tbuckley/cabot-search huggingface dataset:
A novel B7-H3 x CD3 bispecific T-cell engager for the treatment of B7-H3<sup>+</sup> tumors.
Authors: Feng Li, Ming Liu, Yanan Hua, Xuemei Wei, Luying Qin, Guangcan Cao, Daniel Chunxu Yang, Wenjun Zhang
Journal: Journal of Clinical Oncology (2024)

e14509 Background: B7-H3 (CD276) is a transmembrane protein highly expressed in solid tumors but with limited expression in normal tissues. Its presence is strongly associated with the inhibition of T-cell activity, cancer progression, and invasion. Furthermore, B7-H3 is strongly associated with poor prognosis and reduced patient survival. Given its crucial role in tumor biology, B7-H3 has emerged as an attractive therapeutic target for drug development. We utilized ExMab heterodimer platform and common light chain technology to develop EX105, a next-generation B7-H3×CD3 bispecific antibody. This innovative T-cell engager exhibits excellent anti-tumor activity in mouse models and good safety profile in NHP tox study. Methods: EX105 was generated using ExMab heterodimer platform and common light chain technology to form a heterodimeric IgG1 structure. Preclinical pharmacology studies, efficacy, and safety were evaluated. Anti-tumor activity study of EX105 includes in vitro T-cell cytotoxicity assays and in vivo PBMC reconstituted xenograft mice models. Preclinical safety evaluation of EX105 was performed through GLP single-dose and repeat-dose tox studies in non-human primates (NHPs). Results: Based on ELISA and FACS analyses, EX105 can bind to both human and cynomolgus monkey B7-H3 and CD3 antigens. Furthermore, SPR data suggest that EX105 exhibits a high affinity to B7-H3 and a much lower affinity to CD3. In consistent with that, EX105 only induced relatively low cytokine release. Nevertheless, EX105 showed a potent in vitro T cell cytotoxicity against B7-H3 + tumor cell lines. The in vivo anti-tumor activity of EX105 was further determined in several tumor xenograft models. Treatment with EX105 resulted in remarkable tumor regression in both “hot” tumor model and “cold” tumor model, indicating its effectiveness across a range of tumor types. Tox study in NHPs showed minimal adverse effects and no liver impairment after EX105 administration, even at high doses. The cytokine release data observed in this study suggests a good safety profile of EX105, with much lower cytokine release compared to other T cell engagers. Conclusions: These findings collectively indicate that EX105 has the potential to become a promising therapeutic agent for the treatment of various B7-H3 positive cancers. The first-in-human clinical trial for patients with advanced B7-H3 positive cancers is due to start.
First-in-human phase I/II safety and preliminary efficacy of PM1032, a bispecific antibody targeting CLDN18.2 and 4-1BB, in patients with advanced solid tumors.
Authors: Ye Guo, Lihua Wu, Yong Li, Jinhua Wen, Junli Xue, Zhuoyi Wang, Pu Li, Wei Zhao, Jingfeng Liu, Xi Rao, Qun Li, Liqiong Xue, Xiaoxiao Ge, Fengjuan Lin, Wenbo Tang, Jiuli Zhou
Journal: Journal of Clinical Oncology (2024)

2662 Background: PM1032 is an anti-CLDN18.2 x 4-1BB bispecific antibody that activates immune cells, such as T and NK cells, via CLDN18.2-mediated crosslinking of 4-1BB. Potent anti-tumor efficacy is facilitated with limited toxicity as immune activation is only stimulated in the context of CLDN18.2 expression on target cells. Here, we present the preliminary safety and efficacy results from an ongoing Phase I/II trial, which is a first-in-human (FIH), dose-escalation, and expansion study of PM1032 in patients (pts) with advanced solid tumors. Methods: This FIH study of PM1032 with adults with previously treated, advanced or metastatic solid tumors includes dose escalation (3+3 design; regardless of CLDN18.2 expression) and dose expansion stages (CLDN18.2+ gastrointestinal (GI) cancers). During the dose escalation stage, PM1032 was administered