bluuebunny/crossref_metadata_2025_split huggingface dataset:
Open-label, phase 1, multicenter study to evaluate the safety and preliminary anti-tumor activity of NT-175 in human leukocyte antigen-a*02:01-positive adult subjects with unresectable, advanced and/or metastatic solid tumors that are positive for the TP53 R175H mutation.
Authors: Becerra Carlos Roberto , Awad Mark M. , Hecht J. Randolph , Paulson Andrew Scott , Lee Jennifer , Palluconi Gabi , Dalton Jaquelin , Patel Anuradha , Yan Ying , Perez Arianne , Xie Sunny , Cohen Sarah , Fakih Marwan 
Published: June 2024

e14514 Background: The TP53 tumor suppressor gene is the most commonly mutated gene across all cancer types, and TP53 R175H is the most common recurrent mutation across indications, identified in 6.7% of patients with breast cancer, 6% of patients withs colorectal cancer, and 4.2% of patients with pancreatic cancer. No therapy is approved for treatment directly targeting TP53 R175H. NT-175 is an armored autologous T-cell product expressing an HLA-A*02:01-restricted TCR recognizing TP53 R175H with disruption of the endogenous TCR and the transforming growth factor beta receptor type 2 (TGFBR2) genes. Methods: This first-in-human phase I, open label study will assess the safety and preliminary anti-tumor activity, identify the maximum tolerated dose (MTD), and evaluate the persistence, and functional capacity of NT-175 in subjects with advanced, recurrent unresectable/metastatic solid tumors refractory to treatment options. The study will enroll approximately 24 subjects harboring TP53 R175H and HLA-A*02:01. Enrolled patients will undergo leukapheresis from which CD4 and CD8 T cells will be enriched and activated ex vivo. The endogenous TCR α and β chain gene are knocked out utilizing clustered Regularly Interspaced Short Palindromic repeats (CRISPR-Cas9) and the TCR encoding an HLA-A*02:01-restricted TCR specific to the TP53 R175H mutation is inserted in the TCR α locus. Additionally, the T cells are edited to disrupt the gene encoding the TGFBR2 to reduce the immunosuppressive effect of TGF-β in the tumor microenvironment. Subjects will undergo lymphodepletion chemotherapy with fludarabine and cyclophosphamide followed by a single infusion of NT-175 and subcutaneous recombinant IL-2 administration for up to 8 days. Dose escalation will occur across 3 ascending dose levels following the BOIN design. Subjects will be monitored for dose-limiting toxicities for 28 days after NT-175 infusion. Tumor response will be assessed by RECISTv1.1 criteria. All subjects will be followed for up to 15 years. Primary endpoints include safety, dose limited toxicities, MTD determination, and recommended Phase II dose. Secondary endpoints include preliminary efficacy measures. Translational analysis will evaluate potential biomarkers for insights into mechanism of action, response prediction, or resistance mechanisms. The study was activated in March 2023 and is open to accrual; 5 patients have been enrolled as of 4 Jan 2024.
Next generation CD44v6-specific CAR-NK cells for the treatment of solid tumors.
Authors: Pecher Gabriele , Franzén Alexander Sebastian , Boulifa Abdelhadi , Radecke Clarissa , Stintzing Sebastian , Raftery Martin 
Published: June 2024

e14518 Background: There is a medical need to develop new and effective therapies against solid tumors. CD44v6, an adhesion molecule that is implicated in tumorigenesis and metastases, was identified as a suitable target in solid tumors such as triple negative breast cancer (TNBC) or glioblastoma. Methods: We have developed a next-generation CAR targeting CD44v6 that incorporates IL-15 superagonist and checkpoint inhibitor molecules to overcome the immunosuppressive microenvironment (TME). NK cells were used due to their potential for allogeneic usage. Results: CD44v6 CAR-NK cells demonstrated effective cytotoxicity against TNBC and glioblastoma in 3D spheroid models. The IL-15 superagonist was specifically released upon recognition of CD44v6 on TNBC and contributed to the cytotoxic attack. Competitive inhibition of PD1 neutralized inhibition by PD1 ligands. We have validated iPSC-derived CD44v6 CAR-NK cells. Conclusions: Next generation CD44v6 CAR-NK cells are resistant to TME immunosuppression and offer a new therapeutic option for the treatment of solid tumors.
The promising feeder-free allogenic NK cell therapy: Clinical outcomes of GIC-102 monotherapy (GIC-102101) and synergistic potential with GI-101 (CD80-IgG4 Fc-IL2v) in advanced solid tumors and hematologic malignancies.
Authors: Lee Soohyeon , Hong Junshik , Cho Hyungwoo , Lee Woo Yul , Jang Do Soo , Lee YooJoon , Jang Myoung Ho , Yoon Dok Hyun 
Published: June 2024

