bluuebunny/crossref_metadata_2025_split huggingface dataset:
High transferrin receptor expression marks tumors with increased immune-effector infiltration and expression of targetable checkpoint molecules: Results of a multi-cancer analysis in solid tumors.
Authors: Trabolsi Asaad , Arumov Artavazd , Gandhi Nishant , Farrell Alex Patrick , Kang Irene , Hoon Dave S. B. , Wei Sam , Radovich Milan , Sledge George W. , Liu Stephen V. , Ma Patrick C. , Schatz Jonathan Harry 
Published: June 2023

2613 Background: The cell-surface transferrin receptor, TFR1, encoded by TFRC, imports iron-bound transferrin into cells to drive tumor proliferation. We have found worse prognosis with high TFRC expression across multiple tumor types. The mechanism by which TFRC drives tumor cell- intrinsic oncogenesis is multifactorial, but its interaction with the tumor microenvironment (TME) has not been studied. Here, we assessed TME infiltration by immune effector populations and immune checkpoint expression. Methods: Tissue samples underwent comprehensive molecular profiling at Caris Life Sciences: Next-gen sequencing of DNA (592 Gene Panel, NextSeq, or whole exome sequencing, NovaSeq), RNA- seq (NovaSeq, whole transcriptome sequencing, WTS) and immunohistochemistry. RNA deconvolution analysis by the Microenvironment Cell Populations (MCP)-counter method quantified immune populations to assess T cells, B cells, natural killer cells (NK) and myeloid dendritic cells (MDC). Analyses compared quartiles of TFRC mRNA expression between Q4 ( TFRC-H) high and Q1 ( TFRC-L) low expressors. Results: Among 27,607 patients with non-small cell lung cancer (NSCLC), 5,332 with prostate cancer (PC), and 14,287 with colorectal cancer (CRC), TFRC-H tumors were associated with high tumor mutational burden (TMB-high, ≥10 mutations/MB), and TP53 mutation (q<0.05). Multiple immune checkpoint genes showed significantly higher expression in TFRC-H relative to TFRC-L in all tumor types, including CD274 (PDL1), LAG3, PDCD1LG2 (PDL2), and CTLA4 (Table; All values are statistically significant: q<0.05). Moreover, TME assessment by MCP-counter showed significantly increased infiltration by total T cells, CD8+ cells, B cells, NK cells, and MDCs in TFRC-H (Table). Finally, among patients who received Check-point inhibitors (CPI), TFRC-L had improved survival (HR=0.807 (95% CI 0.76 – 0.85) p<0.00001) in NSCLC but no difference was found in CRC or PC. Conclusions: Our study is the first to reveal the TME characteristics associated with TFRC expression in a variety of solid tumor types. We found TFRC-H tumors have increased infiltration by immune effector populations but also express significantly higher levels of immune checkpoint molecules, highlighting immune exhaustion. Altered iron metabolism has been shown to promote tumorigenesis and here we identify a new role for TFRC in remodeling the TME. TFR1- targeting therapeutic agents are in clinical development and warrant further investigation in combination with CPIs. [Table: see text]
Genomic landscapes to characterize mismatch-repair deficiency (dMMR)/microsatellite instability-high (MSI-H) gastrointestinal (GI) cancers stratified by tumor mutation burden (TMB).
