bluuebunny/crossref_metadata_2025_split huggingface dataset:
A first-in-human study of MIL95, an anti-CD47 monoclonal antibody (mAb), in patients with advanced solid tumors and lymphomas.
Authors: Zhang Qingyuan , Liu Aiguo , Shi Jianhua , Cai Qingqing , Qu Zerui , Liu Sijun , Song Yuqin 
Published: June 2023

e14513 Background: CD47 provides a potent “do not eat me” signal that allows the tumor to escape removal by the innate immune system. MIL95 is a humanized, anti-CD47 lgG4 monoclonal antibody and that mediated blockade of CD47 can induce macrophage phagocytosis of cancer cells. To evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and antitumor activity of MIL95, we conducted a first-in-human phase 1 trial in pts with advanced solid tumors and lymphomas (Protocol number MIL95-CT101, Beijing Mabworks Biotech Co. Ltd.) at 5 clinical study sites in China. Currently the study is still ongoing. Methods: We enrolled pts aged 18 years or older with advanced solid tumors and lymphomas whose disease had progressed after standard systemic treatments. Pts were required to ECOG PS score of 0-1 and adequate organ functions. Pts were enrolled in this two-part dose-escalation study: Part A, to determine a priming dose at 0.1, 0.3, 0.8, 1 mg/kg; Part B, to determine optimal weekly maintenance dose at 3, 10, 20, 30, 45 mg/kg. Dose escalation was performed using an accelerated titration followed by traditional 3+3 design during a 14-day (Part A) or 28-day (Part B) dose-limiting toxicity (DLT) observation period. Results: As of 18 Dec 2022, 24 pts (median age 54.5 years; 37.5% male; 54.2% ECOG PS 1) were treated: 8 in part A, 16 in part B. The common tumor types were lymphomas (25.0%) and breast (25.0%), lung (12.5%) cancers. MIL95 toxicity was manageable, no DLT was observed, and dose escalation was ongoing at 45mg/kg. The most common treatment-related adverse events (TRAEs) occurring in ≥10% of pts were anemia (37.5%), blood bilirubin increased (37.5%), leukopenia (20.8%), pyrexia (16.7%), and fatigue (16.7%). Most toxicities were Grade 1 or 2. Five pts had ≥Grade 3 TRAEs (Grade 3 anemia in 2 pts, Grade 3 decreased appetite in 1 pt, Grade 3 enteritis infectious in 1 pt, Grade 4 platelet count decreased in 1 pt). 4 pts had SD as a best response, with 1 pt (Cholangiocarcinoma at dose 20 mg/kg) on study for >5 months. Conclusions: MIL95 was well tolerated at 1 mg/kg priming dose following by maintenance doses of up to 45 mg/kg weekly. Further antitumor activity may need to be combined with other therapies. Clinical trial information: NCT04651348 .
Therapeutic effect of a VSIG4-specific mAb EU103 in a preclinical model of patient-derived ascites of ovarian cancer.