at doses of 0.3, 1, 3, 5, 8 and 12 mg/kg for the assessment of drug limiting toxicity (DLT) after 3 weeks, followed by administration Q2W until disease progression (PD) or observations of intolerable toxicity. Responses were evaluated according to RECIST 1.1. Adverse events (AEs) were graded using CTCAE v5.0. CLDN18.2 positivity was defined as ≥1% of tumor cells with ≥1+ signal intensity by immunohistochemistry. Results: As of January 12, 2024, a total of 30 pts received PM1032 (18 pts during dose escalation and 12 pts during dose expansion) with no DLTs observed (median age 54y; most pts had ≥2 metastatic sites). CLDN18.2 expression was evaluable in 80% of the pts and 66.7% were positive. The most common tumor types were GI cancers including 14 gastric and gastroesophageal junction cancers (GC/GEJ), 10 pancreatic adenocarcinoma (PDAC) and 5 other GI cancers. All pts had ≥1 line of prior therapy and 17 pts (56.7%) had prior immunotherapy. TRAEs occurred in 22 subjects (73.3%), and ≥ Grade 3 TRAEs occurred in 3 subjects (10%). The most common TRAEs were nausea (20%) and aspartate transaminase increase (16.7%). Among a total of 16 CLDN18.2+ pts enrolled at the 5, 8, and 12 mg/kg dose levels who completed at least one tumor evaluation, 2 pts achieved PR, 7 pts had SD and 3 pts were Non-CR/Non-PD. Additionally, the ORR was 20% in 10 measurable and evaluable CLDN18.2+ GC/GEJ pts. The longest treatment duration was 18 months and 5 pts had treatment durations ≥ 6 months. Pharmacokinetics (AUC0-336h &amp; Cmax) were dose-proportional across the dose ranges of 0.3 mg/kg – 12 mg/kg with a terminal half-life of 6.0~10.1 days. Conclusions: PM1032 was well-tolerated up to 12 mg/kg Q2W and demonstrated preliminary anti-tumor activity in CLDN18.2+ tumors. Further development of PM1032 as a monotherapy and/or combination therapy for CLDN18.2-positive cancers is planned. Clinical trial information: NCT05839106 .
Pre-clinical safety and efficacy evaluation of sodium chloride nanoparticles for treating non-muscle invasive bladder cancer.
Authors: Andrew Gdowski, Lucia Kim, Xining Lai, Xinrui Ma, John Raupp, Shuyue Zhan, Wolfgang Beckabir, Michael Sturdivant, Sara Elizabeth Wobker, Zibo Li, Jin Xie, William Y. Kim
Journal: Journal of Clinical Oncology (2024)

e14591 Background: Non-muscle invasive bladder cancer (NMIBC) presents a significant therapeutic challenge. Current treatment modalities such as BCG and intravesical chemotherapy given after transurethral resection of bladder tumors (TURBT), while effective, are associated with high cost burdens and are difficult for patients to tolerate due to side effects. This ultimately limits treatment regimen duration and decreases the effectiveness of the therapy which frequently leads to local recurrence. Sodium Chloride Nanoparticles (NaCl-NPs) have previously shown promise in preclinical models of intra-tumoral injection of various tumor types but has not been tested in more clinically relevant models of bladder cancer. In this study, we evaluate the safety and efficacy of NaCl-NPs as a local intravesical therapy for preventing tumor development in a preclinical murine model of bladder cancer. Methods: We conducted a dose escalation experiment via intravesical instillation of increasing doses of NaCl-NPs (300 ug/ml-2700 ug/ml, n=3 mice per group) to identify the maximum tolerated dose. Mice were treated on a weekly dosing schedule and toxicity was evaluated at day 35 as a composite of: evaluation of bladder histology with Hematoxylin and Eosin (H&amp;E) staining by a board-certified pathologist, blood chemistry measurements, complete blood counts, as well as body weight measurement. Secondly, we assessed the efficacy of the nanoparticles through a tumor prevention experiment where MB49 bladder cancer cells were instilled in the murine bladder and shortly after treated with intravesical: 1.) Saline, 2.) Gemcitabine, or 3.) NaCl-NPs for 1 hour (n=18 per