bluuebunny/crossref_metadata_2025_split huggingface dataset:
Implications of GITR expression profile for precision immunotherapeutics.
Authors: Moussa Peter , Kurzrock Razelle , Nishizaki Daisuke , Miyashita Hirotaka , Lee Suzanna , Nikanjam Mina , Eskander Ramez Nassef , Patel Hitendra , Botta Gregory P. , Pabla Sarabjot , Nesline Mary K , Conroy Jeffrey M. , DePietro Paul , Sicklick Jason K. , Kato Shumei 
Published: June 2023

e14561 Background: Glucocorticoid-induced TNFR-related protein (GITR) is a type I transmembrane protein expressed mostly on CD25+CD4+ T-regs and upregulated on all T-cells upon activation. It serves as a T-cell co-stimulatory receptor and its role in cancer treatment is being explored. While pre-clinical data using combination therapies involving GITR agonism showed promise, early clinical trials have not shown improved outcomes to date. Methods: RNA expression levels of 397 genes in 514 patients with a variety of cancer types were assessed and analyzed at OmniSeq. Transcript levels were normalized to internal housekeeping gene profiles and ranked as percentiles using a reference population. High expression was defined as ≥ 75th percentile, and low-moderate as <75th percentile. Univariate p-values were calculated using Welch t-test or Fischer’s exact test. Multivariate p-values were calculated using logistical regression. Results: A total of 99 patients (19.3%) had GITR high expression. Cancers with the highest proportion of GITR high expression were lung (7/20, 35%) and breast (19/49, 39%), and both these cancers showed a statistically significant association with GITR high expression on multivariate analysis (lung: OR 3.5, p = 0.04, 95% confidence interval (CI) 1.06 – 10.06 CI and breast: OR 4.59, p <0.001, 95% CI: 2.11 – 9.85). 30% of lung and 30.6% of breast cancer patients had a GITR high with ligand low-moderate expression profile; these cancers had the highest proportion of patients with this profile. GITR high expression showed significant association with high RNA expression of multiple known immune checkpoint proteins (PD-1, PD-L1, CTLA4, LAG3, OX40, ICOS and CD137, but not TIM3) as well as PD-L1 IHC ≥1 on univariate analysis, but statistically significant association was only seen with PD-L1 IHC ≥1 (p = 0.007) and OX40 high expression (p = 0.001) on multivariate analysis. Conclusions: While clinical trials with GITR agonism are ongoing, our data suggests selection of certain types of malignancies depending on GITR status may be required. Moreover, there is a correlation between high GITR and high OX40 RNA expression, which could imply increased efficacy using this targeted combination. Further clinical development based on this immune-profiling is warranted. [Table: see text]
PD-L1 in head and neck cancers: Audit for tertiary care centre in India.
Authors: Peelay Zoya Ravish , Mittal Neha , Patil Vijay Maruti , Singh Ajaykumar Chandrabhan , Noronha Vanita , Prabhash Kumar , Menon Nandini Sharrel , Shah Minit Jalan 
Published: June 2023

e14565 Background: There is no data on the expression of Programmed Death Ligand 1 (PD-L1) in Head and Neck cancers (HNC) from the Indian population. Hence, this audit was done to estimate the incidence of PD-L1 expression in HNC’s and to detect factors affecting the same. Methods: Data was collected from 466 cases who were advised for PD-L1 gene expression testing from the HNC OPD of Tata Memorial Hospital, Mumbai. Ethics committee approval for this retrospective audit was obtained. Tumor Proportion Score (TPS) scoring for PD-L1 expression was performed using the VENTANA SP263 PD-L1 Assay. PD-L1 status was determined by the percentage of tumor cells with any membrane staining above the background. The demographic details and factors such as Eastern Cooperative Oncology Group (ECOG) performance status (PS), tobacco use, site of tumor, histopathology and time of biopsy. Descriptive statistics were used for analysis. Factors affecting PD-L1 gene expression were sorted using logistic regression analysis. Results: 466 patients were evaluated with a median age of 49 years (Range:16-85), PD-L1 expression was divided as scores and was observed that TPS-0% (Tumor proportion score) was seen in 73 patients (15.7%), TPS >0-20% was seen in 174 patients (37.3%), TPS >20-50% was seen in 88 patients (18.9%) and TPS >50% was seen in 131 patients (28.1%). Higher expression of PDL-1 was seen in oral cavity as site of tumor (p=0.000), squamous cell histology (p=0.000) and consumption of tobacco (p=0.001). Conclusions: This is one of the first studies evaluating real world data on the expression of PDL-1 in HNC’s in the Indian population and factors affecting it. PDL1 expression of 1% or more is seen in 84.3% of HN cancers in India. The histology of the tumor is the major impacting factor. The data provides novel insight into many factors affecting the expression of PDL-1 in HNC’s and in the future can be of help in developing treatment plans with various immunotherapies. [Table: see text]
Upgrading the non-gene-editing, allogeneic ThisCART platform for extending persistence in vivo.