Authors: Kim Hye Jeong , Kang Kyung-Jung , Shin Jeamin , Lee Joong Won , Kim Byoung-Gie , Park Sang-Yoon , Jeong Joseph H. , Kwon Byoung S. S 
Published: June 2023

e14516 Background: V-set and immunoglobulin domain-containing 4 (VSIG4) is one of the B7 family-related proteins that includes PD-L1, VISTA, and CTLA4 ligand. VSIG4 overexpression is correlated with poor prognosis in patients with ovarian cancer, lung cancer, gastric cancer, high-grade glioma, and multiple myeloma. VSIG4 is also known to function as a receptor for complements and the negative regulation of T cell proliferation. Although VSIG4 is highly expressed in tissue-resident macrophages and tumor-associated macrophages (TAM), its role in the tumor microenvironment (TME) is not fully elucidated. Methods: We previously developed a therapeutic antibody, EU103, in a humanized form of a VSIG4-specific antibody. Most importantly, we demonstrated that EU103 directly acts on the tumor-associated macrophages (TAM) and mechanistically induces repolarization of TAM to tumor killing M1 macrophages and blocks VSIG4-mediated T cell suppression, eventually leading to CD8+ T cell proliferation and tumor suppression in a PBMC-humanized human lung cancer mouse model. Results: Expanding our previous findings with the therapeutic potential of EU103 in a non-small cell lung carcinoma (NSCLC), here, we also proved its therapeutic effect in human ovarian cancer. Firstly, TAMs isolated from ovarian cancer patients express high levels of VSIG4 with immunosuppressive M2 macrophage phenotype. Secondly, EU103 treatment of the TAMs in in vitro studies induces M2-to-M1 conversion and activation of T cells in the ascites leading to ovarian tumor cell killing in a dose-dependent manner. Thirdly, in vivo therapeutic efficacy of EU103 in ovarian cancer, especially through M2-to-M1 conversion, is also verified in both CD34+ cell and peripheral blood mononuclear cell (PBMC) humanized mouse models. Finally, we validate the results above by treating ovarian cancer patient-derived ascites with EU103. Conclusions: Almost 300,000 women are diagnosed with ovarian cancer worldwide each year, and ovarian cancer ranks fifth in cancer deaths among women. In the United States alone, we expect approximately 20,000 new diagnoses and more than 12,000 deaths for this year. Given our findings in this study and clinical significance, we propose here the therapeutic potential of EU103, previously developed by our proprietary antibody discovery and engineering technology, in ovarian cancer.
Hypophosphatemia and thrombocytopenia: A retrospective chart review to identify markers for prediction of CRS and ICANS in CAR T-cell therapy.
Authors: Barker Kenneth , Bertolo Aaron , Uhland Cole , Koza Shannon , Katsanis Emmanuel , Husnain Muhammad 
Published: June 2023

e14524 Background: CAR T-cell therapy has transformed the treatment landscape of B cell malignancies. Adverse effects of CAR T include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). We aimed to identify biomarkers predictive of CRS and ICANS post CAR T-cell therapy. Methods: A total of 34 patients (19 male and 15 female) with a median age of 68 years and ranging from 38 to 80 years old treated with CAR T-cells for B-cell malignancies at Banner University Medical Center/University of Arizona Cancer Center were evaluated. Phosphate (Ph), IL-6, ferritin, lactate dehydrogenase (LDH), and platelet count from each patient were recorded through retrospective chart review. A simple two-sample t test and ANOVA T-test were run to determine statistical significances by comparing the values of each parameter of interest between groups. Results: Of the 34 patients, 19 (56%) developed CRS without ICANS, 8 (24%) had both CRS and ICANS, and 7 (20%) developed neither. Of the 19 patients with CRS without ICANS, 13 (68%) had clinical hypophosphatemia compared to 0% of patients without CRS or CRS+ICANS. Average phosphate (Ph) nadir levels in the patients with CRS were significantly lower at 2.08 mg/dL compared to those in patients without CRS at 3.20 mg/dL ( P= .00007). Patients with CRS + ICANS had even lower Ph levels at 1.99 mg/dL when compared to patients without ( P= .004). Thrombocytopenia at time of infusion was significantly associated with the development of CRS with those patients having an average platelet count of 114 x 109/L compared to 184 x 109/L in patients without CRS or CRS+ICANS (P = .037). Interleukin-6 (IL-6) levels were elevated in all of patients who developed CRS with an average peak level of 102 pg/mL, however, an inadequate number of patients without CRS or CRS+ICANS were sampled thus precluding a statistical comparison in peak IL-6 levels between groups. Conclusions: Hypophosphatemia is associated with the development of both CRS alone and CRS+ICANS after CAR T cell therapy. A proposed mechanism is thought to be related to increased phosphate consumption by CAR T cell induced metabolic activity. Thrombocytopenia at the time of infusion was significantly associated with the development of CRS. Hypophosphatemia and thrombocytopenia show promise as markers for the prediction of CRS and ICANS in CAR T-Cell therapy.
Investigator-initiated phase 1 clinical trial of synthetic TIL: Autologous peripheral T cells engineered with polyclonal TIL-derived TCRs.
