tbuckley/cabot-search huggingface dataset:
Safety and preliminary efficacy of EIK1001 in combination with atezolizumab in participants with advanced solid tumors.
Authors: Manish R. Patel, Drew W. Rasco, Melissa Lynne Johnson, Omid Hamid, David Sommerhalder, Carolyn Cho, Meihua Wang, Etah Kurland
Journal: Journal of Clinical Oncology (2024)

2618 Background: Immune checkpoint inhibitors (ICIs) relieve immunosuppression of tumor-reactive T cells and enhance antitumor immune response; however, not all patients benefit and some become refractory. EIK1001 is a Toll-like receptor (TLR)7/8 agonist that stimulates myeloid and plasmacytoid dendritic cells, activating immune and inflammatory responses. This dual activity provides another pathway, distinct from effects on checkpoint proteins, to enhance antitumor T-cell activity alone or in combination with ICIs. Methods: Study BDB001-102 was a Phase 1, open-label, dose-escalation/expansion study of EIK1001 combined with atezolizumab (comb Rx). Enrollment criteria included participants (pts) ≥ age 18 with confirmed, RECIST-measurable advanced solid tumors. Primary study objectives included safety and tolerability, and secondary objectives included evaluation of dose-limiting toxicities, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy by RECIST 1.1. During dose escalation, pts received a range of doses of EIK1001 (QW IV) in combination with atezolizumab (1200 mg Q3W). Results: Forty-one pts (median age 65 years [range = 32 to 79]) with multiple, distinct histological tumor types and a median of 3 prior Rx regimens were enrolled. Overall, a total of 28/41 (68.3%) receiving EIK1001 + atezolizumab experienced a treatment-related adverse event (TRAE). Of these, 4/41 (9.8%) experienced a ≥ Grade 3 TRAE, including fatigue, nausea, hyponatremia, and lymphedema. Only 1/41 (2.4%) experienced manageable cytokine release syndrome. There were no deaths due to TRAEs. Of the efficacy-evaluable pts (n = 37), complete response (CR) or partial response (PR) was observed for 3/37 (8.1%). Disease control (including CR, PR, or stable disease) was observed in 19/37 (51.4%). The median duration of response (DOR) was 13 months (range = 10 to 27). One responder was PD-L1 negative yet had a &gt; 12-month DOR; another had a history of prior anti-PD-1 Rx yet experienced a 10-month DOR on comb Rx. EIK1001 PK was linear and dose-proportional, and was not affected by combination with atezolizumab. Conclusions: Overall, EIK1001 was well-tolerated with a manageable safety profile and showed encouraging preliminary efficacy across several tumor types in combination with atezolizumab. Responses were observed even in pts not anticipated to respond to atezolizumab monotherapy. Further development of EIK1001 is underway. Clinical trial information: NCT04196530 .
Detection of immune-related adverse events among hospitalized patients using large language models.