e14526 Background: The allogeneic Natural Killer (NK) cell therapy derived from healthy donors may overcome the short lifespan and dysfunctional anti-tumor activity of current autologous approach. This limitation often restricts treatment efficacy and necessitating high dosages and frequent infusions. GIC-102, non-engineered / feeder-free, highly potent allogeneic NK cell derived from healthy donors, is a promising alternative. Here, we present the clinical outcomes from the Phase 1 study of GIC-102, along with nonclinical evidence demonstrating outstanding pharmacokinetics (PK) and pharmacodynamics (PD) when used in combination with a novel bi-specific Fc fusion protein, GI-101 (CD80-IgG4 Fc-IL2v/NCT04977453/KEYNOTE-B59). Methods: GIC-102101, a first-in-human study, evaluated GIC-102 monotherapy at doses of 1x109 QW and 3x109 QW in patients with advanced solid tumors or hematologic malignancies. A lympho-conditioning strategy using cyclophosphamide (300 mg/m2) and fludarabine (30 mg/m2) was implemented every two cycles before GIC-102 treatment. The study employed a conventional 3+3 dose escalation scheme. The primary endpoint was to determine the safety and tolerability of GIC-102, with tumor response assessed as secondary endpoints. Additionally, the PK/PD profile of GIC-102 in combination with GI-101 was evaluated in a mouse model. Results: As of December 31, 2023, six patients have been treated with GIC-102 monotherapy including two patients with Non-Hodgkin lymphoma (NHL), and four patients with metastatic colorectal cancer (CRC). The median number of prior treatments for patients with CRC and NHL was 4 and 6, respectively. No dose limiting toxicities (DLTs) were observed and maximum tolerated dose was not reached. Treatment-related adverse events (TRAEs) occurred in 5 patients (83%), with the majority being associated with the lympho-conditioning procedure; hyponatremia, neutropenia, lymphopenia and anemia. The best overall response was complete response (CR) in 1/6 patient (NHL) and stable disease (SD) in 4/6 patients (3 CRC, 1 NHL). Treatment for 1 CR (NHL) and 2 SD (CRC) is ongoing (for NHL, 215+ days/for CRC, 160+ days and 153+ days). The in-vivo study of GIC-102 in combination with GI-101 showed significantly enhanced anti-tumor activity and in-vivo NK cell proliferation lasting up to 4 weeks. Conclusions: The GIC-102, feeder-free allogeneic NK cell, was well tolerated without DLTs and demonstrated early promise in efficacy in patients for advanced solid tumors and hematologic malignancy. Further clinical investigation of GIC-102 in combination with GI-101, bi-specific Fc fusion protein, is currently ongoing. Clinical trial information: NCT05880043 .
Cardiotoxicity of immune checkpoint inhibitors: A retrospective cohort study of 93,362 patients.
Authors: Barzkar Hasti , Miles Brittany , Mehta Ankit 
Published: June 2024

