tbuckley/cabot-search huggingface dataset:
CD4 effector T cell expansion to identify objective responses to the CD40 agonist mitazalimab in combination with modified FOLFIRINOX (mFFX) as first-line therapy for metastatic pancreatic ductal adenocarcinoma (mPDAC) in the OPTIMIZE-1 study.
Authors: Max Miller Wattenberg, Karin Enell Smith, Yago Pico de Coaña, David Gomez Jimenez, Sumeet Vijay Ambarkhane, Peter Ellmark, Gregory Lawrence Beatty
Journal: Journal of Clinical Oncology (2024)

2569 Background: CD40 agonists have the potential to enhance the efficacy of standard of care chemotherapy and to trigger antitumor immunity. Preclinical models indicate that the success of this approach depends on appropriate sequencing of chemotherapy with a CD40 agonist. Preliminary efficacy results from the OPTIMIZE-1 Phase II study (NCT04888312) combining mitazalimab (anti-CD40) with mFFX chemotherapy in patients with mPDAC have been previously reported. Here, we investigated immunological determinants associated with favorable outcomes with this combination therapy. Methods: Newly diagnosed, chemotherapy-naive patients with mPDAC received mitazalimab (900 µg/kg) on day 1 prior to beginning an every 2-week mFFX regimen on day 8, followed by mitazalimab 48 hours later. Tumor response was determined using RECIST v1.1 criteria. Peripheral blood was analyzed for selected cytokines and chemokines and by flow cytometry to assess changes in leukocyte subsets including B cells, monocytes, T cells, and NK cells. Flow cytometric data from evaluable patients were subjected to unsupervised hierarchical clustering to identify immune subsets. A classifier was generated from an interim dataset (n=21) using a random forest model to predict cell populations and their association with tumor response, which were then applied to the full dataset (n=47). Results: Mitazalimab triggered an expected immune response characterized by transient cytokine (IFNg and MCP-1) release and B cell depletion. Chemotherapy caused a reduction in classical monocytes and proliferating CD4 + T cells. Both mitazalimab and chemotherapy caused a transient reduction in circulating dendritic cells and NK cells. Tumor response was associated with an expansion in the frequency of effector CD4 T cells (p &lt; 0.0001) at day 8 after receiving mitazalimab. In a blinded analysis based on the classifier, CD4 T cell expansion was linked to an early tumor response to treatment (accuracy 70%, sensitivity 68%, specificity 72%). Conclusions: Mitazalimab and mFFX differentially modulate immune responses in patients with mPDAC. Pharmacological analyses identify mitazalimab-induced expansion of CD4 effector T cells one week after first administration as a correlate of treatment outcomes. These data suggest the contribution of mitazalimab to tumor responses, and further substantiate a priming dose of mitazalimab, prior to administering chemotherapy.
Preliminary safety, antitumor activity, and pharmacodynamics of intratumoral ABO2011 (IL-12 mRNA) in patients with advanced solid tumors.
Authors: Ning Li, Ning Li, Yong Wang, Ningyi Cui, Xin Wang, Yu Tang, Yuting Chu, Qingwei Meng, Rui Lin, Yan Wu, Bo Ying
Journal: Journal of Clinical Oncology (2024)

e14583 Background: Interleukin (IL)-12 is a potent immunomodulatory cytokine demonstrating robust antitumor activity in multiple preclinical studies and potent immune-stimulating potential in humans. However, systemic delivery of IL-12 can result in life-threatening toxicity and therefore has shown limited efficacy at doses that can be safely administered. ABO2011 is a human IL-12 mRNA encapsulated in lipid nanoparticle and has been developed to be more effective and less toxic through the use of novel delivery technology and intratumoral injection. Methods: This phase I trial enrolled adults with advanced solid tumors who failed available standard treatments (NCT05392699). The trial was designed to primarily evaluate the safety of ABO2011 in single-dose cohorts and multiple-dose cohorts using “3+3” dose escalation approach. Patients (pts) would receive intratumoral ABO2011 at either a single dose, QW with 3 doses overall, every 3 weeks (Q3W) or QW followed by Q3W. Results: As of 09 December 2023, a total of 20 pts were enrolled and received at least one dose of ABO2011 at 4 μg single dose, 4 μg QW for 3 times, 12 μg single dose, 12 μg QW for 3 times followed by Q3W, 