tbuckley/cabot-search huggingface dataset:
Combination treatment effect of an immunotherapeutic agent with microtubule inhibitors.
Authors: Benjamin Thor Perrin Hee, Edgar K. Kazarian, Jacob A. Karp, Ernest Hamel, Charitha Madiraju
Journal: Journal of Clinical Oncology (2024)

e14619 Background: The microtubule (MT) is a polymer formed by self-assembly of αβ-tubulin heterodimers. MT inhibitors either stabilize or destabilize microtubule assembly and halt cell proliferation during the mitotic phase of the cell cycle. However, due to non-specificity, high resistance, and adverse reactions observed with MT-targeting drugs, various approaches to novel combination chemotherapies are being used in the clinic. The specific goal of this study is to investigate the ability of an immunotherapeutic agent to alter the activity of MT-targeting chemotherapeutics when used in a combination treatment approach. Methods: The combination treatment effect of the immunotherapeutic agent with microtubule inhibitors was investigated using two methods: 1) Tubulin polymerization studies using purified tubulin and microtubule inhibitors, paclitaxel (a microtubule stabilizing agent) and dolastatin 10 (a microtubule destabilizing agent), studied alone or in combination with the immunotherapeutic agent. (2) Co-culture system expressing the stably expressing Nuclear Factor of Activated T cells (NFAT)- Renilla luciferase (NFAT- Rluc) reporter gene to study anti-tumor immune response of MT inhibitors alone or in combination with the immunotherapeutic agent. Results: Spectrophotometric-based tubulin polymerization studies demonstrated that the immunotherapeutic agent (0.01 - 0.1 mg/mL) altered tubulin polymerization when studied in combination with either paclitaxel (10 µM) or dolastatin 10 (0.5 mM). Luminescence-based reporter gene expression studies in a co-culture system, consisting of CD3− antigen presenting Chinese hamster ovary and CD3+ effector Jurkat T cells, demonstrated the combination treatment effectively induced NFAT- Rluc activity when compared to the controls, the immunotherapeutic agent alone or to the MT-inhibitor alone. Statistical analysis was done using one-way analysis of variance (ANOVA). A significant difference ( p &lt; 0.05) in mean IC 50 values (expressed as ng/mL ± SEM, N=4) was observed between the immunotherapeutic plus dolastatin 10 versus the immunotherapeutic agent alone, and a 6.5-fold decrease (85% reduction) in the IC 50 value was observed for induction of NFAT- Rluc activity in the presence of immunotherapeutic plus dolastatin 10 versus the immunotherapeutic alone. There was a notable decrease (1.9-fold or 46% reduction) in the IC 50 value observed for induction of NFAT- Rluc activity in the presence of the immunotherapeutic plus paclitaxel versus the immunotherapeutic alone. Conclusions: These results suggest a boost in T-cell stimulation by the immunotherapeutic agent in the presence of MT inhibitors. The implications of enhanced T-cell activation on antitumor immunity and modulation of tubulin polymerization by a combination treatment of the immunotherapeutic agent and microtubule inhibitors are currently under investigation.
The promising feeder-free allogenic NK cell therapy: Clinical outcomes of GIC-102 monotherapy (GIC-102101) and synergistic potential with GI-101 (CD80-IgG4 Fc-IL2v) in advanced solid tumors and hematologic malignancies.