Authors: Virginia H. Sun, Julius C. Heemelaar, Ibrahim Hadzic, Vineet K. Raghu, Chia-Yun Wu, Leyre Zubiri, Giselle Alexandra Suero-Abreu, Azin Ghamari, Jessica Wu, Alexandra-Chloé Villani, Jor Sam Ho, Megan J. Mooradian, Meghan E. Sise, Daniel A. Zlotoff, Steven Michael Blum, Michael L. Dougan, Ryan J. Sullivan, Tomas G. Neilan, Kerry Lynn Reynolds, Molly Fisher Thomas
Journal: Journal of Clinical Oncology (2024)

2638 Background: Immune checkpoint inhibitor (ICI)-induced colitis, hepatitis, and pneumonitis are common immune-related adverse events (irAEs); however, the true incidence for these irAEs remains incompletely understood. Chart review is the gold standard for their detection but is time-consuming and cannot be implemented in large cohorts. The use of ICD codes is limited in sensitivity and specificity. Large language models (LLMs) are a scalable method of answering queries from human-generated text, though there is no data on the use of LLM for the identification of irAEs. Therefore, we investigated the application of a LLM to identify ICI-colitis, hepatitis, and pneumonitis among hospitalized patients, comparing its performance to manual chart review and ICD codes. Methods: Hospital admissions of patients on ICI therapy from February 5 th , 2011, to November 3 rd , 2021, were manually reviewed by a multidisciplinary immunotoxicity team using established published definitions for the presence of ICI colitis, hepatitis, and pneumonitis. Standard ICD codes and a LLM pipeline with retrieval-augmented generation (RAG) were used to detect irAEs. Performance was measured via sensitivity, specificity, and model runtime. The LLM was validated with a second dataset of inpatients with ICI colitis, hepatitis, and pneumonitis admitted from November 4 th , 2021, to September 5 th , 2023. Results: Among 5,677 hospitalized patients on ICI therapy in the initial cohort, there were 132 cases adjudicated with ICI colitis, 57 with ICI hepatitis, and 47 with ICI pneumonitis. The LLM was more sensitive in detecting all three irAEs compared to ICD codes (94.2% vs. 71.8%), achieving significance for ICI hepatitis (p&lt;0.001) and pneumonitis (p=0.006), while having similar specificities (92.5% vs 91.1%, Table 1). The LLM approach was also efficient, spending an average of 9.42s per chart, compared to an estimated 15 minutes per chart for individual chart review. The mean sensitivity and specificity of the LLM on the validation dataset for adjudicated ICI colitis (n=20), hepatitis (n=24), and pneumonitis (n=6) were 96.9% and 93.2%, respectively. Conclusions: LLMs serve as a useful tool for the detection of ICI colitis, hepatitis, and pneumonitis, significantly outperforming ICD-codes in accuracy and manual chart review in efficiency.[Table: see text]
The efficacy of immune checkpoint inhibitors in patients with cancer with pseudoprogression.
Authors: Marina Lyadova, Denis Fedorinov, Olesya Pardabekova, Margarita Nosova, Veronika Tuleiko, Vladimir Lyadov, Evgenia Kuzmina, Tatiana Antonova, Konstantin Lyadov, Vsevolod Galkin, Irina Poddubnaya
Journal: Journal of Clinical Oncology (2024)

2620 Background: Pseudoprogression (PsP) is quite a common phenomenon in cancer patients undergoing therapy with immune checkpoint inhibitors (ICI). It could be defined as temporary increase of tumor volume or the number of tumor lesions after beginning of ICI treatment (immune unconfirmed progressive disease - iUPD) followed by clinical response. However, many specialists in real clinical practice are hesitant to continue ICI therapy in patients with iUPD because of medical or financial constraints. We aimed to evaluate the efficacy of ICI in patients with clinical evidence of PsP. Methods: We retrospectively analyzed 1001 cases of ICI treatment (male 58,4%, age 28-90 years) in patients with various solid malignancies: melanoma – 316, lung – 280, kidney – 247, GI cancer – 96, cervix of the uteri – 62. The patients were treated in 2 regional referral centers in Moscow and Moscow Region between June 2018 and Dec. 2022. Unconfirmed progressive disease (iUPD) according to iRECIST criteria was diagnosed in 316 patients at the first imaging control after the beginning of ICI treatment (31,6%). Results: Among 316 patients with iUPD the presence of progression (immune confirmed progressive disease – iCPD) was verified in 105 (33,2%): melanoma – 109 (34,5%), lung – 86 (30,7%), kidney – 75 (30,4%), GI cancer – 42 (43,8%), cervix of the uteri – 4 (6,5%). Stable disease was found in 144 (45,6%), partial response in 50 (15,8% - iPR), complete response in 17 patients (5,4% - iCR). Altogether, PsP was diagnosed in 211 of 1001 patients (21,1%). Overall objective response rate in 316 patients with iUPD reached 21,2%, control over disease was achieved in 66,8% of cases. Severe immune-mediated adverse events (3-4 st. according to CTC AE 5.0) were diagnosed in 9 patients (2,8%). Median overall survival in patients with iUPD and ORR was 16,85 mon (95% CI 15,1–18,5), in patients without iUPD and ORR – 14,93 mon (95% CI 13,78–16,0). Conclusions: PsP was diagnosed in 21,1% of patients getting ICI treatment in real clinical practice with median survival in PsP patients with objective response of about 17 months. Only 10,5% of patients had iCPD after their second follow-up. We feel that close adherence to iRECIST criteria to verify true progression is mandatory in patients under ICI treatment to exclude unnecessary cessation of treatment.