Authors: Liu Kaichun , Pc Z , He Ling , Zhang Yinhang , Chen Shanshan , Jiang Yuchen , Xu Guanggui , Fu Jianmin , Wang Baolei , Li Sujun , Wang Xingbing , Li Jun 
Published: June 2023

e14569 Background: Lack of in vivo persistence is the major challenge in allogeneic CAR-T field. Various HLA-related gene-editing strategies are being explored to prevent rejection by host T and NK cells (Table 1). This study reports a platform upgrade on ThisCART (TCR and HLA-I intracellular sequestered), represented by ThisCART19C cells. Methods: ThisCART19C cells were produced with a single lentivirus vector, encoding a CD19-targeting CAR, a KDEL-tagged anti-CD3 scFv, and the HCMV US11 protein. The surface expression of CAR19, TCRαβ and HLA-A/B/E was measured by flow cytometer. Specific tumor cytotoxicity was evaluated both in vitro and in vivo. Furthermore, the safety of donor derived ThisCART19C cells were tested in a xenogeneic GvHD model. Results: Similar to our ThisCART19A product currently in multi-center trials, ThisCART19C cells were readily produced to a quantity and quality supporting clinical investigation. ThisCART19C cells demonstrated an anticipated and stable surface immunotype: CAR19+, TCRαβ-, HLA-A-, HLA-B-，HLA-E+，with great potential for simultaneous evasion of both host T and NK cells. Similar to autologous CD19-directed CAR-T, ThisCART19C exhibited potent CD19-specific cytotoxicity in vitro and in vivo. No xenogeneic GvHD reaction was observed in murine model over an extended period. Conclusions: To our knowledge, ThisCART19C represents the first application of viral evading strategy in promoting the clinical persistence of allogeneic CAR-T cells. Its efficient processing, potent cytotoxicity and favored preclinical safety profile warrant clinical investigation. [Table: see text]
A multi-targeted T-cell engagement of PD1-resistant colorectal cancer cells via delivery of glycopeptide conjugates.