Authors: Soohyeon Lee, Junshik Hong, Hyungwoo Cho, Woo Yul Lee, Do Soo Jang, YooJoon Lee, Myoung Ho Jang, Dok Hyun Yoon
Journal: Journal of Clinical Oncology (2024)

e14526 Background: The allogeneic Natural Killer (NK) cell therapy derived from healthy donors may overcome the short lifespan and dysfunctional anti-tumor activity of current autologous approach. This limitation often restricts treatment efficacy and necessitating high dosages and frequent infusions. GIC-102, non-engineered / feeder-free, highly potent allogeneic NK cell derived from healthy donors, is a promising alternative. Here, we present the clinical outcomes from the Phase 1 study of GIC-102, along with nonclinical evidence demonstrating outstanding pharmacokinetics (PK) and pharmacodynamics (PD) when used in combination with a novel bi-specific Fc fusion protein, GI-101 (CD80-IgG4 Fc-IL2v/NCT04977453/KEYNOTE-B59). Methods: GIC-102101, a first-in-human study, evaluated GIC-102 monotherapy at doses of 1x10 9 QW and 3x10 9 QW in patients with advanced solid tumors or hematologic malignancies. A lympho-conditioning strategy using cyclophosphamide (300 mg/m 2 ) and fludarabine (30 mg/m 2 ) was implemented every two cycles before GIC-102 treatment. The study employed a conventional 3+3 dose escalation scheme. The primary endpoint was to determine the safety and tolerability of GIC-102, with tumor response assessed as secondary endpoints. Additionally, the PK/PD profile of GIC-102 in combination with GI-101 was evaluated in a mouse model. Results: As of December 31, 2023, six patients have been treated with GIC-102 monotherapy including two patients with Non-Hodgkin lymphoma (NHL), and four patients with metastatic colorectal cancer (CRC). The median number of prior treatments for patients with CRC and NHL was 4 and 6, respectively. No dose limiting toxicities (DLTs) were observed and maximum tolerated dose was not reached. Treatment-related adverse events (TRAEs) occurred in 5 patients (83%), with the majority being associated with the lympho-conditioning procedure; hyponatremia, neutropenia, lymphopenia and anemia. The best overall response was complete response (CR) in 1/6 patient (NHL) and stable disease (SD) in 4/6 patients (3 CRC, 1 NHL). Treatment for 1 CR (NHL) and 2 SD (CRC) is ongoing (for NHL, 215+ days/for CRC, 160+ days and 153+ days). The in-vivo study of GIC-102 in combination with GI-101 showed significantly enhanced anti-tumor activity and in-vivo NK cell proliferation lasting up to 4 weeks. Conclusions: The GIC-102, feeder-free allogeneic NK cell, was well tolerated without DLTs and demonstrated early promise in efficacy in patients for advanced solid tumors and hematologic malignancy. Further clinical investigation of GIC-102 in combination with GI-101, bi-specific Fc fusion protein, is currently ongoing. Clinical trial information: NCT05880043 .
Genomic biomarkers of CNS-specific outcomes in patients with breast cancer brain metastases.
Authors: Ishaani S. Khatri, Jordan Eichholz, Lillian A Boe, Anton Safonov, Deborah Ruth Smith, Emanuela Ferraro, Junchao Shen, Brandon S. Imber, Yao Yu, Yoshiya Yamada, Emily Miao, Nelson S. Moss, Jessica Wilcox, Henry S. Walch, Walid Khaled Chatila, Nikolaus Schultz, Pedram Razavi, Luke R. G. Pike
Journal: Journal of Clinical Oncology (2024)

2028 Background: The diagnosis of brain metastasis (BM) is a life- and prognosis-altering event for patients with breast cancer (BC). The standard of care for the management of limited BM remains ablation with stereotactic radiosurgery (SRS). There are no established genomic biomarkers to guide CNS-directed treatment among patients with breast cancer brain metastases (BCBM). Methods: We retrospectively reviewed clinical and genomic features of a cohort of patients who received SRS for newly diagnosed BCBM between 2010 and 2021 at Memorial Sloan Kettering Cancer Center (MSK). Next-generation genomic sequencing (NGS) was performed using the MSK-IMPACT assay, covering all exonic and selected intronic regions for up to 505 genes. Time-to-CNS progression (TTCP) and overall survival (OS) were analyzed using multivariable Fine-Gray and Cox proportional hazards models, respectively, adjusted for clinically relevant factors. Relevant clinical factors and genomic alterations present at an instance at 5% or greater were included in the univariate and multivariate analyses, completed for the overall cohort and BC receptor subtypes. Results: From 2010-2021, 260 patients were identified; 123 (47%), 74 (28%), and 63 (24%) patients had hormone receptor-positive (HR+), HER2+, and triple-negative (TN) disease, respectively. 