24 μg Q3W and 48 μg Q3W. Seventeen (85%) pts experienced treatment-related adverse events (TRAEs), and all were grade 1 or 2, including pyrexia (35%), pain (25%), and gamma-glutamyl transferase increased (25%). There were no dose-limiting toxicities or treatment-related SAEs reported and no TRAEs leading to treatment discontinuation. Of the 17 evaluable pts per RECISIT v1.1, 5 maintained stable disease, and the progression free survivals achieved 6.0 months, 5.6 months and 4.1 months for pts with colorectal cancer (6 th line), non-small cell lung cancer (5 th line) and pancreatic cancer (4 th line), respectively. Peripheral blood IL-12 and IFN-γ levels increased and peaked at 24 hours and 48 hours after dosing, respectively, indicating expression of IL-12 and subsequent induction of IFN-γ after ABO2011 administration. Dose-dependent elevation of CXCL9, CXCL10, CXCL11 in peripheral blood was observed, consistent with the activation of downstream pathway of IFN-γ. CD8 T cells infiltration and PD-L1 expression were increased in tumor microenvironment (TME) at day 7, and further RNA sequencing analysis revealed increase of activated CD8 T cell and antigen processing and presentation after study treatment, suggesting the regulation of TME by ABO2011 and supporting the combination with PD-1(L1) inhibitor. Conclusions: Intratumoral ABO2011 was safe and well-tolerated in pts with advanced solid tumors. The pharmacodynamic changes were as expected. Promising preliminary antitumor activities of the single agent and the pharmacodynamic profiles support further investigation of ABO2011 in combination with immune checkpoint inhibitor. Clinical trial information: NCT05392699 .
Prediction accuracy of biomarkers for response to immune checkpoint inhibitors in advanced non-small cell lung cancer: A systematic review and meta-analysis.
Authors: Wei Zhuang, Jie Zhao, Boyang Sun, Hua Bai, Zhijie Wang, Jia Zhong, Rui Wan, Lihui Liu, Jianchun Duan, Jie Wang
Journal: Journal of Clinical Oncology (2024)

e14652 Background: To compare the predictive accuracy of PD-L1 IHC, tissue or blood tumor mutation burden (tTMB, bTMB), gene expression profiling (GEP), driver gene mutation, and combined marker for immunotherapy response of advanced non-small cell lung cancer (NSCLC). Methods: Systematic searches of PubMed, Cochrane CENTRAL, and Embase were conducted from inception to July 6, 2023. Clinical trials involved with predictive biomarkers exploration for immune checkpoint inhibitors (ICIs) in advanced NSCLC were eligible. The response according to the biomarkers were extracted. The primary outcome was the area under the curve (AUC) of the summary receiver operating characteristic (SROC). Sensitivity, specificity, likelihood ratios and predictive values were evaluated. The subgroup analysis of different PD-L1 cut-off, TMB test and driver gene mutation were performed. Results: 36 articles of 59 biomarker tests were included. The AUC of combined marker (0.75; 95%CI, 0.71-0.78) was higher than PD-L1 (0.64; 95%CI, 0.60-0.68), tTMB (0.64; 95%CI, 0.60-0.68), bTMB (0.68; 95%CI, 0.64-0.72), GEP (0.67; 95%CI, 0.63-0.71), and driver gene mutation (0.51; 95%CI, 0.47-0.55). Combined marker also had higher specificity, positive likelihood ratio and positive predictive value than single biomarkers (Table). In subgroup analysis, PD-L1 with cut-off 50% had higher AUC (0.67; 95%CI, 0.63-0.71) than cut-off 1% (0.62; 95%CI, 0.58-0.66); EGFR mutation had higher AUC (0.69; 95%CI, 0.65-0.73) than KRAS (0.53; 95%CI, 0.49-0.58); tTMB measured by Whole Exosome Sequencing (WES) had approximate AUC to that measure by targeted gene panel. The predictive accuracy of the biomarkers was further compared for patients receiving ICI-based combination therapy. The AUC of combined marker (0.70; 95%CI, 0.66-0.74) remained the highest for combination therapy. Conclusions: Combined marker (PD-L1+tTMB/bTMB/GEP) has superior predictive accuracy than single biomarkers for immunotherapy response of NSCLC. bTMB is a promising liquid biopsy biomarker. The prescription of ICI for patients with EGFR mutation should be cautious. Further investigation is warranted to precisely identify biomarkers in various clinical settings. [Table: see text]
TROCEPT: An oncolytic virus platform engineered for αvß6 integrin targeted tumor-localised expression of an immune checkpoint inhibitor following intravenous delivery.