Authors: Adesokan Yemi , Schwarzfischer Marlene , Wyss Romain , Miao Yong , Asare Paul , Spalinger Marianne Rebecca , Scharl Michael 
Published: June 2023

e14571 Background: Glycan-based cancer immunotherapies are novel therapeutic strategies that use the pivotal role of aberrant glycosylation patterns in cancer progression. Targeting hybrid epitopes consisting of altered glycans and carrier peptides enhances the efficacy and specificity of the anti-tumor immune response. Here, we exploit ensembles of glycopeptide conjugates to steer a multi-targeted yet tumor-specific T-cell response, a technology we call GLAAD (glycopeptides with adjuvant and tumor-associated antigen delivery). By inducing T cells that recognize and eliminate tumor cells and promoting their antigenicity in a therapeutic setting, we show the potential of our GLAAD candidate GNU-101 to overcome the transient and heterogeneous responses frequently observed with traditional immunotherapies. Methods: Using the MC38 syngeneic mouse model of colorectal cancer (CRC) in a therapeutic setting, we tested whether GNU-101 reduces tumor burden when orally administered alone or combined with immune checkpoint inhibitors (ICI). On day 0, 20 C57/BL6J mice were injected subcutaneously with MC38 CRC cells in each flank. On day 6, mice were supplemented with 3% GNU-101 in the drinking water, while control mice received normal drinking water. On days 6, 9, 12, and 15, half of the mice in each group received an anti-PD1 antibody (aPD1), while the others received isotype control. On day 16, the mice were sacrificed. Results: In this therapeutic setting, a standalone therapy of GNU-101 successfully reduced tumor growth as demonstrated by a statistically significant reduction in both tumor volume and weight. As expected, the aPD1 therapy had only a non-significant effect on tumor growth. Remarkably, its efficacy was improved when combined with GNU-101, leading to a statistically significant reduction of >90% in tumor volume and weight. The analysis of the immune cell population in the tumor microenvironment revealed the activation of CD8 T cells and a reduction of immunosuppressive signals, which likely mediates the anti-tumor efficacy of GNU-101. This was obvious by a higher abundance of CD8 T cells producing IFNγ and secreting granzyme B & perforin and, conversely, lower amounts of Tim3+ CD8 T cells and regulatory T cells (FoxP3+ CD4 T cells) found in mice treated with GNU-101 vs control mice. Conclusions: We demonstrate the immunomodulatory and therapeutic potential of GNU-101 in a pre-clinical mouse study in which the growth of established tumors was significantly reduced, either as a standalone therapy or in combination with existing treatment. By specifically promoting anti-cancer CD8+ T cells while reducing immunosuppressive signals, this easy-to-administer glycopeptide has the potential to create the conditions for long-term cancer control and improve treatment outcomes in cancer that are frequently resistant to immunotherapy, such as many epithelial cancers.
Immunomodulatory AVM0703 enhances R-CHOP anti-lymphoma effect with reduced toxicity: Immune-resistant, aggressive A20 lymphoma model.
Authors: Deisher Theresa , Mittal Sandeep , Sawas Spencer , Patterson Elizabeth , Nakamura Evan , Jarzyna Peter 
Published: June 2023

e14583 Background: Rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone (RCHOP) is the standard of care for most aggressive B-cell lymphomas. RCHOP requires numerous treatment cycles, typically 6, with challenging side effects, including toxicity and long-term secondary malignancies. Trials have demonstrated that 4 cycles of RCHOP was non-inferior to 6 with similar secondary malignancies, however, real world experience has demonstrated that long term outcomes are superior when patients achieve minimal residual disease negative (MRD-) status after the 3rd cycle (1,2). Addition of a novel agent to RCHOP that could reduce the number of cycles to 3 while maintaining response, could overcome the long-term side-effects and allow frail and elderly patients to receive full dose RCHOP in each cycle to improve outcomes. For example, addition of Lenalidomide with RCHOP improved outcomes in ABC-DLBCL patients (3), but leads to therapy related myeloid neoplasm in