116 (45%) patients had 1 BM and 184 (71%) patients had at least 1 BM greater than 1 cm in axial diameter. Median follow up for the overall cohort was 18 months (Interquartile range (IQR) 9, 36). Among patients who progressed, median TTCP was 6 (IQR 4, 13) and 6 (4, 13), 11 (5, 18), and 4(3, 8) months for the overall cohort, and HR+, HER2+, and TN subgroups, respectively. Median OS was 19 (95% CI 16, 23) and 15 (13, 21), 58 (39, --), and 13 (11, 20), for the overall cohort, and HR+, HER2+, and TN subgroups, respectively. In the overall cohort, shorter TTCP was associated with TN subtype, &gt;5 BMs, and pathogenic alterations in MYC, AGO2, PTEN, AURKA, and NF1 (p &lt; 0.05); decreased OS was associated with non-HER2+ subtype, presence of extracranial metastatic disease, and oncogenic alterations in TP53, CDH1 and NF1 (p &lt; 0.05). In stratified analyses by receptor subtype, shorter TTCP was associated with oncogenic alterations in GAB2 and PTEN in the HR+ subgroup, AURKA, DDR2, and NF1 in the HER2+ subgroup, and with MYC and RB1 in the TN subgroup (p &lt; 0.05). Conclusions: In this large clinico-genomic analysis of CNS-specific outcomes in BC, we identified clinical and putative genomic biomarkers associated with BCBM receiving SRS that could be used to risk stratify patients and optimize treatment strategies.
<i>Fusobacterium nucleatum</i> to promote esophageal squamous cell carcinoma progression via CCL20/CCR6-mediated migration of macrophages to the tumour micro environment.
Authors: Yu Su, Jin Yang, xue Cong Zhu, Jing Zuo
Journal: Journal of Clinical Oncology (2024)

e14668 Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common digestive malignant tumor in China. Recent studies have shown that Fusobacterium nucleatum ( F. nucleatum) promotes ESCC progression through various mechanisms. One of them is about changing the tumor micro- environment through cytokine–cytokine receptor interaction. Methods: From January 2022 to June 2023, a total of 34 patients with ESCC from 4th Hospital of Hebei Medical University thoracic surgery were enrolled. All of the patients did not apply any neoadjuvant therapy before and received radical resection. Real-time reverse transcriptase - PCR (RT-PCR) were performed to examine the expressions of F. nucleatum in tumor tissues and para-tumor tissue. According to the CT values of the RT-PCR results, the level of the F. nucleatum infection could be separated in two groups - positive group and negative group. Immunohistochemistry (IHC) staining were used to examine the expressions of chemokine CCL20 in both groups. Immunofluorescence (IF) was characterised homing receptors CCR6 on CD206 + macrophages. In addition, transwell assay was carried on to quantify macrophages migration ability towards chemokines CCL20 in vitro. Results: F. nucleatum DNA positivity was significantly associated with higher expression of chemokine CCL20 and accumulation of CD68 + CD206 + macrophages. F. nucleatum DNA positivity was also significantly correlated with worse histopathological grading. Otherwise, there were no significant correlation between F. nucleatum infection and gender, age, tobacco or alcohol use, T or N grade, TNM stage, tumor locations, blood vessel or nerve invasion and tumor size. IHC showed that the expression of CCL20 were higher in F. nucleatum DNA positive tumor tissue. After coculture with F. nucleatum and KYSE30 cell lines in vitro, the CCL20 production by KYSE30 cells were accelerated. In addition, immunofluorescence showed that CCL20 could recruit M2-like macrophages into the tumor environment by bonding CCR6 existed on the cell surface. Furthermore, the migration ability of macrophages was distinctly elevated by CCL20 result from F. nucleatum infection. Conclusions: F. nucleatum promotes esophageal squamous cell carcinoma progression via CCL20/CCR6-mediated migration of M2-like macrophages to the tumor micro- environment and deteriorates the suppression of the local immune micro- environment within the tumor. Such bacteria may be a biomarker to predict the efficacy of immunotherapy in ESCC. [Table: see text]
Immune checkpoint inhibitor-related reproductive adverse effects: A pharmacovigilance analysis based on the FAERS database.
