bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of time-of-day infusion of camrelizumab combined with chemotherapy on efficacy in advanced malignant tumors.
Authors: Sun Li-Yue , Xu Xian , Xu Quan-An , Xian Ke-Xin , Zeng Xin-Xin , Li Hua-Gen , Zhang Xu-Hui 
Published: June 2024

e14634 Background: The combination of immune checkpoint inhibitors (ICIs) with chemotherapy has emerged as a standard first-line treatment strategy for advanced cancers. Camrelizumab and Tislelizumab, representative ICIs, have approval by the Chinese NMPA for first-line treatment of advanced cancers such as lung cancer and esophageal cancer. Previous studies have indicated that the timing of drug administration can influence the efficacy of ICIs. However, studies on the ICIs plus chemotherapy are lacking. Therefore, we conducted a retrospective study to explore the effect of the timing of infusion on patients with advanced cancer undergoing treatment with ICIs combined chemotherapy. Methods: We retrospectively enrolled a total of 253 patients diagnosed with advanced cancers between 2017 and 2023 in Guangdong Second Provincial General Hospital. Among these patients, 109 received camrelizumab (Cam cohort) plus chemotherapy and 65 received tislelizumab (Tis cohort) plus chemotherapy. Patients were grouped into morning (AM) and afternoon (PM) categories based on the timing of their ICIs administration (< 1 times versus ≥ 1 times after 16:00). The Response Evaluation Criteria in Solid Tumors Criteria V.1.1 was used to evaluate the response to treatment. The primary endpoint was progression-free survival (PFS). Results: The results consistently showed that the PM group had a longer PFS than the AM group in the overall patients (p < 0.01). In the Cam cohort, the PM group (n = 48) exhibited a longer PFS compared to the AM group (n = 61) (16.8 months vs. -, p = 0.02). However, no significant difference in PFS was observed among patients in the Tis cohort (AM vs. PM, n = 34 vs. n = 31, 16.1 months vs. -, p = 0.51). Subgroup analyses indicated that the PM group had a more favorable PFS treatment effect in most subgroups. The incidence of any Treatment Emerged Adverse Event (TEAE) (Cam cohort, AM vs. PM, 98.52% vs. 92.68%; Tis cohort, AM vs. PM, 97.05% vs. 100.00%) and grade 3 TEAEs (Cam cohort, AM vs. PM, 5.80% vs.7.30%; Tis cohort, AM vs.PM - vs. 12.90%) was similar in the Cam cohort and Tis cohort. The most common adverse events are anemia (Cam cohort vs. Tis cohort, 70.58% vs. 79.41%), thrombocytopenia (Cam cohort vs. Tis cohort, 54.41% vs. 58.82%) and lymphopenia (Cam cohort vs. Tis cohort, 44.11% vs. 44.11%). Conclusions: The findings of this study highlight a significant variation in daily rhythms among advanced cancer patients undergoing treatment with ICIs plus chemotherapy. Interestingly, a trend was observed in patients treated with camrelizumab, where those receiving treatment in the afternoon demonstrated a longer PFS. However, this trend was not observed in patients treated with tislelizumab. These results suggest that time-of-day infusion could potentially serve as a personalized strategy for patients treated with combination ICIs therapy.
The rationale of reprogramming TREM2+ macrophages for overcoming the resistance to immune checkpoint inhibitors in pancreatic adenocarcinoma.