recent studies (4). AVM0703, an immunomodulatory drug, mobilizes bispecific and i-TCR double-positive NKT cells (AVM_NKT). In the aggressive, immune resistant A20 mouse lymphoma model, neoadjuvant AVM0703 was additive/synergistic, when cyclophosphamide/fludarabine (CyFlu) was dosed 3 + 24 hours later, with no additional toxicities. Therefore, we hypothesized that combining AVM0703 with RCHOP would be an effective and well tolerated treatment of DLBCL. Methods: Tumor-bearing mice were made by sc flank injection of 2x106 murine A20 B-cells in 10-week-old Balb/c mice. When tumor size reached established ~100 mm3, 48 mice (1:1 male: female) were randomized (12 mice each cohort) 1) Placebo 2) 1 cycle RCHOP 3) AVM0703 (18mg/kg HED) 4) AVM0703+1 cycle RCHOP combination treated as described previously (5,6). When Placebo tumors reached ~ 2000 mm3, all mice were sacrificed and tumors, blood, spleen, bone marrow were analyzed for the presence of remnant A20, and immune cell state by flow cytometer. Results: One RCHOP only mouse died from the chemo. There were no deaths in AVM0703+RCHOP group. Tumor remnant live A20 were significantly reduced in all 3 treatment groups compared to Placebo. Interestingly, AVM0703+RCHOP significantly increased the number of MRD- A20 tumors compared to RCHOP alone. Conclusions: Based on this study we plan to determine whether 3 cycles of AVM0703+RCHOP can induce long term CR and if AVM0703 could replace R and reduce long term side effects. 1) Poeschel Lancet 2019. 2) Spurgeon J Natl Canc Inst 2016. 3) Nowakowski JCO 2021. 4) Sperling Blood 2022. 5) Bascuas J Transl Med 2016. 6) Bongard PLoS Pathog 2019. [Table: see text]
Anti-drug antibodies related to CTLA-4, PD-1, or PD-L1 inhibitors across tumour types: A systematic review.
Authors: Pinato David J. James , Galle Peter R , Mitchell Catherine R , Ndirangu Kerigo , Ramji Zahra , Redhead Gabrielle , Finn Richard S. 
Published: June 2023

e14600 Background: Treatment-emergent anti-drug antibodies (ADAs) are postulated to reduce the efficacy of immune checkpoint inhibitors. A systematic review (SR) was conducted to evaluate the incidence of treatment-emergent ADAs with programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors and their impact on treatment outcomes in patients with cancer. Methods: Electronic databases MEDLINE, EMBASE and Cochrane Library were searched in February 2022 for studies reporting incidence of ADAs and the impact of immunogenicity on treatment efficacy in oncology patients treated with PD-1, PD-L1, or CTLA-4 checkpoint inhibitors. Results: Of the 4,612 articles identified, 34 publications reporting on 68 trials were included. An additional 41 and 32 records were identified from clinicaltrials.gov and packaging inserts respectively. In total, 141 trials of 15 checkpoint inhibitors and 16 tumour types were included. There was considerable variability in the reporting of ADAs, and comparisons between trials were challenging due to intra-study heterogeneity. The incidence of ADAs ranged from 0 to 74%. Across trials, in analyses with the largest sample sizes, atezolizumab was associated with the highest incidence of ADAs (29.6%), then nivolumab (12.2%), followed by the remaining treatments (0-4.4%). The incidence of neutralising antibodies (nAbs) mirrored ADA distribution, being highest for atezolizumab (4.3–27.5%) vs other treatments. Only 17 trials reported on ADA impact on treatment outcomes. Of 11 trials examining efficacy, two reported a negative effect of ADAs, eight reported no measurable effect and another had insufficient patient numbers. The impact of ADAs on treatment safety, and pharmacokinetics was also inconclusive. Conclusions: Treatment-emerging ADAs are inconsistently reported across trials and documented in up to 30% of subjects treated with checkpoint inhibitors across indications. Emergence of nAbs follows but does not perfectly mirror ADA titers, raising questions around the functional meaning of different ADAs. Standardised reporting of ADAs and nAbs should be advocated to facilitate more conclusive immunologic and clinical insight as to the relationship with ADAs and response. [Table: see text]
Safety and clinical efficacy of sintilimab in pediatric patients with advanced or recurrent malignancies in a phase I study.