Authors: Bahadır Köylü, Ozgur Oktem, Bugra Han Esen, Sevval Nur Bektas, Lasin Ozbek, Fatih Selcukbiricik
Journal: Journal of Clinical Oncology (2024)

e14707 Background: There exists a critical need to systematically understand the extent and magnitude of immune checkpoint inhibitor (ICI)-related reproductive adverse effects, which may not only pose long-term implications for patients who may desire future fertility, but also impact the quality of life. We aim to better understand this underexplored area. Methods: Our focus was on ICIs approved by the FDA as of June 31, 2023, including anti-PD-1 agents (nivolumab, pembrolizumab, cemiplimab, dostarlimab, retifanlimab), anti-PD-L1 agents (atezolizumab, avelumab, durvalumab), anti-CTLA-4 agents (ipilimumab, tremelimumab), and an anti-LAG-3 agent (relatlimab). We analyzed 13,702,373 cases from January 1, 2015, to June 30, 2023. We included adverse reactions under the 'Reproductive system and breast disorders' category in the SOC (System Organ Classes). For signal detection, we used the reporting odds ratio (ROR) method. Results: We identified 133,512 patients administered with ICIs, among whom 568 reported irRAEs. Abnormal spermatogenesis (ROR025: 7.91), scrotal irritation (ROR025: 3.83), scrotal oedema (ROR025: 1.90), perineal rash (ROR025: 1.38), prostatitis (ROR025: 1.25), acquired phimosis (ROR025: 1.20), and scrotal erythema (ROR025: 1.08) in males and genital tract fistula in females (ROR025: 2.72) were detected as significant irRAEs. Among them, the most commonly reported irRAEs were prostatitis (n=29), scrotal oedema (n=12), and abnormal spermatogenesis (n=6) in males and genital tract fistula (n=34) in females. Male patients had a lower risk compared to females (OR=0.68 [0.57-0.81], p&lt;0.0001). There was no marked difference between the patients on polytherapy vs. monotherapy (OR=0.90 [0.71-1.13], p=0.36). PD-1 inhibitors pose the greatest risk when compared with CTLA-4 inhibitors (OR=1.65 [1.05-2.79], p=0.045). Gynecologic cancers in females (OR=3.77 [2.82-4.99], p&lt;0.0001) and urogenital cancers in males (OR=1.56 [1.17-2.06], p=0.0018) were strong risk factors. Additional targeted therapy, particularly lenvatinib (OR=3.79 [2.71-5.15], p&lt;0.0001) and cabozantinib (OR=2.69 [1.66-4.09], p&lt;0.0001) significantly increased the risk (OR=1.87 [1.52-2.29], p&lt;0.0001) and this risk appeared to be more pronounced in females (OR=2.32 [1.76-3.02], p&lt;0.0001). Additional chemotherapy was associated with a significantly reduced risk in males (OR=0.65 [0.42-0.96], p=0.042). However, doxorubicin (OR=2.58 [1.10-5.05], p=0.013) and cyclophosphamide (OR=2.36 [0.93-4.83], p=0.038) were linked to an elevated risk. Conclusions: Our findings demonstrated that ICIs could lead to a wide range of irRAEs in both males and females. Additional therapies could change the risk of irRAEs. Despite the current lack of high-quality clinical data on this topic, it is reasonable to inform patients about the plausible risk of irRAEs.
Anti-TNFR2 monoclonal antibody LBL-019 in patients with advanced malignant tumors: A phase I, first-in-human, open-label, multicenter, dose escalation Study.