Authors: David Krige, Rahul C. Khanolkar, James A. Davies, Alexander T. Baker, Thomas A. Webb, Somayeh Shahreza, Hanni K. Uusi-Kerttula, Lucy M. Williams, Emma Henderson, Samantha L. Moore, Johanne M. Pentier, Bent K. Jakobsen, Alan L. Parker, David K. Cole, Andrew B. Gerry
Journal: Journal of Clinical Oncology (2024)

e14579 Background: TROCEPT is a novel tumor-selective replicating, oncolytic adenovirus type 5 (Ad5) rationally engineered to remove all natural tissue tropisms. This engineering addresses the main limitation of other viral therapies which infect normal tissues and are rapidly removed by the liver and are therefore limited to local delivery. TROCEPT has been further engineered to specifically bind to αvβ6 integrin which is expressed at high frequency in the majority of epithelial cancers, so that following intravenous delivery the virus targets tumor tissue where it replicates and amplifies. In addition, the TROCEPT platform encodes transgenes which enables in-tumor production of powerful therapeutic drugs. The lead programme, TROCEPT-01, encodes a fully human, full length immune checkpoint inhibitor (ICI) antibody. TROCEPT-01 is currently undergoing IND-enabling studies and is expected to enter First in Human studies in 2024 in multiple solid tumor indications. Methods: Proof of concept studies, both in vitro and in vivo, to demonstrate TROCEPT-01’s tumor selectivity and toxicity profile have been performed. Results: In vitro experiments demonstrate that viral replication, transgene expression and oncolytic cell death following infection with TROCEPT-01 is highly selective for αvβ6 integrin positive tumor cells compared to a panel of normal human primary cells. Intravenous delivery in in vivo SKOV3 ovarian human tumor xenograft mouse models demonstrate virus delivery, replication, and transgene expression in the tumor. In comparison to the parental Ad5 virus, the engineering of TROCEPT-01 leads to more viral delivery to the tumour, less delivery to normal tissue including liver, reduced markers of liver toxicity and reduced inflammatory cytokine release, all of which validate the tumour selectivity and safety profile of the virus. Conclusions: We have demonstrated that TROCEPT engineering enables highly selective tumor targeting and significant tumor exposure following intravenous delivery. TROCEPT-01’s in-tumor selective expression of ICIs enables high local drug concentration in the tumor, potentially reducing systemic toxicity and increasing efficacy. TROCEPT-01 is currently undergoing IND-enabling studies and is expected to enter First in Human studies in 2024 in multiple solid tumor indications.
PD-1 checkpoint inhibitors related immune-mediated hepatitis in colon cancer: A systematic review and meta-analysis.
Authors: Dhruvi Reddy Sanikommu, Ahmed Nadeem, Kanishka Uttam Chandani
Journal: Journal of Clinical Oncology (2024)

e14615 Background: Immune checkpoint inhibitors have revolutionized the management of advanced colon cancers by targeting programmed death-1 (PD-1) proteins. Along with PD-1, other checkpoint inhibitors PDL-1 and CTL4 have been approved for the treatment of various type of cancers since a decade. However, many immune-related side effects have been associated with them. There is limited data in the literature on PD-1 related hepatotoxicity, mainly immune mediated hepatitis. This systematic review and meta-analysis aim to study the impact of PD-1 checkpoint inhibitors on immune-mediated hepatitis in the context of colon cancer, its incidence among different immunotherapies, risk factors associated with it and exploring treatment modalities. Methods: The study was conducted in accordance with PRISMA guidelines. Multiple databases such as PubMed, EMBASE, Scopus, Cochrane Library and Web of Science from past 10 years were searched up to November 2023. Studies from cohort studies, randomized control trials and case series that have reported on immune-mediated hepatitis in colon cancer patients treated with PD-1 inhibitors were included. Results: Overall pooled incidence of immune mediated hepatitis was between 1% -5% with an average of 4.1% (95% CI, 2.8-5.8) among patients with advanced colon cancer treated with PD-1 inhibitors. Among different inhibitors, incidence was lowest with Pembrolizumab, around 1.4%; and highest with Cemiplimab with 5.1%. This is crucial in optimizing treatment for advanced colon cancers. The meta-analysis also found risk factors of male gender, older age and pre-existing liver-conditions (Hepatitis B and C), contributing to the development of hepatitis. Subgroup analysis will be performed to explore potential differences in incidence rates based on patient characteristics, dosages of medications, duration of treatment and concomitant medications. Other objectives include determining the timeline and grades of toxicity. Conclusions: By incorporating data from other studies and understating safety profiles, the findings will highlight the need for close surveillance for toxicity monitoring. This would also provide insight for clinical providers to make informed decisions regarding treatment selection. Toxicities are noted to be under-reported; hence we urge clinicians to report such immune toxicities. Further research is needed to elucidate underlying mechanisms to develop strategies for mitigating adverse events.