Authors: Ravichandran Harshitha , Kung Heng-Chung , Zhang Rui , Chen Kai , Fu Juan , Zheng Lei 
Published: June 2024

e14649 Background: Pancreatic ductal adenocarcinoma (PDAC) resists to immune checkpoint inhibitors as single agents. TAMs expressing the triggering receptor expressed on myeloid cells (TREM2) protein were found to be a dominant macrophage population in PDAC; targeting TREM2 has been found to enhance the efficacy of immune checkpoint inhibitor-based therapies in preclinical studies of other malignancies. Here, we studied the role of targeting TREM2 in PDAC by testing the combination of non-depleting anti-TREM2 antibody and anti-PD-1 antibody in a mouse model of PDAC. We also examined the relationship between TREM2 expression and effector T cells in surgically resected human PDAC collected from a previous clinical trial treated with the neoadjuvant combination therapy of nivolumab (anti-PD-1 antibody), urelumab (anti-CD137 agonist antibody), and the pancreatic cancer GVAX vaccine. Methods: C57BL/6 mice were orthotopically implanted with KPC tumors. Anti-TREM2 was injected intraperitoneally (i.p.) once a week and anti-PD-1 was injected i.p. twice a week. Tumor volume was measured by ultrasound. TREM2 was stained on slides which were previously obtained from surgically resected PDACs following the neoadjuvant combination treatment of nivolumab, urelumab, and GVAX and stained for multiple immune cell markers with a multiplex staining-striping immunohistochemistry (IHC) technique. Results: Tumor growth post-tumor implantation was found to be significantly decreased by the anti-PD-1 and anti-TREM2 combination compared with anti-PD-1 alone, anti-TREM2 alone, or control treatment (p < 0.0001). Survival of tumor-bearing mice was significantly prolonged by the anti-PD-1 and anti-TREM2 combination when compared to anti-PD-1(p < 0.05), anti-TREM2(p < 0.05), and control (p < 0.01). Multiplex IHC analysis of human PDACs following neoadjuvant immunotherapy showed a higher density of granzyme B+CD8+ effector T cells correlated with higher density of TREM2+ cells (p = 0.0357). Conclusions: Our study demonstrates the anti-tumor efficacy of anti-TREM2 antibody in combination with an immune checkpoint inhibitor in mouse PDAC. However, the analysis of human PDAC following neoadjuvant immunotherapy suggests that TREM2 on TAMs may be activated following the activation of effector T cells. Taken together, our results suggest that TREM2+ TAMs should be reprogrammed instead of being depleted in the design of anti-TREM2-based therapy for PDAC.
Advancing drug development by leveraging microdissection for proteogenomic analysis of histological sections.
Authors: Johann Donald Joseph , Shin Ikjae Jae , Tangrea Michael , Emmert-Buck Michael 
Published: June 2024

e14660 Background: Combining laser capture microdissection (LCM) with proteogenomics in cancer research offers a targeted way to way to explore the intricate interactions between the tumor microenvironment and tumor cells proper. For immuno-oncology (IO) research, this is especially important, since improvements in the predictability of patient response to IO-based drugs is greatly needed. An improved understanding of the spatial relationships involving tumor cells, stromal cells, blood supply and immune cell interactions may help to inform drug development and improve the indicators of success for IO-based drug regimens. Methods: From fresh frozen tissue, LCM is used to isolate and obtain distinct histological cell types. Nucleic acids and proteins are extracted from captured cells for in-depth multi-modality molecular profiling assays. This includes multiple genomic modalities and a customized solution-based mass spectrometry proteomics approach for samples or specimens with a limited amount of tissue. Results: Optimizing the analysis of minute tissue quantities from LCM captured cells is challenging. Following the isolation of nucleic acids, DNA sequencing can be performed for the discovery and analysis of actionable mutations, copy number variation, and methylation profiles. RNA-seq may be performed for gene expression. Regarding genomic-based studies, commercial kits are often utilized for these steps due to their general availability, rapid innovation, and the robust performance of these products. However, this kit-based adaptive approach is not true for proteomics. There remains a need for highly sensitive proteomic methods targeting small-sized samples. Our novel proteogenomics approach is focused around a customized enhanced liquid chromatography mass spectrometry (LC-MS) analysis of micro-scale and/or nano-scale tissue sections. This is achieved with a silver-stained one-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis (1D-SDS-PAGE) approach developed for LC-MS analysis of fresh-frozen tissue specimens obtained via LCM. This includes an in-gel digestion method adjusted and specifically designed to maximize the proteome coverage from amount-limited LCM samples to better facilitate in-depth molecular profiling. Conclusions: A proteogenomic approach is reported that is utilizing amount limited tissue quantities from microdissected fresh frozen tissue. The methodology may also be applicable to other types of specimens having limited nucleic acids, protein quantity, and/or sample volume.
Melanoma tumor microbiome as a predictor of anti-PD-1 and anti-CTLA-4 immunotherapy response.