Lung-MAP S1800D: A phase II/III study of N-803 (ALT-803) plus pembrolizumab versus standard of care in participants with stage IV or recurrent non-small cell lung cancer (NSCLC) previously treated with anti-PD-1 or anti-PD-L1 therapy.
Authors: John M. Wrangle, Mary Weber Redman, Hatim Husain, Karen L. Reckamp, Tom Stinchcombe, Martin Joseph Edelman, Ticiana Leal, Bryan A. Faller, Katherine Minichiello, Hossein Borghaei, Karen Kelly, Roy S. Herbst, Jhanelle E. Gray
Journal: Journal of Clinical Oncology (2024)

2619 Background: IL-15 is a member of the IL-2 common gamma chain family of cytokines. N-803 is IL-15 administered in complex with IL-15 receptor alpha. Lung cancer, despite advances in targeted therapies and immunotherapy, remains the leading cause of cancer related death in the United States. Strategies to improve the performance of immunotherapy in advanced NSCLC is a clinical unmet need. Methods: Lung-MAP S1800D was a randomized study comparing N-803 plus pembrolizumab (NP) to investigators’ choice standard-of-care chemotherapy (SoC) for previously treated advanced NSCLC. Patients were enrolled into an Acquired Resistance Cohort (ARC) if disease progression on prior anti-PD-(L)1 occurred &gt; 84 days from start of treatment and otherwise into a Primary Resistance Cohort (PRC). The ARC was a phase II/III study with a sample size goal of 334 patients. The PRC was a phase II with sample size of 134 patients. The first interim analysis (IA1) in the ARC evaluated futility among the first 25 patients treated with NP which required ≥1 response and ≥50% with disease control at 12 weeks to continue accrual. The primary endpoint in both cohorts was overall survival (OS). Secondary endpoints were progression-free survival (PFS), response, and toxicity. Results: Accrual in the ARC and PRC were closed at the IA1 in the ARC with 74 pts in the ARC and 8 in the PRC. Of the 74 ARC patients, 71 met eligibility (36 SoC, 35 NP), and 32 pts on each arm received treatment. With 44 events, OS was not significantly different between the two arms (HR (95%CI: 0.73(0.40-1.36), p=0.32) with a 12-month OS rate of 25% with SoC and 44% with NP. With 61 events, PFS was not significantly different but numerically worse (HR (95% CI): 1.29 (0.78-2.13, 95% CI), p=0.33). There were 3 unconfirmed partial responses and 1 confirmed complete response with NP and 3 unconfirmed partial responses and 2 confirmed partial responses with SoC. On the NP arm, there were 10 Grade 3 (1 hematologic) and 1 Grade 5 treatment-related adverse events reported as Disease Progression (34% Grade 3+ TRAE). The Grade 3+ TRAE rate on the SoC arm was 53% with 10 Grade 3+ hematologic toxicities. Conclusions: While the study failed to continue accrual past IA1, there is an indication of a subgroup that might benefit from NP with a potential OS difference at 12 months. NP was safe when compared to SoC, and responses were seen in both treatment arms, including partial and complete responses in the NP group. Evaluation of tumor and patient characteristics will be critical to define if there are those who may benefit from N-803 plus pembrolizumab. Clinical trial information: NCT05096663 .
Phase 2 trial of brentuximab vedotin (BV) with pembrolizumab (pembro) in patients with previously treated metastatic non-small cell lung cancer (NSCLC) or cutaneous melanoma (SGN35-033): Overall survival.