Authors: Wang Jingyuan , Xiu Joanne , Farrell Alex Patrick , Battaglin Francesca , Arai Hiroyuki , Millstein Joshua , Soni Shivani , Zhang Wu , Shields Anthony F. , Grothey Axel , Weinberg Benjamin Adam , Marshall John , Lou Emil , Khushman Moh'd M. , Sohal Davendra , Hall Michael J. , Oberley Matthew James , Spetzler David , Lenz Heinz-Josef 
Published: June 2023

2618 Background: TMB is a predictive biomarker for immune checkpoint inhibitor treatment in dMMR/MSI-H cancers. We aimed to characterize specific molecular features of a large cohort of dMMR/MSI-H GI tumors with a range of TMB levels. Methods: A total of 2272 GI tumors tested as dMMR/MSI-H were analyzed using Next-generation sequencing (NGS) and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ). MMR/MSI status was evaluated by a combination of IHC, Fragment Analysis and NGS. TMB-H were defined using differing TMB cutoffs (10, 20, 50 mutations/Mb). Molecular features were compared in four groups (TMB < 10 vs 10-20 vs 20-50 vs ≥50mutations/Mb) using Fisher-Exact or Chi-square and adjusted for multiple comparison by Benjamini-Hochberg. The impact of TMB on tumor immune environment was analyzed using a TCGA cohort. Significance was determined by adjusted (adj) P < 0.05. Results: Tumors with TMB over 10, 20, 50 mutations/Mb were observed in 95.38%, 86.05% and 14.47% respectively in the dMMR/MSI-H GI cohort. Compared to other groups, dMMR/MSI-H GI tumors with TMB over 50 mutations/Mb exhibited the highest mutations rates in RNF43, MSH6, KMT2D, BRCA2 and ASXL1 (Top 5, all Padj< 0.0001). Among the four MMR genes, only MLH1 mutation had no association with higher TMB. The rates of CNNE1 amplification (i.e. the Cycle E1 gene) and HER2 overexpression were the highest in tumors with TMB below 10 mutations/Mb (all Padj< 0.05). The association between PD-L1 positivity and TMB levels was only observed in gastroesophageal cancers ( P= 0.03). The lymphocyte infiltration signature score, IFNγ response and M1 macrophage infiltration were significantly lower, while fraction of genome alterations was significantly increased in dMMR/MSI-H tumors with TMB below 10 mutations/Mb, compared to other subgroups (all P< 0.05). Neoantigens were significantly enriched in those with TMB over 50 mutations/Mb, compared to other subgroups ( P< 0.0001). Conclusions: This is the largest study to investigate the distinct molecular landscape of dMMR/MSI-H GI cancers with different degrees (magnitude) of TMB. These data may inform our understanding of the efficacy of ICB in dMMR/MSI-H GI tumors.
Spatial distribution of B cells and lymphocyte clusters for the treatment of non-small cell lung cancer.
Authors: Ramos Corinne , Gerstenberg Amandine , Boute Melodie , Ponzoni Adele , Stauber Jonathan 
Published: June 2023

2622 Background: The presence of tertiary lymphoid structure (TLS) in tumor tissues has been reported to be a factor associated with a good prognosis in several types of cancers including non-small cell lung cancer (NSCLC). However, the relationship between TLS spatial organization and the treatment response remains unknown in NSCLC who received ant-PD-1 antibody. The purpose of this study was to evaluate the effect of the various stages of the spatial organization of the TLS from locally concentrated aggregates of immune cells, through clearly defined B cell follicles to mature follicles in NSCLC and its relationship with the tumor microenvironment on anti-PD1 treatment response. Methods: Frozen sections from retrospectively collected surgically resected NSCLC tumors treated with adjuvant pembrolizumab therapy were used. The TLS in tumor tissues was detected by high-plex imaging mass cytometry staining and the difference in TLS spatial organization was compared to the features of the tumor microenvironment and the objective response rate of the patients. Results: TLS identified and characterized according to their spatial organization within or adjacent to the tumor showed that the presence of tumor-associated TLS (TA-TLS) correlated with favorable response to anti-PD-1 therapy. The abundance and the spatial distribution of B cells allowed for a better definition of the correlation between B cell subsets with clinical outcomes showing that the heterogeneity in these TA-TLS influences the predictivity significance to anti-PD-1 therapy. Conclusions: Identifying the phenotypic heterogeneity of intratumor B cells and their functional connection to CD8 T cell helps optimally guide the anti-PD-1 treatment strategy. This spatial mechanistic insight also provides an exciting opportunity for translation of B cell-based immunotherapies into clinics complementary to existing T cells centric strategies.
Clinical and biological activity of FLX475, an oral CCR4 antagonist, in advanced cancer.