Authors: Uzelac Matthew , Li Wei Tse , Li Yuxiang , Ongkeko Weg M. 
Published: June 2024

e14666 Background: In 2023, it is estimated that 97,610 melanoma diagnoses were made in the United States, resulting in 7,990 deaths. For high-risk melanomas, immune checkpoint inhibitors are often administered as an adjuvant to surgery, though they yield variable response rates. The gut microbiome’s association to these treatments’ success has been demonstrated, largely through fecal transplant and probiotic trials. In this study, we seek to determine whether tissue-resident microbes in melanoma tumors could be used to predict immunotherapy response. Methods: Sequencing data of 289 melanoma tumor tissue samples was downloaded across three distinct studies. Intratumor microbial species abundances were derived from RNA or DNA sequencing data through direct alignment to microbial reference databases. Gene expression profiling was also performed. Microbial abundance values were used to construct models predicting patients’ responses to check-point blockade immunotherapies, which were then validated on an external dataset. Results: 12 and 14 microbial species were differentially abundant in anti-PD-1 responders and anti-CTLA-4 responders, respectively. We identified significant correlations of these species to genes of the PD-1 and CTLA-4 signaling pathways. Among others, greater abundance of Corynebacterium kroppenstedtii and Streptococcus gordonii correlated to decreased expression of PD1 and CTLA-4. With the abundances of these taxa and the expressions of 37 genes known to be implicated in immunotherapy response, we developed two classifiers to predict a patient’s response to anti-PD-1 and anti-CTLA-4 therapies. When tested externally, these models successfully predicted a majority of responders and non-responders with sensitivities of 80.0% and 60.0% and specificities of 95.2% and 95.8%, respectively. Conclusions: Our study revealed that checkpoint blockade response for melanomas could be predicted with microbe abundances. Our analysis demonstrates the potentially promising clinical utility of intratumor microbiota in cancer treatment. Given their location in the tumor microenvironment and their ability to influence immune processes, intratumor microbes could play a critical role in modulating the therapeutic effects of immune checkpoint blockades. We hope that our results could also be applied to other solid tissue cancers, where a significantly smaller fraction of patients respond to immunotherapy. [Table: see text]
First-in-human study of ZGGS15, a dual specific antibody targeting LAG-3 and TIGIT, as monotherapy in patients with advanced solid tumors.
Authors: Zhu Ji , Wang Zhen , Chai Xiaoli , Wu Lihua , Qu Song , Liu Linlin , Liu Yanyan , Sun Yan 
Published: June 2024

e14678 Background: ZGGS15 is a recombinant humanized bispecific antibody composed of a monoclonal antibody against LAG-3 and TIGIT. It can specifically bind LAG-3 and TIGIT. It reverses LAG-3 and TIGIT immune suppression to T and NK cells, relieves suppression of Treg to T and NK cells, promotes the activation and proliferation of T and NK cells, and cytokines release. ZGGS15 restores T and NK cell functions to kill tumor cells. In non-clinical studies, we found that ZGGS15 had significant anti-tumor effects and synergistic anti-tumor effects with Anti-PD-1 antibody. Therefore, we conducted a Phase 1 clinical study to assess the tolerability, safety, and preliminary efficacy of this drug as monotherapy in patients with advanced solid tumors. Methods: During the dose escalation stage, an accelerated titration design (ATD) in the first dose (1 subject if ≤Grade 2 treatment-related adverse event occurred) and the standard "3+3" design in the rest doses were used. Subjects were patients with advanced solid tumors who failed to the available standard treatments. The dose groups were set from 0.3 to 30 (0.3, 1, 3, 10, 20, 30) mg/kg, intravenous infusion, once every 3 weeks. The first 21-day period was defined as the dose-limiting toxicity (DLT) observation period. Subjects could continue to receive ZGGS15 until treatment discontinuation criteria were met. Tumor response was assessed by RECIST1.1 and iRECIST. Pharmacokinetics (PK) and receptor occupancy (RO) profiles were also assessed in this study. Results: A total of 12 patients (4 males and 8 females) completed the DLT observation in the first four dose groups (0.3 to 10 mg), with a median age of 57 years. Eight (66.7%) of them received at least 3 lines of antineoplastic therapies, and five (41.7%) have been exposed to PD-1 or PD-L1 inhibitors. There was no DLT event observed. Thirty-eight treatment-related adverse events (TRAEs) occurred. Up to now, TRAEs were all grade 1 ~ 2. The most frequent TRAEs were proteinuria (33.3%, 4/12), hypokalemia (25%, 3/12), hypoalbuminemia (25%, 3/12), and hypertriglyceridemia (25%, 3/12). The Cmax and AUC increased from 0.3-1 mg/kg approximately in dose proportion. Nearly complete and sustained RO of T and NK cells in PBMCs was observed at 1 mg/kg dose of ZGGS15 for at least 3 weeks. Conclusions: The first four dose levels of ZGGS15 were very well tolerated. A good PK profile, and a long-lasting RO were observed in this escalation study. It is anticipated that this product could provide an additional benefit only when use in combination with an anti-PD-1 antibody. Clinical trial information: NCT05864573 .
