A machine-learning model was developed to identify responders and non-responders. At the same time, we also explored the influence of antibiotic use on the above results. Results: Specific species, Bacteroides caccae and Bacteroides uniformis, were positively correlated with responders. In non-responders, Prevotella copri was the main enrichment species. The α diversity of microbiota in responding patients was significantly higher than that in non-responding groups, and antibiotic use increased this trend. There was no significant difference in β diversity between the two groups, but LEFSE analysis also could obtain biomarkers of biological significance between the two groups. We used the biomarkers from the above analysis to construct a random forest model, and the area under the receiver operating characteristic curve (AUC) (species level: 82.10%; genus level: 79.4%). In addition, our studies suggested that metabolism such as amino acid metabolism, valine, leucine might be important in regulating the immunotherapy response that warrants further investigation. Conclusions: Overall, our study explored the relationship between microbial composition and immunotherapy efficacy in LC patients and mined relevant markers, and further research is needed to investigate the mechanisms of action of these key strains in influencing immunotherapy in the future.

Clinical and molecular mechanisms for predicting the efficacy of immunotherapy for hepatocellular carcinoma based on gut microbiome.

e16222 Background: Hepatocellular carcinoma (HCC) is an aggressive malignant tumor, ranking as the fifth most common cancer and the third leading cause of cancer-related deaths globally, posing a significant global health issue. Increasing evidence suggests that the gut microbiome and their metabolites play a crucial role in the development and therapeutic processes of cancer. Immune checkpoint inhibitors (ICIs) have recently become a treatment option for unresectable advanced HCC. To further guide the selection of immunotherapy for clinical HCC patients, it is necessary to further elucidate the prediction of immunotherapy efficacy for HCC based on the microbiome. Methods: The study enrolled 26 unresectable advanced HCC patients and collected baseline clinical laboratory data. We administered ICIs therapy to HCC patients every three weeks. After 6 months of treatment, patients were divided the responsive group (R group) and the non-responsive group (NR group) based on imaging evaluation according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Prior to the application of anti-tumor treatment, fecal samples were collected from the patients for 16S rRNA microbiome sequencing analysis. Immunofluorescence was used to detect the expression of PD-L1 in tumor tissue, and immunohistochemistry was used to assess changes in lymphocyte subsets CD3+T cells, CD4+T cells, CD8+T cells and Treg cells, as well as the expression of TNF-α, γ-IFN, and GZMB. Additionally, the peripheral blood lymphocyte subsets CD3+T cells, CD4+T cells and CD8+T cells were analyzed by flow cytometry. Results: In our study, R group showed higher taxa richness and more gene counts than those of NR group. Comparing with NR group, the relative abundance of Firmicutes were significantly increased, whereas Proteobacteria and Bacteroidota were significantly decreased in R group at phylum level (all P &lt; 0.05). Our study showed that R group had high level of lymphocyte subsets CD3+T cells and CD8+T cells and low level of CD4+T cells and Treg cells compared to NR group (all P &lt; 0.05). And the expressions of PD-L1, TNF-α,γ-IFN and GZMB were upregulated in R group(all P &lt; 0.05). Conclusions: These findings suggested that the characteristics of gut-microbial diversity and composition at the early treatment period of ICIs therapy in HCC may have distinct implications on drug efficacy and disease prognosis. ICIs therapy reshaped HCC tumor microenvironment in parallel with regulating the gut microbiome and lymphocyte subsets immunity.