Authors: Yousef Zakharia, Sylvia Lee, Robert M. Jotte, Amanda Lynn Gillespie-Twardy, Inderjit Mehmi, Sunandana Chandra, Omid Hamid, Graham Thomas Watson, Patrick J. Ward, Marya F. Chaney, Hailing Lu, Jason Berndt, Kapil Rathi, Anumeha (Anu) Gupta, Charles Lance Cowey
Journal: Journal of Clinical Oncology (2024)

2617 Background: BV, a CD30 directed antibody-drug conjugate, may selectively deplete a subset of regulatory T-cells (Tregs) that express CD30 and re-sensitize tumors to anti-PD-1 therapy. This ongoing, multi-cohort, multicenter, open-label trial evaluating the efficacy and safety of BV+pembro in patients (pts) with anti-PD-1 refractory solid tumors previously reported an ORR (8-22%), DCR (67-80%), and CD8+T cell infiltration in on-treatment biopsies of responders (Lee, SITC 2023). Here we report OS and biomarker analyses. Methods: Pts with primary refractory (progression without response or SD for &lt; 6 months) or secondary refractory (progression after response for ≥3 months or SD for ≥6 months) NSCLC or melanoma who progressed on anti-PD-1 therapy were included. Pts received BV (1.8 mg/kg) and pembro (200 mg) every 21 days. The primary endpoint was confirmed ORR. Exploratory endpoints included OS and biomarker analyses of blood and tumor samples. Results: 55 pts with NSCLC and 58 pts with melanoma were dosed (86% white, 63% male; 57% ≥ age 65 yrs). Pts received 3 median prior lines of therapy (as previously reported). Investigator-assessed response was measured according to RECIST v1.1. At a median follow up of 17.2 months, median OS (mOS) was 13.9 months (NSCLC) and 12.9 months (melanoma) (Table 1). The estimated probability of survival (Kaplan-Meier) at 12 months was 54.0% (95% CI 43.69, 63.22) for the study population. Immune mediated AEs were reported in 25% of pts, Grade ≥3 TEAEs in 56%, TESAEs in 42%, and TE peripheral neuropathy (SMQ) in 48% of pts. 17% of pts discontinued treatment due to TEAEs. No new safety signals were identified and no deaths due to treatment-related AEs were reported. Paired tumor biopsies from 19 pts showed increased CD8+T cell infiltration in 11 pts. Conclusions: These data support the immunomodulatory capacity of BV with pembro. This combination shows encouraging OS data in pts with solid tumors who have progressed on anti-PD-1 therapy. The safety profile is comparable to previously reported data. The study remains ongoing. Clinical trial information: NCT04609566 . [Table: see text]
Hepatic noradrenergic innervation acts via CREB/CRTC2 to activate gluconeogenesis during cold
Authors: Henrique J N Morgan, Heitor B P Delfino, Aline Z Schavinski, Samuel A Malone, Camille Charoy, Natany G Reis, Ana P Assis, Natalia Lautherbach, Wilian A Silveira, Lilian C Heck, Dan Guton, Ana I Domingos, Isis C Kettelhut, Marc Montminy, Luiz C C Navegantes
Journal: Metabolism (2024)
BGB-A317-212: A multicenter, open-label, phase II study to evaluate the efficacy and safety of tislelizumab in combination with lenvatinib in patients with selected solid tumors.