e14529 Background: The advent of immune checkpoint inhibitors (ICI) as therapy for a wide array of cancer types has extended patient survival and propelled the field of oncology into a new era. However, notable immune-related adverse events have been observed that transgress self-tolerance. Among these adverse events, myocarditis is emerging as a serious and often lethal toxicity. This study aims to assess whether a significant association exists between immune checkpoint inhibitors and myocarditis and/or pericarditis. Methods: The TriNetX research network was used for this study. Two patient cohorts were created by using International Classification of Disease 10 (ICD-10) codes and HCPCS codes. Both patient cohorts consisted of patients with malignancy (C00-D49) and no history of myocarditis. One cohort was treated with immunotherapy while the other was excluded from such exposure (HCPCS codes were used for ipilimumab, nivolumab, pembrolizumab, and durvalumab). The cohorts were balanced for age, race, gender, and ethnicity by propensity score matching and the greedy nearest neighbor algorithm, resulting in 46,681 patients in each arm. They were then evaluated for the development of myocarditis or pericarditis (I51.4, I31, I30) over the subsequent 5 years. Results: Cancer patients treated with immunotherapy were significantly more likely to experience myocarditis or pericarditis than those who did not receive those agents (7% vs 1.2%, RR 5.8, 95% CI (5.33,6.36), P value <0.0001). Conclusions: This study suggests a significant association between the use of immunotherapy agents and the development of myocarditis and pericarditis. Further studies are necessary to better delineate the mechanism by which these cardiac toxicities occur, establish guidelines for surveillance of its onset, and discover how to suppress the immune-toxicities while retaining anti-tumor effect.
Retrospective analysis on association of body mass index and immune checkpoint inhibitor response.
Authors: Batra Akshee , Vyas Abhinav , Khosla Atulya Aman , Chitkara Akshit , Alejos David , Xu Xiaocao , Jatwani Karan , Rehman Hibba Tul , Ahmed Shahid Sattar , Singh Rohit 
Published: June 2024

e14536 Background: The relationship between Body Mass Index (BMI) and cancer is a complex. We aim to study the impact of BMI on the response to immunotherapy in cancer patients. Methods: We did a retrospective observational study to investigate the influence of different BMI groups on patients receiving Immune Checkpoint Inhibitors (ICIs) at the University of Vermont Cancer Centre. We examined the medical records of people who received ICIs between January 2017 and June 2022 and collected demographic data, including age, sex, ethnicity, cancer stage, BMI, type and metastasis. We looked at Hazard Ratio (HR) in BMI subcategories compared to normal. The occurrence of immune-related adverse events (irAEs), metastasis and receipt of chemotherapy in different BMI subgroups was evaluated with relative risks (RRs). Results: A total of 288 cases were identified, out of which 269 had documented BMI, including 58% males, 94.8% whites with 64.17 years mean age. Lung cancer was most common at 41.3%, 46.5% were and 63.2% were stage 4. Total 71.4% of people received Pembrolizumab and 42.8% had concomitant chemotherapy. The median ECOG was 1 and the Charlson comorbidity index was 6. irAEs observed in 33% of cases, whereas mortality in 36%. The BMI distribution had 36.1% normal, 27.1% overweight, 16.5% obese, 14.5% extremely obese and 5.6% underweight. The HR in underweight subgroup was significant at 5.223 (p <0.001; 95CI: 2.2 to 12.4) compared to normal. The HR of overweight, obese and extremely obese decreased with HR of 1.15, 0.77 and 0.18 respectively but wasn’t significant as seen in Table 1. Table also shows that relative risk of irAEs, cancer stage, metastasis and concomitant chemotherapy were not significant. Conclusions: Clinically significant association was found between being underweight and mortality in cancer patients receiving immunotherapy. [Table: see text]
First-line immunochemotherapy modulates peripheral immune landscape in advanced gastric cancer and gastroesophageal junction cancer (GC/GEJC): Prediction of response to combination therapy.
Authors: Wu Hao , Meng Enqing , Li Ping , Jiang Rongqi , Cheng Xu , Zhu Chan , Zhang Xing , Chen Dongsheng 
Published: June 2024