Authors: Que Yi , Lu Suying , Wang Juan , Sun Feifei , Zhu Jia , Huang Junting , Zhen Zijun , Zhang Yizhuo 
Published: June 2023

e14601 Background: This is a first phase I study investigating the safety and efficacy of sintilimab in pediatric patients with advanced or recurrent malignancies. Methods: During dose escalation, patients received a single-dose intravenous infusion of sintilimab. The planned dosing groups were 1, 3 and 10 mg/kg. During dose expansion, patients received sintilimab every three weeks. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to sintilimab according to the Response Evaluation Criteria in Solid Tumours version 1.1. PD-L1 expression of tumor in subjects were identified by immunohistochemistry (DACO,22C3). Whole exome sequencing (WES) was performed in 15 patients to characterize the mutational landscape and CNV status. Results: 29 patients were enrolled, including 10 patients with Hodgkin lymphoma (HL), 19 patients with other tumor types. Some special pathological types, including thymoma, choroid plexus carcinoma, and NK-T cell lymphoma are included. Patients were pretreated with a median of 3 prior lines of systemic treatment. Sintilimab was well tolerated without dose-limiting toxicity. By the safety data cutoff date, all patients experienced treatment related adverse events (TRAE) with most adverse events being grade 1 or 2, and ≥ grade 3 TRAEs occurred in 10%. Among all 27 subjects evaluated, 4 confirmed complete response (2HL, 1 NK/T lymphoma, 1 anaplastic ependymoma), 7 confirmed partial responses (4 HL, 1 Ewing sarcoma, 1 diffuse large-B lymphoma and 1 thymoma), and 7 stable disease were observed, for an objective response rate of 40.7%, and a disease control rate of 66.7%. Subjects with PD-L1-positive expression benefited more from sintilimab treatment than PD-L1-negative subjects (66.7% ORR versus 33.3% ORR, p=0.314) although statistically insignificant. The genomic profiling of WES indicatedpatients with a specific genomic mutation type predict the response of PD-1 therapy. Conclusions: Sintilimab was well tolerated and demonstrated promising anti-tumor activity in pediatric HL. The completion of the current phase I study has led to the initiation of the first prospective anti-PD-1 registration trial in Asia focusing on pediatric patients and serve as the basis for its potential study in combinatorial regimens for childhood cancer. Clinical trial information: NCT04400851 . [Table: see text]
Efficacy and safety of switching other tyrosine kinase inhibitors to regorafenib combined with primary PD-1 antibodies in patients with hepatocellular carcinoma.
Authors: Pan Shida , Yu Yingying , Wang Siyu , Qiu Qin , Shen Yingjuan , Yang Luo , Liu Xiaomeng , Luan Junqing , Meng Fanping 
Published: June 2023

e14612 Background: Currently, formal tyrosine kinase inhibitors (TKIs) such as sorafenib or lenvatinib in combination with PD-1/PD-L1 immune checkpoint inhibitor had achieved promising results in patients with hepatocellular carcinoma (HCC). However, a portion of patients experienced drug-resistant tumor progression and/or severe adverse events associated with TKIs during the course of treatment, resulting in unfavorable disease control and poorer overall survival. Therefore, a better medication strategy is urgently needed in aim to improve the prognosis of these patients who experienced discontinuing medication of TKIs. Methods: We reviewed the medical data of 23 HCC patients with disease progression after received sorafenib or lenvatinib combined with PD-1 antibodies from Jan Feb 2020 to Sep 2021 at the Fifth Medical Center of PLA General Hospital in China. These patients had switched to regorafenib PO for 3 weeks on/1 week off combined with primary PD-1 antibodies after experienced tumor progression and/or severe adverse events with respect to sorafenib or Lenvatinib. All patients were followed up regularly. Changes of tumor lesions, survival data and adverse events (AEs) were detailed recorded after switched. All AEs were evaluated according to the CTCAE v5. Results: Initially, 20 (87.0%) patients were treated with lenvatinib and 3 (13.0%) patients were treated with sorafenib before switched to regorafenib. Of all patients, tumor progression caused 15 (65.2%) switching and severe AEs caused 8 (34.8%) switching, and the initial daily dose of regorafenib were 80mg (95.6%) and 40 mg (4.4%), respectively. Before switched to regorafenib, the most common mild AEs were hypertension, hypothyroidism and granulocytopenia, and the most common severe AEs were rash, hepatitis, and lung infections. In contrast, the most common AEs was mild hoarseness after switched to regorafenib. During the follow-up, 12 (52.2%) patients died, 3 (13.0%) patients lost and 8 (34.8%) patients sustained survival. The overall median survival time (MST) was 22.47 months [95% confidence interval (CI): 2.98 months to 41.96 months], the MST after switched to regorafenib was 10.53 months (95% CI: 0.257 months to 20.81 months). Of note, size of tumor lesion decreased in 7 (30.4%) patients and increased in 3 (13.0%) patients, and the other 13 (56.6%) patients could not be evaluated due to incomplete data after switching to regorafenib. Conclusions: For patients who are resistant to other TKIs, switching to regorafenib showed good efficacy and manageable safety. Therefore, this treatment protocol can be considered as a potential treatment for patients without clinical benefits after first or second-line combination therapy.