Authors: Brockstedt Dirk G. , Grant Adam , Adamik Juraj , Trujillo Damian , Goyal Rakesh Kumar , Ho William , Ikeda Shoji , Zhu Qingfeng , Anders Robert A. , Sabouri Mohsen , Kassner Paul D 
Published: June 2023

2625 Background: FLX475 is a potent and selective CCR4 antagonist, designed to block the recruitment of immunosuppressive regulatory T cells (Treg) into tumors without affecting healthy tissues. Blocking migration of Treg into the tumor microenvironment (TME) has the potential to restore antitumor immunity and synergize with a variety of conventional and immunotherapy-based approaches to overcome immune resistance and broaden clinical efficacy. In a recent interim clinical update from the ongoing FLX475-02 Phase 1/2 trial, evidence of monotherapy and combination activity were reported. FLX475 monotherapy induced complete responses in two of the six evaluable subjects enrolled with EBV+ NK/T cell lymphoma. In checkpoint inhibitor naïve non-small-cell lung cancer (NSCLC), 4/13 subjects (31%) had confirmed partial responses (PRs) following treatment with the combination of FLX475 and pembrolizumab. In this analysis we present biomarker data from patients with broad range of tumor types treated with FLX475 monotherapy. We provide evidence to substantiate the mechanism of action and support the combination of FLX475 with pembrolizumab. Methods: Flow cytometry was used to measure relative proportions of Treg in the periphery. CD8 and FOXP3 positive cells in tumor biopsies were quantified by immunohistochemistry (IHC).Gene set enrichment analysis and immune deconvolution methods were used to interrogate RNAseq data derived from tumor biopsies. Results: FLX475 monotherapy results in a small but significant increase in proportion of circulating CD25+CD127-/low CD4+ Treg by day 8 of treatment. IHC analysis revealed a trend towards increased CD8:FOXP3 ratio in the TME of patient biopsies. Transcriptomic profiles from tumor biopsies of FLX475 monotherapy treated patients exhibited significant changes in immune pathways likely to benefit the antitumor response. Using global gene expression analyses we identified that FLX475 monotherapy altered the transcriptome of tumors to resemble those from patients with favorable clinical outcome to anti-PD(L)-1 treatment. Consistent with the proposed mechanism of action, immune deconvolution identified that FLX475-treated patients experienced a decrease in Treg cell populations. Conclusions: FLX475 monotherapy results in beneficial changes in the TME consistent with our proposed mechanism of action. FLX475 monotherapy is modifying the tumor microenvironment toward a phenotype associated with response to anti-PD-1/anti-PD-L1. Clinical trial information: NCT03674567 .
Phase 1 dose escalation study of DSP107, a first-in-class CD47 and 4-1BB targeting fusion protein, in combination with atezolizumab in patients with advanced solid tumors.
Authors: Saeed Anwaar , Bashir Babar , Luke Jason J. , Chantre Reuven , Amsili Shira , Tabakman Rinat , Shwartz Yaffa , Foley-Comer Adam , Jimeno Antonio 
Published: June 2023

2632 Background: DSP107 is a bi-functional fusion protein composed of sequences from the extracellular domain of SIRPα and 4-1BB ligand (4-1BBL). The SIRPα arm targets CD47 overexpressed on tumor cells, blocking the “don’t eat me” checkpoint and anchoring trimeric 4-1BBL to the tumor, which interacts with 4-1BB expressed on activated immune cells. This results in proliferation and conditional activation of effector cytotoxic T-cells in the tumor microenvironment. Thereby, DSP107 triggers both innate and adaptive immune responses. Phase 1 monotherapy dose escalation data demonstrated an excellent safety profile with no binding to red blood cells and no dose limiting toxicities (DLTs), hematological or hepato-toxicities. Here we describe data from the completed DSP107 plus atezolizumab combination dose escalation portion of study NCT04440735. Methods: Adult patients with advanced solid tumors were treated with weekly intravenous DSP107 infusions (1, 3 or 10 mg/kg; N = 6-7 patients/dose cohort) and atezolizumab (1200 mg) Q3W during 3-week treatment cycles. The primary objective was to determine the safety and tolerability of DSP107 in combination with atezolizumab. Restaging imaging was performed every two months and evaluated by RECIST v1.1 criteria. Results: In 19 patients, DSP107 with atezolizumab was well tolerated with no DLTs. Grade 1-2 treatment related adverse events (AEs) were observed in 68% of patients (13/19). The most frequent AEs included diarrhea (21%), fatigue (21%), infusion related reaction (IRR; 16%), nausea, decreased appetite, arthralgia, myalgia and Grade 1 anemia (11% each). IRRs were managed during subsequent infusions by reducing the infusion rate and administering IV fluids. Stable disease (SD) as best response was observed in 8/19 (42%) patients with treatment duration currently up to 10.5 months. At the highest dose of DSP107 (10 mg/kg), 3/7 patients had SD (1 microsatellite stable-colorectal cancer (MSS-CRC) patient with KRAS mutation had 16% target lesion shrinkage and no progression for 7 months). An additional 2 patients with advanced MSS-CRC (with BRAF and KRAS mutations, respectively) demonstrated deep and durable responses (-73 and -76% reduction in target lesions) including disappearance of pulmonary and hepatic target lesions in one patient. These patients currently continue to receive treatment after > 8 and > 6 months, respectively. Conclusions: DSP107 is a novel, CD47 and 4-1BB targeting fusion protein with a differentiated safety, binding and pharmacodynamic profile compared to other CD47 and 4-1BB targeting agents. These Phase 1 data suggest that the combination of DSP107 with PD(L)1 blockade may have anti-tumor activity in cold tumors such as MSS-CRC. Clinical trial information: NCT04440735 .