group). Mice were monitored for tumor development with 3D bladder ultrasound. In additional, overall survival (OS) was assessed. Results: The dose escalation study showed that there was no local or systemic toxicity in the NaCl-NP treated mice, even at the highest concentration (2700ug/ml). The tumor prevention study showed that mice treated with NaCl-NPs had a significant 2.55 fold reduction in tumors that developed at 4 weeks compared to saline (22% vs 56% respectively, p &lt;0.05). This reduction was similar to that seen with intravesical gemcitabine, which is clinically, a standard of care intravesical chemotherapy. We also found an improvement in overall survival in the NaCl NP group with 70% of mice alive at 60 days compared to the other treatment groups (65% gemcitabine; 40% saline). Conclusions: Our findings suggest that NaCl-NPs could provide a safe and effective alternative therapy for preventing recurrence of NMIBC following transurethral resection of bladder tumors. This opens avenues for safer treatment protocols that can mitigate the side effects commonly seen in the management of early-stage bladder cancer.
Phase I safety and preliminary efficacy of PM1009, a bispecific antibody targeting TIGIT and PVRIG, in patients with advanced solid tumors.
Authors: Liqiong Xue, Lihua Wu, Wenbo Tang, Zhuoyi Wang, Junli Xue, Qun Li, Xiaoxiao Ge, Fengjuan Lin, Wei Zhao, Jiuli Zhou, Ye Guo
Journal: Journal of Clinical Oncology (2024)

e14695 Background: PM1009 is an anti-TIGIT x PVRIG bispecific antibody containing a fully human anti-TIGIT IgG1 fused with a fully human anti-PVRIG scFv at the C terminus. PM1009 can potently block the TIGIT/CD155/CD112 and PVRIG/CD112 signaling pathways, and supports the depletion of TIGIT-positive Treg cells in the tumor microenvironment through FcγR engagement. This leads to the enhancement of T cell and NK cell activity towards the killing of tumor cells. PM1009 showed robust in vitro and in vivo efficacy with good safety in preclinical studies. Methods: This is the first-in-human study of PM1009, which includes a dose escalation stage (accelerated titration &amp; 3+3 design) followed by dose expansion. In the dose escalation stage, PM1009 was administered as flat doses of 120, 300, 600 and 1200 mg for DLT evaluation after 3 weeks followed by administration Q2W. Primary endpoints were safety and tolerability, and the secondary endpoints were PK, ORR and DCR (per RECIST 1.1). Results: As of February 1, 2024, a total of 12 patients were enrolled for dose escalation and received at least one dose of PM1009, with 3 patients in each of the 120, 300, 600 and 1200 mg dose-levels. Median number of prior therapies was 5 lines (range 1- 9). No DLTs were observed up to 1200 mg. Any-grade TRAEs occurred in 11 patients (91.7%), and ≥ Grade 3 TRAEs occurred in 2 patients (16.7%). Any-Grade irAEs occurred in 7 patients (58.3%), and ≥ Grade 3 irAEs occurred in 1 patient (8.3%). Treatment interruption due to TRAE occurred in 2 patients (16.7%), with infusion related reaction (the main symptom was nausea, and the single infusion was eventually completed), and neutrophil count decrease respectively. Treatment discontinuation due to TRAE occurred in 2 patients (16.7%), with acute myocardial infarction, and neutrophil count decrease respectively. The most common TRAEs were ALP elevation (33.3%) and AST elevation (25.0%). 12 patients completed at least one tumor evaluation. The DCR per RECIST 1.1 by investigator was 33.3% (4/12; 95% CI: 9.92 - 65.11), best overall response was SD. Pharmacokinetics were dose-proportional with a terminal half-life of 5.2-7.4 days across the dose range of 120-1200 mg. Conclusions: PM1009 was well-tolerated up to 1200 mg with signs of anti-tumor activity. These findings support further clinical investigation of PM1009 especially for the combination with chemotherapy or PD-1/L1-based checkpoint inhibitors. Clinical trial information: NCT05607563 .