Doxorubicin to enhance the abscopal effect depending on tumor cell mitochondrial DNA and cGAS/STING.
Authors: Wang Liqun , Luo Ren , Onyshchenko Kateryna , Gabriele.Niedermann@Uniklinik- No Firstname 
Published: June 2023

e14616 Background: Localized radiotherapy (RT) can cause a T cell-mediated abscopal effect on non-irradiated tumor lesions, especially in combination with immune checkpoint blockade (ICB). However, this effect is still clinically rare and improvements are highly desirable. We investigated whether triple combination with a low dose of clinically approved liposomal doxorubicin (Doxil) could augment abscopal responses compared with RT+ICB, Doxil+ICB, or RT+Doxil. Methods: We used Doxil in combination with RT and αPD1 in two tumor models (B16-CD133 melanoma and MC38 colon carcinoma) with mice bearing two tumors, only one of which was irradiated. Results: Triple therapy with RT, αPD1, and single low-dose Doxil strongly enhanced the RT-induced abscopal effect compared to all double and single treatments in both tumor models ( p < 0.05, n = 5-10 mice/group). Complete cures of non-irradiated tumors were mainly observed in triple-treated mice. Triple therapy induced more cross-presenting dendritic cells (DCs) and tumor-specific CD8 T cells than RT/αPD1 and Doxil/αPD1 ( p < 0.05, n = 5 mice/group), particularly in non-irradiated tumors. CD8 T cell depletion or implanting STING-deficient tumor cells abolished the abscopal effect. By using inhibitors and knockout cells, we show that doxorubicin/Doxil-induced IFNβ1 markedly depended on the cGAS/STING pathway ( p < 0.05) which drives antitumor CD8 T cell responses through cross-presenting DCs. In mitochondrial DNA (mtDNA)-depleted tumor cells, doxorubicin/Doxil induced less IFNβ1 ( p < 0.05), the related T cell-recruiting chemokine CXCL10 ( p < 0.0001), and ATP ( p < 0.0001); coincubation with mtDNA-depleted tumor cells strongly reduced IFNβ1 ( p < 0.01) secretion by DCs. Implantation of mtDNA-depleted tumor cells, particularly at the non-irradiated site, substantially diminished the Doxil-enhanced abscopal effect and tumor infiltration by tumor-specific CD8 T cells ( p < 0.05). Conclusions: Single low-dose Doxil can substantially enhance the RT-induced abscopal effect, with a strong increase in cross-presenting DCs and CD8 tumor-specific T cells particularly in abscopal tumors compared with RT/αPD1 and Doxil/αPD1. The mtDNA/cGAS/STING/IFN-I axis is important for the immunogenic doxorubicin effects. Our ﬁndings may be helpful for the planning of clinical radiochemoimmunotherapy trials in (oligo)metastatic patients.