A phase I study of nelmastobart (hSTC810), an anti-BTN1A1 antibody, in patients with advanced solid tumors.
Authors: Lee Soohyeon , Shin Sangjoon , LoRusso Patricia , Rolfo Christian Diego , Jung Hyunjin , Yoo Stephen Sunghan , Hong David S. 
Published: June 2023

2633 Background: Butyrophilin 1A1 (BTN1A1) is a novel immune checkpoint that is primarily expressed by tumor cells in a manner that is mutually exclusive with PD-(L)1. BTN1A1 can potentially be targeted to extend new immunotherapeutic treatment options to patients (pts) whose tumors are unresponsive to anti-PD-(L)1 therapy. This phase I study describes the safety and clinical activity of Nelmastobart (hSTC810), a humanized monoclonal antibody targeting BTN1A1, in pts with advanced solid tumors. Methods: Nelmastobart was administered intravenously every 2 weeks across 6 dose levels from 0.3 mg/kg to 15 mg/kg. The primary objectives were to determine the safety profile and maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). Using a 3+3 design, dose-escalation cohorts were evaluated for dose-limiting toxicities (DLT) during the first 2 cycles. Backfill cohorts were allowed once a dose was deemed safe. Response was assessed using RECIST 1.1 every 4 cycles (8 weeks). Pts were treated until disease progression or unacceptable toxicity. Results: As of January 30, 2023, enrollment in the dose-escalation cohorts is complete. A total of 39 pts with colon (n=14), lung (NSCLC n=3; SCLC n=2), urothelial (n=3), breast, cholangiocarcinoma, melanoma, ovarian, pancreatic (n=2) each, adrenocortical, anal, esophageal, H&N, PEComa, skin, and thymic (n=1) cancers each were treated in the dose-escalation and backfill cohorts. Median duration of therapy for all pts was 8 weeks (maximum 29 weeks). Most common treatment related adverse events (TRAEs) reported were grade 1-2 fatigue (6%), headache (5.9%), and nausea (4.4%); furthermore, there were no TRAEs ≥ 3. No pts was discontinued or required dose reduction due to TRAEs. There were no DLTs across all dose levels and the MTD was not reached. In evaluable pts, one confirmed partial response was observed in MSI-H colon cancer (3 mg/kg) and 13 pts (colon, H&N, lung, melanoma, ovarian, thymic carcinoma) had a best response of stable disease (SD) across multiple dose levels. Median duration of PR/SD pts on study was 17.5 weeks. Interim pharmacokinetics (PK) analysis demonstrated consistent exposure with linear PK. Pharmacodynamic analysis measuring cytokines and cell-based markers is pending and will be presented. Based on the safety, efficacy, and PK, we recommend 15 mg/kg Q2W as the RP2D. Conclusions: Nelmastobart is well-tolerated without DLTs up to the final dose of 15 mg/kg. Current data show evidence of anti-tumor activity and durable SD. Clinical development planning for a phase Ib/II clinical trial is underway to further characterize the therapeutic dose and efficacy in select solid tumors. Clinical trial information: NCT05231746 .
Association between physical activity, immune-related adverse events, and mortality in patients undergoing immune checkpoint inhibition.