Bronchoalveolar lavage fluid analysis in patients with checkpoint inhibitor pneumonitis.
Authors: Chen Ruxuan , Shi Yujie , Huang Hui , Wang Mengzhao , Xu Yan 
Published: June 2024

e14683 Background: Checkpoint inhibitor pneumonitis (CIP) is a relatively uncommon but potentially life-threatening immune-related adverse event (irAE). Lung biopsies have not been commonly performed for CIP patients. Bronchoalveolar lavage fluid (BALF) analysis is a useful diagnostic approach for interstitial lung disease. However, BALF features were inconsistent across different studies. Methods: We retrospectively reviewed the medical records of 154 patients with pathologically confirmed malignancies and suffering from CIPs between July 2018 and December 2022. Patients who had bronchoalveolar lavage (BAL) data available were enrolled in our study. Patient clinical, laboratory, radiological and follow-up data were reviewed and analyzed. In our study, patients with grade 1 or grade 2 CIPs were defined as low-grade CIPs, and patients with grade 3, grade 4 or grade 5 CIPs were defined as high-grade CIPs. Results: The BALF differential cell count and lymphocyte subset analysis were performed for 42 CIP patients. There were 32 males (76.2%). The mean age at diagnosis of CIP was 62.0 ± 10.4 (range: 31-78) years. The median time to onset of CIP was 98.5 days after the start of immunotherapy. Most of the patients were diagnosed with lung cancer (36 patients, 85.7%). There were 3 patients with esophageal squamous cell cancer, 1 patient with hepatic cell cancer, 1 patient with gastric signet ring cell cancer and 1 patient with pericardial malignant mesothelioma. There were 18 patients (42.9%) with low-grade CIPs and 24 patients (57.1%) with high-grade CIPs. The mean lymphocyte percentage was 36.7 ± 22.5%. There were 34 (81%) CIP patients with a lymphocytic cellular pattern. The median ratio of CD3+CD4+/CD3+CD8+ lymphocytes was 0.5 (0.3, 1.0). The ratio was less than 1.0 for 31 CIP patients (73.8%). However, there was no significant difference in the BALF features between patients with low-grade CIPs and those with high-grade CIPs. Conclusions: The CD3+CD8+ lymphocytosis pattern was the main inflammatory profile in the BALF of CIP patients in this cohort. Targeting CD3+CD8+ lymphocytes might be a treatment option for CIPs.
Immune related adverse events: Timing, identification patterns, and impact on survival.
Authors: Deviley Jake Anthony , Hayashi-Tanner Yacki , Krause Joshua , Arenz Andrea , Frankki Susan M , Marinier David E. 