Authors: Fei Zhou, Wei Li, Yu Chen, Jing Lin, Ling Chen, Huishan Zhang, Xiaorong Dong, Fan Tong, Ruiguang Zhang, Yongmei Yin, Yan Liang, Nong Yang, Sheng Hu, Wei Zhuang, Tao Li, Shengli Cai, Caicun Zhou
Journal: Journal of Clinical Oncology (2024)

e14580 Background: LBL-019 is a humanized monoclonal IgG1 antibody against TNF receptor 2 (TNFR2). It specifically binds to TNFR2 with high affinity, co-stimulates TNFR2 in Fc crosslinking-dependent manner, results in activation of NF-κB signaling and T cell activation and expansion, promoting antitumor immunity. Here we report the preliminary safety and efficacy of LBL-019 in patients with advanced malignant tumors. Methods: This is a phase Ⅰ, open-label, multicenter, dose-escalation study to evaluate the safety, tolerability, and PK of LBL-019 in patients with advanced solid tumors that progressed after standard systemic therapy. The dose escalation phase consists of 7 dose cohorts of LBL-019 at 0.2, 0.8, 3, 10, 15, 20, and 30 mg/kg (iv Q2W), using accelerated titration design (first dose) followed by 3+3 design. The primary endpoints were tolerability and safety. The second objectives were pharmacokinetics, pharmacodynamics, and preliminary efficacy (per RECIST 1.1). Results: As of January 02, 2024, 26 patients [17 (65.4%) male, median age 57 years (range:27, 72), 22 (84.6%) ECOG score of 1] were treated in phase Ⅰ. Tumor types include 7 (26.9%) hepatocellular carcinoma (HCC), 4 (15.4%) melanoma, and 15 (57.7%) other tumors. 19 (73%) previously received anti-PD(L)-1 treatment. During the study, no DLT was observed, and the MTD was not reached. The median follow-up was 12.2 months (95%CI: 7.5, 15.9). 19 patients (73.1%) experienced TRAEs of all grades, with 2 (7.7%) having grade ≥3 TRAEs. The most common TRAEs (≥10%) included lipase increased (19.2%), anaemia (19.2%), aspartate aminotransferase increased (15.4%), pruritus (11.5%), rash (11.5%). Treatment interruption and permanent discontinuation due to TEAEs occurred in 12 (46.2%) and 1 (3.8%) patient, respectively. Thirteen patients (50.0%) experienced SAEs, and one of SAE was related to treatment. Out of 23 who underwent efficacy evaluation, 1 patient with HCC achieved PR, and 7 patients achieved SD. The patient with PR and 6 patients with SD received prior immunotherapy, the ORR and DCR were 4.3% and 34.8%, respectively. The DoR in the patient with PR has exceeded 10 months. Conclusions: LBL-019 is well tolerable and has demonstrated preliminary efficacy in patients with advanced malignant tumors. Clinical trial information: NCT05223231 .
Platelet-mediated circulating tumor cell evasion from natural killer cell killing via immune checkpoint CD155-TIGIT.
Authors: Yun-Fan Sun, Tong Li, Lin Ding, Jiyan Wang, Chen Chen, Te Liu, Yu Liu, Qian Li, Chuyu Wang, Ran Huo, Hao Wang, Tongtong Tian, Chunyan Zhang, Baishen Pan, Jian Zhou, Jia Fan, Xin-Rong Yang, Wenjing Yang, Beili Wang, Wei Guo
Journal: Journal of Clinical Oncology (2024)

e14552 Background: Circulating tumor cells (CTCs) are precursors of cancer metastasis. However, how CTCs evade immunosurveillance during hematogenous dissemination remains unclear. The interaction between platelets and CTCs is the most extensively studied of all blood cells, and it is well known that CTCs are surrounded by platelets, which form microplots on their surface and play a crucial role in cancer metastasis. The precise mechanisms platelets employ to contribute to CTC immune evasion have not been fully elucidated. Our previous single-cell RNA sequencing data indicated high expression of platelet-related genes in CTCs. Here, our study demonstrated that platelet adhesion to CTCs is prevalent in multiple cancers and is indispensable for CTCs metastasis. Methods: CTC isolation was performed by our self-established ChimeraX-i120 platform. CTC-platelet adhesions were identified by single-cell RNA sequencing and multiplex immunofluorescence of blood samples from multiple cancer types. The cytotoxicity of natural killer (NK) cells was assessed by the reduction in tumor cell numbers measured using the xCELLigence system. In vitro and ex vivo co-culture systems were established by using platelets and