Authors: Cheng Zhongping , Wu Wei , Xuan Jiekun , Zhao Yue , Cai Jun , Porter Ely , Chen Xi 
Published: June 2023

e14525 Background: The efficacy of tumor-infiltrating lymphocyte (TIL) therapy is limited by the rarity of anti-tumor TCRs and exhausted status of the product. Its improvement should focus on a high frequency of diverse anti-tumor TCRs with stem-like phenotype, which can be achieved synthetically by identifying multiple anti-tumor TCRs from the patient's intra-tumor TCR repertoire and subsequently engineering them into the patient’s peripheral T cells. Such a ‘synthetic TIL’ is cost-prohibitive using existing technologies. To enable a synthetic TIL product, we developed ultra-high throughput TCR gene synthesis and screening methods to synthesize and screen > 50,000 TCRs from scRNA-Seq data from > 30 patients and identified > 100 tumor/NeoAg-reactive TCRs. The gene expression patterns of the T cells carrying such experimentally validated tumor/NeoAg-reactive TCRs gave rise to an algorithm called Interpreter to predict potentially anti-tumor TCRs from scRNA-Seq data. Methods: To translate synthetic TIL to the clinic, we developed a method to generate up to 100 sequence-verified TCR-encoding plasmids (selected by Interpreter) from fresh tumor biopsy in just 3 weeks. Our GMP-grade production uses a collective knock-in approach, where a mixture of up to 100 plasmids (each encoding a distinct TCR) at equal proportion are packaged into AAV which serve as template to precisely insert the TCR genes into a primarily monoallelic locus and simultaneously inhibit the endogenous TCR. This gene editing is characterized by a modified scRNA-Seq method called EntrySeq. In first-in-human, N-of-1 trials, 109 to 6x109 synthetic TIL cells were administered to solid tumor patients with or without lymphodepletion and IL2. An investigator-initiated Phase 1 trial was then opened to evaluate safety, preliminary efficacy, and cellular activity of synthetic TIL and to determine RP2D and MTD. Subjects with relapsed, unresectable locally advanced solid tumors who received at least 1 standard systemic therapy are allowed to enroll in this study. Those patients with no standard treatment regimens available, or those who are unable to obtain effective treatment due to economic conditions are also permitted. Results: EntrySeq confirmed that > 80% of the T cells express only 1 TCR, avoiding mispairing of different TCRs. The frequencies of different TCRs were largely uniform and were stable through plasmid, AAV and T-cell mixtures. Up to 1.5x1010 synthetic TIL cells were produced from a patient’s leukopak. 40 to 60% of the T cells in the product for infusion express an exogenous TCR. In first-in-human trials, the administered T cells showed favorable persistence and safety profile. The Phase 1 trial is ongoing. Conclusions: We established a fast, affordable, and GMP-compliant process to manufacture synthetic TIL products, enabling a Phase 1 trial.
WTX212, an erythrocyte-anti-PD1 antibody conjugate, to demonstrate anti-tumor activities in tumor models and patients with cancer with acquired resistance to immunotherapy.