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<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 .
Development of a novel cell-free DNA fragmentomics assay for monitoring disease progression in real-time for stage IV cancer patients.
Authors: Sinha Sudhir , Brown Hiromi , Knopf Kevin B. , Hall Patrick , Shannon William G. , Haack William 
Published: June 2024

e14544 Background: Advances in oncology have improved treatment response rates and overall survival. Many treatments, even targeted therapies, can fail to deliver an initial response to stage IV patients. We aimed to evaluate cfDNA as a biomarker of non-response to therapy in metastatic cancer. Methods: Blood samples were prospectively collected in Streck tubes at baseline and 12 - 21 days after initiating treatment, along with detailed clinical data, including imaging assessments captured in a cohort of metastatic non-small-cell lung (50), small-cell lung (8), breast (21), and colorectal (51) cancer study participants. To determine the fragmentation pattern of the DNA in the patient plasma, cfDNA was extracted using QIAamp Circulating Nucleic ACID Kit (Qiagen). cfDNA fragment concentrations were quantitated using two multiplexed qPCR assays on a QuantStudio 5. Primers and probes for the qPCR assay were designed using the high copy number retrotransposons Alu and SVA, represented across all 23 chromosomes. The two assays were performed on each specimen: an >80bp, >265bp and internal positive control (IPC) assay and an >105bp, >265bp with IPC assay. Following analytic validation of the assays, specimens from all participants were analyzed. The results from both assays were combined and merged with the clinical results and statistically analyzed. Results: 130 patients were included in the analysis. The qPCR assays work across all tumor and therapy types analyzed. A logit regression model was developed which calculates the likelihood that a patient’s cancer is progressing. The area under the ROC is 0.93 with a p-value of <0.001. Results clustered above the logit value of 0.65 (n=15) are all progressors by imaging (PPV=100.0%). All logit values below 0.045 (n=69) are non-progressors by imaging (NPV=0.0%). Bootstrap resampling (1,000 iterations) suggests a 99.3% PPV at the 0.9 logit cut point. Healthy subjects (9) and patients with a variety of conditions (33) known to create elevated fragmented levels of cfDNA were also analyzed to determine which patients are not appropriate patients for the assay. Results indicate patients with following conditions within 10 days of a blood draw should be excluded: stroke, myocardial infarction, severe acute autoimmune event, and severe acute COPD exacerbation; and patients treated with a chemotherapy agent (i.e., methotrexate) within 10 days of a blood draw. Conclusions: These data support the value of a blood-based biopsy test for evaluating cancer cfDNA. cfDNA fragment assay is applicable to lung, colorectal, and breast cancer, and is agnostic to any mutation status. The cfDNA fragment analysis is a promising biomarker to monitor patient treatment and save time and the expense of clinically ineffective therapies, allowing the medical oncologist to evaluate the response to therapy in real-time and provide the best care possible for the patient.
Analytical and clinical validation of a personalized, tumor-informed circulating tumor DNA assay for minimal residual disease detection.
Authors: Yang Zuoquan , Zhou Yanqing , Chen Yaru , Teng Jiaman , An Heng , Cheng Shaochen , Xu Mingyan , Chen Shifu 
Published: June 2024