Authors: Verheijden Rik Jasper , Cabane Ballester Anna , van Eijs Mick JM , van Lindert Anne SR , Suijkerbuijk Karijn , May Anne Maria 
Published: June 2023

2643 Background: Immune checkpoint inhibitors (ICIs) have improved prospects for some, but not all patients with cancer and frequently induce severe immune-related adverse events (irAEs). While physical activity (PA) has been associated with prolonged survival and diminished toxicity of chemotherapy, its association with ICI efficacy and toxicity is currently unknown. Hence, here we study the association between PA in patients undergoing ICI, and survival and severe irAE occurrence. Methods: Patients with advanced cancer receiving anti-PD-(L)1 based immunotherapy at our academic center were enrolled in the UNICIT cohort. All participants who completed the PA questionnaire (SQUASH) at ICI initiation between 10-2019 and 01-2022 were included in this study. PA was quantified by calculating Metabolic Equivalent Task (MET) hours per week and moderate to vigorous sport and leisure time activity. Association of PA with overall survival (OS) was assessed using Cox proportional hazard regression. Association of PA with occurrence of a severe irAE (grade 3 or higher) within one year was assessed using logistic regression in patients with at least one year follow-up. All analyses were adjusted for sex, age, tumor type, treatment intent and ICI type. Results: In total, 251 patients were included, with a median follow-up of 20 months and a median age of 64 years. The majority (153 patients) had melanoma. Median OS was not reached. Compared to low levels of total PA, intermediate and high levels of total MET-hours were associated with prolonged survival (adjusted hazard ratios: 0.56 (95%CI 0.31-1.02) and 0.47 (95%CI 0.26-0.86), respectively; table). Thirty eight out of 209 patients with at least one year of follow-up developed severe irAEs within the first year. Compared to patients with low total PA levels, patients with intermediate or high levels of total PA have a lower odds of developing severe irAEs (adjusted odds ratios: 0.35 (95%CI 0.12-0.90) and 0.19 (95%CI 0.06-0.56), respectively). Similar trends of prolonged OS and reduced odds of severe irAE occurrence were observed in patients who performed more moderate to vigorous sport and leisure time activity. Conclusions: Higher physical activity levels at start of ICI treatment are associated with prolonged survival and lower risk of severe irAEs. Future research needs to elucidate whether inactive patients benefit from increasing PA levels after diagnosis. [Table: see text]
Effect of fecal transplantation on patients’ reported outcome after immune checkpoint inhibitor colitis.
Authors: Wang Yinghong , Varatharajalu Krishnavathana , Shatila Malek , Shen Shu-En , Herrera Mary , Gonzalez Elizabeth , Wang Xin Shelley , Thomas Anusha , Jiang Zhi-Dong , DuPont Herbert L. 
Published: June 2023

2645 Background: The use of fecal microbiota transplantation (FMT) has traditionally been reserved for the treatment of recurrent Clostridioides difficile infections (CDI). As the gut microbiome has been increasingly acknowledged to play a role in a variety of bodily processes, FMT has seen its application extended to other gastrointestinal disorders. Immune-mediated colitis (IMC) is a similar entity to inflammatory bowel disease and arises as a side effect of immune checkpoint inhibitor therapy to stimulate the immune response. Treatment of IMC is mostly limited to immunosuppressants e.g. corticosteroids, infliximab, and vedolizumab. Cases refractory to such medications pose a significant challenge. FMT has been shown to be a successful treatment in refractory IMC in small case series, further large studies are needed to determine its efficacy. Methods: We measured the efficacy of FMT for refractory IMC among 47 patients via chart review and clinical assessment and patients’ reported outcome (PRO) via established MD Anderson Symptom Inventory (MDASI). Among them, 9 patients had concurrent CDI as well at the time of diagnosis. Results: Forty-seven patients were included in our study. Most patients had a peak diarrhea grade ≥ 3 (93.6%) and colitis grade ≥ 2 (91.5%). Ulcerous (23, 49.0%) and non-ulcerous (12, 25.5%) inflammation were the predominant endoscopic findings. 45 (95.7%) patients received corticosteroids, and 43 patients (91.5%) received add-on infliximab or vedolizumab. IMC symptom response was 85.1% after FMT with median time to response of 4.5 days. The transient complications rate is 34.0% at 7 days and 17.0% at 30 days. Response rate among the 38 patients without concurrent CDI was 86.8%. Forty-one (87.2%) patients demonstrated clinical remission by the end of the study period. On the PRO analysis, we observed a favorable trend of significant patient-reported symptom reduction on diarrhea during 12 weeks after FMT, along with improved daily physical functioning on working. Conclusions: FMT may serve as a potential treatment option in IMC refractory to standard treatment to avoid long-term steroid dependency and immunosuppression. It is effective to maintain IMC remission with a low complication rate. The role of the gut microbiome in cancer and the implications for FMT remain uncertain and need further elucidation. Clinical trial information: NCT03819296 . [Table: see text]