Authors: Xiaoqian Nie , Liu Yuehua , Chen Yun , Zhang Qi , Tong Xiangmin , Huang Yanjie , Yuan Yang , Zheng Jiawei , Xu Li , Gao Xiaofei 
Published: June 2023

e14529 Background: Despite the success of immune-checkpoint blockade (ICB) treatments, a considerable proportion of patients cannot benefit from ICB therapy due to acquired resistance. One major challenge is the systemic suppression of immune cells induced by the tumor. Recent studies have revealed that successful immunotherapy drives new immune responses arising from peripheral immune system instead of reinvigorating the pre-existing responses in the tumor. Here we designed WTX212, autologous engineered red blood cells (RBCs) conjugated with anti-PD1 antibodies capable of activating the peripheral immune system. We also evaluated its anti-cancer activities in anti-PD1 non-responsive tumor models and a first-in-human (FIH) trial. Methods: The anti-tumor efficacy of WTX212 was evaluated in both PD1 responsive (MC38 colorectal cancer) and non-responsive (KP lung cancer and pB3 breast cancer) mouse tumor models (n=7 / group). Mice were monitored twice a week for clinical signs and tumor sizes. The mechanism of action was investigated in splenectomized mice and by analyzing the biodistribution of WTX212 using a radiolabeling method. The immune landscape was also profiled through cytof mass and scRNA-seq analyses in the spleen, tumor and peripheral blood. The FIH trial (NCT05707325) explores safety, pharmacokinetics and mechanism in cancer patients with acquired resistance to ICB. WTX212 was manufactured by covalently engineering anti-PD1 antibody with RBCs isolated from patients. By 6th Feb 2023, 3 patients have been enrolled and received at least one dose of WTX212 (20*1010 cells, IV, Q3W). Results: Treatment of WTX212 significantly suppressed tumor growth up to 100% in anti-PD1 responsive and non-responsive tumor models and activated tumor microenvironment with increased infiltrated T cells. Unlike antibodies, WTX212 primarily distributed to the spleen and vascular system. The anti-tumor effect of WTX212 was abrogated in corresponding splenectomized mice. Compared to anti-PD1 antibody, single-cell analysis identified the immune landscape remodeling in the spleen from WTX212-treated mice, with down-regulation of PD-L1+ myeloid-derived suppressor cells (MDSCs) and up-regulation of effector CD8+ T cells. In the FIH trial, 3 patients have been administered with total eight cycles of WTX212. No treatment-related AEs greater than Grade 2 were observed. WTX212 remained in the peripheral blood day 21 post transfusion. WTX212 rapidly activates peripheral immune systems with decreased MDSCs, Tregs and increased effector T cells in peripheral blood from all patients. Conclusions: WTX212 demonstrated anti-tumor activities by activating the peripheral immune system to overcome resistance to immunotherapy in both preclinical models and human patients. WTX212 is well-tolerated supporting the future clinical trials.
VHH-based chimeric antigen receptor T cells against CD70 to eliminate primary and re-challenge renal cell carcinoma tumors in preclinical study.
Authors: Jiang Pengfei , Xiong Qinghui , Wang Haiying , Deng Tian 
Published: June 2023

e14540 Background: CD70 is not expressed in normal tissue, but highly expressed on various hematopoietic and solid tumors, including renal cell carcinoma (RCC). It is an ideal target for cancer therapy and recently was proved by good results in clinical trials of CD70 monoclonal antibody. Methods: We obtained 4 VHH antibody（2A5, 8B4, 11C9 and 9D8）against CD70 by screen nanobody library derived from an antigen-immunized alpaca. Generated a panel of CAR-T cells by transduce retrovirus expressing CAR (chimeric antigen receptor) to human T cells isolated from health donors. These CAR constructs include 4 VHH sequences and a human scFv containing VH and VL derived from cusatuzumab. We evaluated CAR-T cell function in vitro included cell phenotype, proliferation, cytotoxicity, and cytokine release. Furthermore, RCC tumor cell-xenograft NOG mice models were used to test the anti-tumor activity of CAR-T cells in vivo. Results: All anti-CD70 CAR-T cells eliminate CD70-positive tumor cells but not CD70-negative cells in vitro. Although there were no significant differences between the killing efficiency of the CAR-T cells, more abundant IL-2 production in two VHH-based CAR-T cells (11C9 and 2A5) were observed in multi-round co-culture assay. CAR-T cells eradicated RCC tumor cell in our Xenograft model. After infusion, human T cells expanded over 250 folds in 11C9 group and over 30 folds in 2A5 group, but only nearly 6 folds in human scFv CAR-T treated group. In our second in vivo experiment, all mice treated with higher dose CAR-T, the VHH groups maintained tumor free statue much longer time than human scFv group. Cured mice were re-challenged by subcutaneously infuse RCC tumor cells, observed and measured tumor in the next 53 days. For 11C9 CAR-T treated group, 3of 7 mice maintained tumor-free, 1 of 7 mice were tumor-palpable but too small to measurement; For 2A5 treated group only 1 of 7 mice maintained tumor-free. A significantly greater expansion of human T cells in 11C9 group but not 2A5 group after re-challenge. Conclusions: Our results indicate a promising VHH-based CD70 CAR-T cells for RCC therapy, supporting further development for future clinical trial and application.