e14545 Background: The detection of minimal residual disease (MRD) through circulating tumor DNA (ctDNA) analysis provides an advanced molecular method for early identification of surgical patients at high risk of recurrence. In this study, we present the development of mClear, a personalized, tumor-informed next-generation sequencing (NGS) assay for MRD detection. Furthermore, we report the analytical and clinical validation processes conducted to evaluate the performance of the MRD assay. Methods: mClear is designed to assess MRD in patients with solid tumors. Whole exome sequencing (WES) was performed on tumor tissues and matched peripheral blood samples to detect somatic variants comprehensively. Personalized MRD assays were carefully designed by selecting up to 40 prioritized variants, including single nucleotide variants (SNVs), small insertions and deletions (InDels), and fusions while ensuring coverage of 21 additional key driver genes. For analytical validation, we utilized a pan-cancer MRD ctDNA quality control product (LDT-999, LDT Bioscience), characterized by known variant allele frequency (VAF) gradients of 0%, 0.005%, 0.05%, and 0.5%, confirmed through droplet digital PCR (ddPCR). We conducted 18 replicate tests at VAF gradients of 0.5% and 0.05%, 23 replicates at the 0.005% VAF gradient, and 16 replicates at the 0% VAF gradient. For clinical validation, preoperative and postoperative blood samples from a cohort of 264 pan-cancer patients were analyzed. ctDNA collected for MRD detection underwent ultra-deep next-generation sequencing (100,000× average depth of coverage). The library preparation process commenced with an input of 30ng DNA. Results: At VAF gradients of 0.5% and 0.05%, the assay achieved an excellent sensitivity of 100%, and at VAF gradients of 0.005% and 0%, it demonstrated a sensitivity of 95.7% and a specificity of 100%. Preoperative ctDNA was detected in 86.7% (72/83) of the pan-cancer patients with 71.4% (5/7), 90.9% (10/11), 85.5% (47/55), and 100.0% (10/10) in pathological stage (pStage)I, pStage II, pStage III, and pStage IV, respectively. In the pan-cancer cohort, the positive rate of longitudinal MRD was 35.7% (75/210) with 17.8% (21/118), 50.0% (13/26), 55.1% (27/49), and 82.4% (14/17) in pStage I, II, III, and IV, respectively. In four patients who relapsed, MRD detection during surveillance preceded radiological recurrence by a lead time of 1-8 months. Conclusions: Our personalized MRD assay demonstrated excellent analytical sensitivity and specificity with a limit of detection (LoD) of 0.005% VAF at the sample level. Furthermore, it displayed high clinical sensitivity for the detection of ctDNA in the pan-cancer cohort, highlighting its potential for monitoring of recurrence.
A novel co-receptor with mutated TIGIT to enhance PSCA CAR-T therapy for bladder cancer.
Authors: Shen Junjie , Dai Depeng , Zhao Wenxu , Liu Tongcan , Zhao Yongchun , Xu Yanmin , Qi Yanan , Hong Juan , Shi Xianxun , Yang Zhi , Huang Xia , Qin Lei , Chen Jun , Qian Cheng 
Published: June 2024

e14574 Background: TIGIT plays a crucial role in immune regulation, particularly in tumor environments, by acting as an inhibitory receptor. Leveraging its interaction with ligands like CD155 on tumor cells, we developed an innovative CAR-T cell therapy using a mutated TIGIT co-receptor to overcome inhibitory effect induced by CD155, together with targeting Prostate Stem Cell Antigen (PSCA) CAR, chosen for its high expression in bladder and other cancers versus its minimal presence in normal tissues. Methods: We initiated our approach by inducing strategic mutations in TIGIT, selecting a variant with heightened affinity for CD155. Bio-Layer Interferometry (BLI) analysis confirmed the variant's high binding affinity (KD = 1.635 nM). This mutated TIGIT, combined with CD28's signaling components, was integrated as a co-receptor in our CAR construct. For PSCA targeting, we isolated a high-affinity ScFv against PSCA from a fully human phage display library. The specificity of this ScFv for PSCA was rigorously validated using Cell Membrane Protein Targeting Catcher (CMPTC) technology, covering over 6000 human cell membrane proteins. Results: In our comparative analyses, CAR-T cells featuring a mutated TIGIT co-receptor (T-PSCA-CAR-T) matched the cytotoxicity of traditional second-generation BBz-structured CAR-T cells (PSCA-CAR-T) against PSCA-expressing HT-1376 bladder cancer cells. However, T-PSCA-CAR-T cells distinguished themselves by producing significantly higher IFN-γ levels (3805.683±65.506 vs 1271.712±39.768 pg/mL). Our in vivo tumor model, utilizing luciferase-expressing HT-1376 cells, demonstrated T-PSCA-CAR-T's enhanced anti-tumor efficacy, as evidenced by a more significant reduction in bioluminescence signal intensity (average decreasing ratio: 0.02 for T-PSCA-CAR-T vs 0.35 for PSCA-CAR-T; p < 0.05). These results underscore the efficacy of the mutated TIGIT co-receptor in improving CAR-T cell therapy. Conclusions: Our study signifies a transformative advancement in CAR-T cell therapy by incorporating a mutated TIGIT co-receptor, markedly improving therapeutic outcomes in bladder cancer treatment. Utilizing PSCA as a model target not only validates the efficacy of this novel approach but also paves the way for its application in a broader range of cancers, representing a significant leap in the field of immunotherapy.