Envafolimab plus chemotherapy as neoadjuvant therapy for resectable esophageal squamous cell carcinoma (ESCC): A prospective, single-arm, phase II study.
Authors: Jinbo Zhao, Xiaolong Yan, Yuquan Bai, Hongtao Duan, Tao Jiang
Journal: Journal of Clinical Oncology (2024)

e14633 Background: Currently, chemotherapy plus PD-1 inhibitor immunotherapy has become a promising option in the neoadjuvant setting of resectable ESCC, nevertheless, the PD-ligand 1 (PD-L1) blockade-based combination has rarely been investigated to date. Envafolimab is the first and only globally approved subcutaneous (SC) PD-L1 inhibitor, which has shown satisfactory efficacy and safety profile in tumors. This Simon’s two-stage, phase II study explored the safety and feasibility of SC administration of envafolimab as an alternative to intravenous (IV) administration of PD-1/PD-L1 inhibitors in the neoadjuvant therapy of resectable ESCC. Here, we reported the results of the stage 1. Methods: In this Simon’s two-stage, phase II study, patients initially treated with locally advanced and resectable (stage II-IVA) ESCC were enrolled and received envafolimab (300mg, SC, day 1), albumin-bound paclitaxel (130mg/m 2 , IV, days 1 and 8), and carboplatin (AUC = 5, day 1) every 3 weeks for 3 cycles. The primary endpoints were safety and pathological complete response (pCR). A Simon’s two-stage design was utilized with following assumptions. Target accrual was 13 patients in the first stage (If 3 or more patients had pCR in stage 1, study could continue in stage 2), total 34 patients were enrolled in the stage 2. Secondary endpoints were major pathological response (MPR). Safety was assessed by adverse events (AEs) and postoperative complications. Results: Between October 2022 and April 2023, 13 (81.3%) of 16 enrolled patients completed neoadjuvant therapy and underwent surgery. All 13 (100%) surgical patients underwent successful R0 resection; of whom, 8 (61.5%) achieved pCR and 9 (69.2%) achieved MPR, respectively. Downstaging occurred in 10 (76.9%) of 13 patients. pCR and MPR were identified to be associated with tumor downstaging but not with PD-L1 expression. CPS levels in MPR and pCR group were significantly higher than that in Non- MPR and Non-pCR group. Grade 3-4 treatment-related AEs (TRAEs) and immune-related AEs (IrAEs) occurred in 12.5% and 37.5% of 16 patients, respectively. 10 (76.9%) of 13 patients reported postoperative complications. No treatment-related surgical delay or death occurred. Conclusions: Envafolimab plus chemotherapy as neoadjuvant therapy demonstrated promising antitumor activity for resectable ESCC with high rates of pCR, MPR and R0 resection, as well as acceptable tolerability. Based on the encouraging efficacy of our regimen in the first stage, we will continue the enrollment of patients in stage 2. Keywords: Esophageal squamous cell carcinoma; Envafolimab; Neoadjuvant therapy; Chemotherapy Clinical trial information: NCT05552651 .
Effect of IL-15 on anti-tumor immune response to radio-immunotherapy through systemic immune activation.