Serum vitamin B12 levels and response to immunotherapy.
Authors: Turgeman Ilit , Reiner Benaim Anat , Regev Tsur Stav , Chahine Haya , Bar-Sela Gil 
Published: June 2023

e14542 Background: Underlying metabolic pathways have a role in regulation of response to cancer immunotherapy. Due to its immunomodulatory properties, we sought to investigate the relationship between elevated serum vitamin B12 (VitB12) and survival among individuals with cancer treated with immune checkpoint inhibitors. Methods: Data from a retrospective chart review were used to identify patients with advanced cancer initiating anti-neoplastic treatment and a concomitant VitB12 measurement (elevated: > 820 ng/L), between 1/2010-1/2022 at our institution. Patients on immunotherapy (IO) and other regimens (control) were compared using Mann-Whitney test for continuous variables, and Chi-square test or Fisher's test for categorical variables. Multivariate Cox regression models were used to assess the effect of VitB12 levels on overall survival (OS) and progression free survival (PFS), with adjustment for potential confounders. Results: A total of 501 patients were included (control, n = 408; IO, n = 93). Groups were well balanced for treatment line (first line, 91.4% vs. 94%), VitB12 levels (elevated, 29.9% vs. 23.7%; mean, 762.4 ng/L vs. 687.6 ng/L) and liver function tests. Cancer diagnoses differed between groups (most common, gastrointestinal vs. lung, p < 0.001). Multivariate analysis revealed that high VitB12 was negatively associated with OS in both groups (control: hazard ratio, HR 1.4, 95% CI 1.01-1.96, p = 0.04; IO: HR 2.74 as sum of linear baseline and interaction effects, in log scale), as were age (HR 1.03, 95% CI 1.02-1.04, p < 0.01), male gender (HR 0.66, 95% CI 0.50-0.88, p < 0.01), and neutrophil to lymphocyte ratio (NLR) (HR 1.05, 95% CI 0.48-0.99, p = 0.01). However, the only negative prognostic factor for PFS was VitB12 in the IO group alone (calculated HR 8.34). No association was observed with patient and cancer characteristics, other laboratory values, chemotherapy (p = 0.3) or biologic therapy (p = 0.8). Mean follow-up in the control and IO groups was 93 vs 54 weeks (OS), and 22 vs 33 weeks (PFS), respectively. Conclusions: Elevated VitB12 levels were negatively associated with response to immune checkpoint inhibitors, independently of other prognostic factors such as age, cancer type, treatment line and NLR. In addition to a direct role in cellular immunity, VitB12 is involved in gut microbiota balance, which in turn affects host immune responses – suggesting a possible immune-metabolic interplay. Further research is needed to elucidate the metabolic regulators of response to immunotherapy and potential strategies of intervention, in order to rationalize and broaden its clinical utility.
Extracellular vesicles budding from stromal macrophages from the blood circulating in patients with metastatic non-small cell lung cancer to predict clinical outcomes.
Authors: Moran Jillian , Adams Daniel L , Edelman Martin Joseph , Lopez Bravo Pablo , Xu Ting , Liao Zhongxing X. , Gardner Kirby P , Tang Cha-Mei , Lin Steven H. 