NK cells isolated from the peripheral blood of patients for direct or indirect co-culturing with cell lines and patient-derived organoids (PDOs). The effects of platelets and NK cells on metastasis and immune responses were investigated in vivo by utilizing mouse models. Results: Clinically, CTC-platelet aggregates were associated with significantly shorter progression-free survival and overall survival in hepatocellular carcinoma patients. In vitro, ex vivo, and in vivo assays demonstrated direct platelet adhesions gifted cancer cells with an evasive ability from NK cell killing by upregulating inhibitory checkpoint CD155, therefore facilitating distant metastasis. Mechanistically, CD155 was transcriptionally regulated by the FAK/JNK/c-Jun cascade in a platelet contact-dependent manner. Further competition assays and cytotoxicity experiments revealed that CD155 on CTCs inhibited NK cell cytotoxicity only by engaging with immune receptor TIGIT, but not CD96 and DNAM1, another two receptors for CD155. Interrupting the CD155-TIGIT interactions with a TIGIT antibody restored NK cell immunosurveillance on CTCs and markedly attenuated tumor metastasis. Conclusions: Our results demonstrated CTC evasion from NK cell-mediated innate immunosurveillance mainly via immune checkpoint CD155-TIGIT, potentially offering an immunotherapeutic strategy for eradicating CTCs.
Strong single-agent and PD-1/PD-L1 combination antitumor activity of antisense oligonucleotides suppressing Neuropilin 1 expression.
Authors: Konstantin Petropoulos, André Maaske, Nicole Kirchhammer, Julia Festag, Mélanie Buchi, Sven Michel, Alfred Zippelius, Richard Klar, Frank Jaschinski
Journal: Journal of Clinical Oncology (2024)

e14592 Background: While the introduction of immune checkpoint inhibitors (ICIs) is considered as a breakthrough in cancer therapy, large proportions of patients still do not respond or develop resistance, indicating a need for new targets and therapies to provide long-term therapeutic benefits. Neuropilin-1 (NRP1) is a membrane-bound multi domain protein expressed by different cell types in the tumor microenvironment. NRP1 promotes cell migration, survival, and angiogenesis via distinct domains. Moreover, it mediates immunosuppression by stabilization of regulatory T cells, attraction of immunosuppressive myeloid cells into the tumor microenvironment, and exhaustion of effector T cells. Therapeutic benefit is expected to be superior by simultaneous suppression of all functions and consequently all domains, which can be optimally achieved by suppression of its expression, for example mediated by antisense oligonucleotides (ASOs), instead of e.g. domain specific antibodies. Methods: Using our in-house bioinformatics and screening systems, we have identified potent and specific locked nucleic acid (LNA) modified ASOs specifically targeting NRP1. Mice bearing established syngeneic MC38 or EMT6 tumors were treated by intraperitoneal injection of unformulated ASO either as monotherapy or in combination with ICIs. Tumor growth and survival were determined as well as target engagement. Results: After systemic administration of different NRP1-specific ASOs we observed a potent downregulation of NRP1 expression in different cell types in tumors, including myeloid cells, T cells and non-immune cells as well as a strong reduction of soluble NRP1 plasma levels. Suppression of NRP1 correlated with both a delayed tumor growth or even complete tumor regression and prolonged survival as a monotherapy which was further improved in combination with ICIs. Particularly in an EMT6 breast cancer model, combination of NRP1 ASOs with PD-1 antibody resulted in tumor rejection and long-term survival in most animals. Rechallenge of long-term surviving mice with EMT6 tumor cells did not result in tumor growth. Conclusions: We could show that ASO-mediated suppression of NRP1 expression has strong potential as a novel therapeutic strategy, especially in combination with ICIs. Additional studies to further elucidate the mechanisms underlying the observed anti-tumor efficacy as well as IND-enabling activities are underway to progress the program towards clinical testing.