Predictive cytokine biomarkers for immune-related adverse events associated with immune checkpoint inhibitor therapy in Hodgkin lymphoma.
Authors: Neeti Luke, Maria Pratt, Judy Gong, Sara Borghi, Catherine S. Diefenbach, Kirsty Hillier
Journal: Journal of Clinical Oncology (2024)

e14651 Background: Immune checkpoint inhibitors (ICIs) show great promise in the treatment of relapsed/refractory classical Hodgkin Lymphoma (cHL) and are being considered for up-front treatment. However, use of ICIs can be limited by immune-related adverse events (irAEs). Identifying predictive biomarkers for the development of irAEs could identify high-risk patients to potentially mitigate AEs. Methods: Eighteen patients with cHL were included; 11 patients treated with ICIs (pembrolizumab, nivolumab and/or ipilimumab) as cases (Cohort A) and 7 patients treated with standard of care chemotherapy as controls (Cohort B). The electronic medical record was reviewed for patient clinical characteristics. T cell cytokine expression and autoantibody profiles were performed on baseline pre-ICI treatment peripheral blood plasma samples using Luminex technology in the NYU Langone Immune Monitoring Core Laboratory; cytokine expression was analyzed by 2-way ANOVA. Results: All patients treated with ICIs had been previously treated with other therapy as opposed to Cohort B which included all newly diagnosed patients. Eight patients developed irAEs, with rash being most frequent (n=5) (Table). Analysis of cytokines showed significant elevation in ITAC for irAE compared to no irAE (p&lt;0.01). Increased IL-6, IL-13, and IL-17 expression and decreased MIP-1b expression in those with irAEs all trended towards significance. There was no identified correlation between autoantibodies and irAEs. Conclusions: irAEs can be a significant challenge in cHL patients treated with ICIs, causing comorbidities and limiting benefit from vital therapies. In patients who developed irAEs, we found a significant elevation in ITAC, a chemokine induced by IFN-gamma that attracts activated T cells. Other inflammatory cytokines such as IL-6, IL-13, IL-17, and MIP-1b trended towards significance, likely due to the small sample size. Expansion of this study in a larger cohort of patients is planned. [Table: see text]
Utility of the NLR and the ratio of NLR after and before adverse events for identifying irAEs and bacterial infections in patients with cancer during PD-(L)1 inhibitors treatment.