Published: June 2023

e14547 Background: Extracellular vesicles (EVs), which include exosomes, microvesicles, and apoptotic bodies, are involved in cellular communication, aiding tumor growth, and in metastasis of cancer. Recently, extracellular budding structures on Cancer Associated Macrophage-Like Cells (CAMLs), a subtype of phagocytic circulating stromal cells found in circulation, was observed in patients with metastatic non-small cell lung carcinoma (mNSCLC). In this prospective analysis of n=104 metastatic NSCLC (mNSCLC) patients, we enumerated EV budding on CAMLs to determine their clinical significance on Progression Free Survival (PFS) & Overall Survival (OS), further subtyping based on treatment with or without PD-L1 Immunotherapy (IMT) based on standard of care treatment. These preliminary data suggests that EV positive (EV+) CAMLs prognosticates for worse PFS & OS in mNSCLC. Methods: We initiated a single blind multi-year prospective study to investigate the relationship between EV budding in CAMLs to PFS & OS prior to start of new treatment lines for mNSCLC. Anonymized blood was procured from n=104 pathologically confirmed mNSCLC patients and filtered to isolate CAMLs to measure EV budding using tumor/EV markers (i.e. cytokeratin, CD63, or CD81) and an immune specific marker (PD-L1). Blood was filtered by CellSieve microfiltration and EV budding was characterized as small (≤1 µm) bulbous protrusions from the cell cytoplasm. EVs were quantified by presence (EV+) or absence (EV-), as well asPD-L1 positivity or negativity in EVs, to compare PFS & OS with hazard ratios (HRs) at 60 months by censored univariate and multivariate analyses. Results: CAMLs were identified in 93% (n=97/104) of all samples, with EV budding (EV+) identified in 62% (n=60/97) of CAMLs. At 60 month follow-up, it was determined that EV+ CAMLs was associated with significantly worse PFS (HR=1.67 95%CI=0.4-1.0, p=0.0410) and OS (HR=1.88, 95%CI=0.3-0.9, p=0.0108). Further, in patients not treated with IMT, EV+ CAMLs was associated with significantly worse PFS (HR=2.51, 95%CI=0.2-0.8, p=0.0251) and OS (HR=2.32, 95%CI=0.2-0.9, 0.0407). In contrast, in patients treated with IMT, EV+ CAMLs had no correlation to PFS (1.18, 95%CI=0.5-1.6, p=0.7050) or OS (HR=1.53, 95%CI=0.3-1.3, p=0.2858), suggesting a clinical benefit in treating EV+ patients with PD-L1 IMT. Conclusions: EV budding on phagocytic stromal cells found in the blood of mNSCLC patients appears to predict for poorer PFS and OS, which is reduced with additional of PD-L1 immunotherapies. Larger validation studies are ongoing in both mNSCLC and stage III NSCLC patients, along with analysis of PD-L1 EV staining.
Relationship of platelet-to-lymphocyte ratio with tumor immune microenvironment and efficacy of anti-PD-1 combined with neoadjuvant chemotherapy in muscle invasive bladder cancer.
Authors: Hu Hailong , Niu Yuanjie , Li Hong Zheng , An Zesheng , Wu Zhouliang , Shen Chong , Zhang Zhe , Zhao Gangjian , Huang Shiwang 
Published: June 2023

e14549 Background: The platelet-to-lymphocyte ratio (PLR) has been used to predict therapeutic response in different tumors. However, no assessments of its usefulness have been performed in muscle-invasive bladder cancer (MIBC) patients receiving anti-PD-1 combined with neoadjuvant chemotherapy. Methods: The respective data of 62 MIBC patients receiving anti-PD-1 combined with neoadjuvant chemotherapy were analyzed. Whether PLR might predict treatment response to anti-PD-1 plus neoadjuvant chemotherapy and the cutoff value of the parameter were determined by ROC curve analysis. Moreover, 31 tumor mRNA sequencing data before the treatment were collected and analyzed using ESTIMATE R package. Results: PLR before the second period (PLR2, cut-off = 122.38, AUC = 0.667, 95% CI: 0.529-0.805, sensitivity = 0.935, specificity = 0.452) seemed to be useful predictors to determine patients who have a response or no response. The PLR2-low and PLR2-high groups were divided according to median score (154.9), and the estimate score and the immune score were significantly higher in the PLR2-low group. Conclusions: The PLR2 allowed for the accurate and efficient stratification of MIBC patients receiving anti-PD-1 plus chemotherapy and is easily applicable for clinical practice at no additional cost. Meanwhile, we identified that the diagnostic performance of PLR2 might reflect the tumor immune microenvironment, which plays an important role in immune therapy.