Authors: Peng Jin, Xue Meng
Journal: Journal of Clinical Oncology (2024)

e14641 Background: In this study, we propose to investigate the key role of IL-15 in radio-immunotherapy and its mechanism in regulating systemic immune activation by radio-immunotherapy. And further explore the potential of IL-15 combined with radio-immunotherapy. Methods: LLC5 and MC38 cells were used in this study. Mouse model and co-culture model were constructed to analyze the effect of IL-15 after radio-immunotherapy. Anti-IL-15 antibody was used to clarify the role of IL-15 on radio-immunotherapy. Flow cytometry and multiplex immunofluorescence were used to clarify IL-15Rα lever in macrophage after radio-immunotherapy. The effect of IL-15 in tumor and secondary lymphoid organ(SLO) was observed after macrophage removal. Macrophage IL-15 level were tested by ELISA. Tumor growth, TME, and memory effect after IL-15 combined with radio-immunotherapy were observed. In co-culture model, CD8+ T cell function were tested. Clearance macrophage of mice to determine the role of macrophage in combination therapy. After macrophages co-cultured with tumor cells, cytokine microarray was used to analyze the cytokine secretion of macrophages in combination treatment. Results: IL-15 secretion was significantly upregulated in TME after radio-immunotherapy. IL-15 and IL-15Rα were most enriched on macrophages and IL-15Rα was significantly increased after radio-immunotherapy. IL-15 inhibition significantly attenuated tumor killing and systemic immune activation and resulted in decreased IL-15Rα expression on macrophages. Removal of macrophages resulted in a significant reduction of IL-15 in tumor and spleen. Radio-immunotherapy in the co-culture model induced a significant increase of IL-15 secreted by macrophages.IL-15 combined with radio-immunotherapy can significantly controlled tumor growth, stimulated systemic immune activation, and CD8+ T cells and memory T cells were significantly increased in the circulation of long-term survival mice. In co-culture experiments, combination treatment stimulated proliferation and secretion of IFN-γ+CD8+ T cells. And it stimulated macrophages secrete more chemokines, especially CCL5, recruit more CD8+ T cells aggregate around macrophages. Macrophage clearance and co-culture experiments confirm that the synergistic effect of this combination therapy is mainly dependent on macrophages. Conclusions: IL-15 plays a critical role in systemic immune activation induced by radio-immunotherapy. Macrophages are the main cellular site of IL-15 effect in the microenvironment of tumor and SLO after radio-immunotherapy. IL-15 combined with radio-immunotherapy had a synergistic antitumor effect, and this combination treatment induced a further enhancement of memory T-cell-mediated systemic immune activation. Macrophage-secreted chemokines such as CCL5 played an important role in the antitumor effect of this combination therapy strategy.
Hyaluronic acid hydrogel to modulate tumor cell clustering and programmed death ligand 1 signaling in cancer stem cells.
Authors: Kaustuv Basu, Luc Mongeau
Journal: Journal of Clinical Oncology (2024)

e14584 Background: The root of malignancy lies in the extracellular matrix (ECM) surrounding the stromal cells. Thus, current therapeutic targets manipulate abnormal tumor microenvironments (TME), which nourish cancer stem cells (CSC) and induce tumor cell clustering (TCC). Notably, despite the first line of clinical therapy with surgery and chemotherapy, uncontrolled self-renewal of CSCs, conversion of non-CSCs to CSCs, and TCC trigger cancer recurrence. The transmembrane glycoprotein CD44 is thought to be a potential master regulator in cancer recurrence as it interacts with hyaluronic acid (HA) in TME, expresses aberrantly on CSCs, induces TCC by homophilic interactions like Plakoglobin despite less understanding on their crosstalk, and promotes expression of pro-tumorigenic factor programmed death ligand 1 (PD-L1). Notably, CD44 is expressed in multiple isoforms, and splice isoform switching of CD44 dictates the properties of CSC, which still needs to be clarified. Hence, we aimed to characterize CSCs based on CD44 isoform expression, investigate the crosstalk between CD44 and Plakoglobin, and then design a novel injectable HA hydrogel that can disguise TME and suppress PD-L1 to combat cancer recurrence. Methods: To characterize CSCs, we prepared different scaffolds of HA of varied molecular weights and other ECM proteins, cultured cancer cells (MDA-MB-231, HeLa), and determined the expression of CD44 isoforms. We sorted CD44+/CD24- expressing CSC by flow cytometry. We implemented immunoprecipitation to detect the interaction between CD44 and Plakoglobin. We created a novel HA hydrogel composed of low and very high molecular weight HA, thiolated gelatin, and other components crosslinked with PEGDA. Using a torsional rheometer, we measured matrix stiffness. We assessed the cell proliferation efficiency of CSC by a colony-forming assay. Results: The study disclosed that CD44 isoforms expressed differently based on ECM properties. Matrix stiffness dictated CD44 isoform expression. We observed that CD44 interacted with Plakoglobin. CD44 ablation upregulated Plakoglobin significantly. Tumor suppressor p53 played a significant role in CD44-Plakoglobin crosstalk. We observed that the injectable hydrogel modulated CD44-Plakoglobin signaling and inhibited TCC, likely promoting anoikis. The hydrogel affected CD44 splicing and modified the activity of the CD44 intracellular domain, which interacts with PD-L1 and thus suppressed PD-L1 expression significantly in CSC. Conclusions: Currently, antibodies targeting PD-1/PD-L1 signaling have been clinically approved for various cancers. However, this regimen of treatment is expensive. We report a novel injectable hydrogel that can disguise TME, modulate CSCs and PD-L1, and may advance an alternative cost-effective avenue for cancer immunotherapy.