Authors: Lu Han, Beibei Huang, Linlin Li, Yonghao Yang, Xiaomin Fu, Lingdi Zhao, Zibing Wang, Quanli Gao
Journal: Journal of Clinical Oncology (2024)

e14620 Background: Identifying immune-related adverse events (irAEs) or bacterial infections in cancer patients undergoing treatment with PD-(L)1 inhibitors can be challenging. This study aimed to assess the effectiveness of the neutrophil-to-lymphocyte ratio (NLR) in distinguishing between irAEs and bacterial infections in cancer patients receiving PD-(L)1 inhibitors. Methods: We conducted a retrospective analysis of cancer patients who received at least one dose of PD-(L)1 inhibitors at Affiliated Cancer Hospital of Zhengzhou University from 2018 to 2023. We compared the changes in peripheral blood cell counts before and after the occurrence of adverse events, as well as the ratio of the NLR at the time of adverse events (post-NLR) to the NLR before adverse events (pre-NLR). Bacterial infections were diagnosed based on clear etiology and/or controlled adverse events through the use of antibiotics without systemic glucocorticoid administration during treatment. irAEs were diagnosed based on clinicolaboratory criteria, or the improvement of immune system disorders after withdrawal of PD-(L)1 inhibitors or systemic glucocorticoid administration, excluding bacterial infection. Data were collected from microbiology, radiography, serology, and physician notes. Results: Among the 4173 patients who were administered PD-(L)1 inhibitors, 217 individuals experienced a total of 249 irAEs, while 256 patients were diagnosed with 257 bacterial infections. When comparing pre-infection levels with those after bacterial infection, it was observed that the NLR increased significantly. Similarly, in the group experiencing irAEs, the NLR also showed a significant increase after the occurrence of the irAEs. Notably, the NLR was significantly higher in patients with bacterial infections compared to those with irAEs [11.08 (6.63, 19.29) vs 2.78 (1.92, 4.31), P &lt; 0.001]. Furthermore, the post-NLR/pre-NLR ratio was higher in the bacterial infection group than in the irAEs group [2.86 (1.56, 6.20) vs 1.16 (0.82, 1.76), P &lt; 0.001]. Appraising the potential of NLR and the post-NLR/pre-NLR ratio in identifying irAEs and bacterial infections in cancer patients, the receiver operating characteristic (ROC) curve analysis was performed. The area under the curve (AUC) was 0.91 for NLR and 0.81 for the post-NLR/pre-NLR ratio, respectively. Using a cut-off value of 4.56 for NLR and 1.96 for the post-NLR/pre-NLR ratio yielded the highest sensitivity and specificity. Conclusions: The NLR along with the post-NLR/pre-NLR ratio could serve as valuable diagnostic indicators for irAEs and bacterial infections in cancer patients undergoing treatment with PD-(L)1 inhibitors.
Interim report of a phase 2 study of sonodynamic therapy (SDT) using SONALA-001 together with MR-guided low-intensity focused ultrasound (MRgFUS) in children with diffuse intrinsic pontine glioma (DIPG).
Authors: Lindsay Baker Kilburn, Roger J. Packer, Adriana Fonseca, Robert F Keating, Sabine Mueller, Kazim Narsinh, Winson S Ho, Toba Niazi, Peter Fenn, Ryan Clanton, Lenora Henry, Wyatt Potter, Corina Andresen, Stuart Marcus, Ely Benaim, Hasan R Syed
Journal: Journal of Clinical Oncology (2024)

2067 Background: Children with DIPG have limited treatment options and a poor prognosis, with median survival of 9-12 months. Preclinical studies reveal that sonodynamic therapy (SDT) with MR-guided focused ultrasound (MRgFUS) activates ALA metabolite, protoporphyrin IX (PpIX), leading to tumor cell death and extending survival in glioma models. Methods: SDT-201 (NCT05123534) is a multi-center, first-in-child dose escalation trial of SDT with SONALA-001 and MRgFUS administered in children aged ≥ 5 years with DIPG, enrolled 4-20 weeks post-radiation therapy and prior to disease progression. The trial evaluates the safety and preliminary efficacy of SDT and pharmacokinetics (PK) of intravenous ALA (SONALA-001) at 5mg/kg, administered 6-12 hours before MRgFUS to the pons (delivered to half the pons 30 days apart for the first patient in each cohort of 3, with subsequent patients receiving entire pons treatment). The trial was subsequently amended to allow up to 12 monthly treatments. Results: Six patients in 2 cohorts were treated (4 male:2 female, range 5-12 years) between August 2022 and December 2023. No DLTs or related AE grade ≥ 3 were observed. For SONALA-001, the C max occurred at the end of infusion, followed by rapid clearance (15.7 mL/min/kg) with plasma half-life of &lt; 1 hour, indicating rapid distribution. The PpIX C max occurred 4-6 hours post-dose and declined with a longer mean half-life than SONALA-001 of 6 hours. Both C max and AUC all demonstrate circulating-PpIX and systemic exposure were significantly lower than for SONALA-001. Two of the first 6 patients achieved a partial response per RAPNO central-review, and 2 subjects continuing treatment are 11 to 15 months from start of study therapy. Conclusions: SDT is a well-tolerated strategy for patients with DIPG after initial radiotherapy. SONALA-001 shows rapid distribution and clearance, and PpIX PK align with metabolite formation. Following dose escalation completion, dose-expansion will be initiated at RP2D offering further insights into safety, PK, and efficacy. Clinical trial information: NCT05123534 .