Published: June 2024

e14705 Background: Increased use of immune checkpoint inhibitors (ICI) has resulted in a rise in immune related adverse events (irAEs), which many non-oncology clinicians may underrecognize. Controversy exists surrounding whether irAE presence has an impact on survival. Our primary goal was to evaluate the timing between detection to diagnosis of irAE, and determine the department responsible for making the irAE diagnosis. We also assess the incidence of single vs multisystem irAEs, impact of irAE on survival, and assess whether standard irAEs (s-irAEs) those diagnosed within 90 days of initial ICI administration vs delayed irAE (d-irAEs) those diagnosed >90 days impacts survival. Methods: We performed an IRB approved retrospective study of patients 18 years and older who received ICIs for a malignancy at Gundersen Health System between January 1, 2011 and December 31, 2021. Statistical analysis included Chi-square, Fisher’s Exact, and Wilcoxon rank sum tests and Kaplan-Meier survival analysis. All analysis was completed in R version 4.2.3 with a p-value <0.05 considered significant. Results: Our study included 664 patients who were 99.6% white, 60% male, and an average age of 67 years. Median Charlson Comorbidity Index was 10. There were 245 (36.8%) patients with at least 1 irAE, and 62 (9.3%) with a multisystem irAE. While 28 (11%) irAEs were initially detected by non-oncology providers, only 10 (4.1%) irAEs were diagnosed by a non-oncology department. Median time (days) from symptoms to diagnosis was 3 for those diagnosed in non-oncology departments and 0 for those diagnosed in oncology (p<0.01). A total of 142 (58.0%) s-irAEs were detected with grades 1-2-3-4-5 accounting for 21.1%-54.9%-19.7%-1.4%-2.8%. There were 103 (42.0%) d-irAEs with grades 1-2-3-4-5 accounting for 23.3%-53.4%-17.4%-5.8%-0%. Of the d-irAEs, 17 (16.5%) occurred >365 days from initiation of ICI. The 3 most common irAE in this patient population included thyroiditis (34%), dermatitis (21%), and pneumonitis (12%). Our data shows a significant survival difference in patients with an irAE compared to those without (p<.01). No significant survival difference was noted between patients who had s-irAE vs d-irAE (p=.069). Conclusions: Our results show that irAEs may be underrecognized and often not formally diagnosed by non-oncology providers. However, median time to diagnosis is short within this context. This may be due to non-oncology providers feeling uncomfortable making the final decision, which emphasizes the importance for oncologists to finalize irAE diagnoses. We did see a positive impact on survival with irAE presence. While oncologists often clinically expect irAEs to surface within the first 6-10 weeks of treatment, our study demonstrates that 42% of irAEs occur after 12 weeks from ICI initiation. There is no difference in survival between s-irAEs vs d-irAEs, and overall grade distribution between these two groups appears similar.
Increased risk of hyperglycemia in patients with advanced urothelial cancer treated with enfortumab vedotin: A systematic review and meta-analysis.
Authors: Cheng Ryan , Boparai Montek , Wu Shenhong 
Published: June 2024

e15001 Background: Enfortumab vedotin (EV), an antibody-drug conjugate targeting anti-nectin-4, which is highly expressed in urothelial cancers, has emerged as an effective therapy in the management of previously treated advanced urothelial cancer. urothelial cancer. Severe hyperglycemia has been recognized as an unexpectedly adverse effect, and can lead to discontinuation of EV or fatal event. To assess the overall risk of hyperglycemia associated with the use of EV, a systematic review and meta-analysis of published clinical trials was performed. Methods: A comprehensive review through 2023 of PubMed and American Society of Clinical Oncology conferences was performed to identify relevant clinical trials and abstracts. Eligible studies were clinical trials of patients with urothelial cancer receiving EV at the standard dose with data on hyperglycemia available. Incidence rates, relative risks, and 95% confidence intervals were calculated using random-effects or fixed-effects models. Results: Our search culminated in the inclusion of 1,150 patients from four trials, with 859 of them receiving EV. The summary incidences for all-grade and high-grade hyperglycemia were 9.9% (95% CI: 7.8-12.5%) and 6.0% (95% CI: 4.6-7.8%) respectively. Patients treated with EV had an increased risk of developing hyperglycemia in comparison with chemotherapy with an RR of 19.66 (95% CI: 2.66-145.55, P=0.004) for all-grade and 26.54 (95% CI: 1.59-444.48, P=0.023). In comparison with single-agent EV, its combination with pembrolizumab did not significantly increase the risk of all-grade hyperglycemia (P=0.148). Conclusions: EV is associated with a significantly increased risk of all-grade and high-grade hyperglycemia.