Long-term pooled safety analysis of tislelizumab as monotherapy or in combination with chemotherapy in patients with advanced cancers.
Authors: Caicun Zhou, Tim Meyer, Rose Huang, Yuan Yuan, Patrick Schnell, John Wu, Alysha Kadva, Jola Mehmeti, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2024)

e14617 Background: The PD-1 inhibitor tislelizumab (TIS) has demonstrated efficacy and tolerability in patients (pts) with advanced cancers. To evaluate long-term safety of TIS as monotherapy (mono) or in combination (combo) with chemotherapy in pts with advanced gastrointestinal (GI) and lung cancers, data were pooled from 8 pivotal phase III studies conducted between 2017 and 2023. Methods: 2636 adult pts with GI (n=1415) or lung (n=1221) cancers and an ECOG PS of 0-1, who received ≥1 dose of study drug, were included. Endpoints included immune-mediated adverse events (imAEs) by tumor type, treatment (Tx) duration, and race. Early and delayed imAEs, defined as occurring within 1 year (yr) and &gt;1 yr after starting TIS, respectively, were also evaluated. Results: Median (range) Tx duration in the GI and lung cancer studies was 4.9 (0.1-50.4) and 6.2 (0.2-44.9) months, respectively, with 20.9% and 29.6% of pts, respectively, having ≥1 yr exposure. Most pts were Asian (GI mono: 76.4%; GI combo: 74.9%; lung mono: 79.2%; lung combo: 100%). ImAEs occurred in 32.5% of pts in the GI mono and combo studies (Table); most were low grade, with grade ≥3 imAEs reported in 6.2% (mono) and 8.2% (combo) of pts. Incidence of imAEs in the mono and combo lung studies, respectively, was 34.3% and 43.7% (grade ≥3: 6.4% and 9.6%). ImAE incidence was comparable between Asian and White race subgroups, respectively, in the GI mono (33.6% vs 29.5%), GI combo (34.9% vs 23.9%), and lung mono (35.5% vs 32.3%) studies. Most imAEs occurred within 1 yr of starting TIS in the GI (mono: 32.0%; combo: 32.4%) and lung (mono: 34.1%; combo: 42.2%) studies. Delayed imAEs occurred less often than early imAEs; of pts still on Tx or in study follow-up 1 yr after initial Tx, 54/757 (7.1%) in GI studies and 86/804 (10.7%) in lung studies experienced a delayed imAE. Frequently reported imAEs were consistent, regardless of time of onset (early vs delayed). Conclusions: This long-term, retrospective, pooled analysis supports TIS as a tolerable Tx for pts with advanced GI and lung cancers. Delayed imAEs were relatively infrequent and were consistent with the established safety profile of TIS. Clinical trial information: NCT03412773 ; NCT03430843 ; NCT03358875 ; NCT03663205 ; NCT03777657 ; NCT03783442 ; NCT03594747 ; NCT04005716 . [Table: see text]