Authors: Yufei Liu, Zhisong He, Mingjun Zhang, Shusuan Jiang, Dahong Zhang, Miao Feng, Shenhong Qu, Wutong Ju, Ke Wang, Ramil Abdrashitov, Jifeng Feng
Journal: Journal of Clinical Oncology (2024)

2610 Background: Tislelizumab, an anti-programmed cell death protein 1 (PD-1) monoclonal antibody, has demonstrated promising efficacy in several advanced solid tumors. However, some patients (pts) do not respond or develop resistance to tislelizumab monotherapy. Lenvatinib, a receptor tyrosine kinase inhibitor targeting VEGFR 1-3, FGFR 1-4, PDGFR alpha, KIT, and RET, has shown a potential synergistic effect with anti-PD-1 therapy. Here, we report the primary results of a phase II study evaluating the combination of tislelizumab plus lenvatinib in pts with solid tumors (NCT05014828). Methods: Pts with histologically/cytologically confirmed selected solid tumors, naïve to lenvatinib and anti-programmed death-ligand 1 (PD-L1)/PD-1 therapies were enrolled. Part 1 (safety run-in) determined the recommended phase II dose (RP2D) of lenvatinib in combination with tislelizumab 400 mg IV every 6 weeks. In Part 2 (expansion), pts received lenvatinib at the RP2D from Part 1 (20 mg orally/day) plus tislelizumab per the Part 1 regimen until disease progression, withdrawal, or death. The primary endpoints were safety and RP2D determination (Part 1) and overall response rate (ORR; Part 2). Results: At data cutoff (Oct 20, 2023; median follow-up 12.1 months [mo; renal cell carcinoma, RCC]; 10.8 mo [head and neck squamous cell carcinoma, HNSCC]; 14.8 mo [gastric cancer, GC], and 22.0 mo [non-small cell lung cancer, NSCLC]), 58 pts were treated in Part 2 (RCC, n=23; HNSCC, n=27; GC, n=3; NSCLC, n=5), 6 of whom were also included in Part 1. The ORR was 66.7% in pts with RCC, 33.3% (HNSCC), 33.3% (GC), and 20.0% (NSCLC). Median duration of response (mDoR) was 18.5 mo and 9.6 mo in pts with NSCLC and HNSCC, respectively; not estimable (NE) for RCC and GC (Table). No new safety signals were identified; grade ≥3 treatment-related adverse events were reported in 78.3%, 59.3%, 33.3% and 60.0%, of pts with RCC, HNSCC, GC, and NSCLC, respectively (Table). Conclusions: Tislelizumab plus lenvatinib had a manageable safety profile and showed preliminary antitumor activity in pts with selected tumor types. Longer follow-up is needed to further investigate the potential of this combination to benefit pts with advanced solid tumors. Clinical trial information: NCT05014828 .[Table: see text]
Single cell sequencing reveals T follicular helper cells as the link between combination ICI therapy and the development of increased IRAEs.
Authors: Rana Yakhshi Tafti, Willy Hugo, Alexandra Drakaki, Trevor E Angell, Melissa G Lechner
Journal: Journal of Clinical Oncology (2024)

2644 Background: Targeting multiple checkpoints via the combination of individual immune checkpoint inhibitor (ICI) therapies has increased anti-tumor effects compared to single agent ICI regimens. Despite these benefits, Dual ICI therapies have a higher risk of immune toxicity and incidence of immune related adverse events (irAEs) compared to single agent immunotherapies. Of note, T follicular helper (TFH) cells have been shown to contribute to both spontaneous and, more recently, irAE autoimmunity. Given the association of TFH cells and Tertiary Lymphoid Structures (TLS) with ICI response, a potential reason for the increased effectiveness of Dual ICI in anti-cancer therapy, TFHs may also be involved in the pathogenesis and increased incidence of irAEs seen with Dual ICI therapy. Methods: To understand the underlying mechanism by which Dual ICI therapy may increase the incidence of irAEs, we obtained thyroid fine needle aspirates from 9 individuals with ICI-thyroiditis, one of the most common irAEs. We performed single-cell RNA sequencing (scRNA-Seq) and compared immune infiltrates of patients receiving anti-programmed cell death protein 1 (PD-1) or anti-programmed cell death ligand 1 (PD-L1) to Dual ICI patients who received PD-1 or PD-L1 in combination with anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4). Results: ScRNA-Seq analyses revealed a 3-fold expansion of TFH and T peripheral helper (TPH) cells in Dual ICI therapy compared to PD-1/L1 patients. CD4T cell trajectory analysis revealed a dominant transition among Dual ICI patients from a naïve SELL+ CCR7+ phenotype to the CXCR5+ TFH and later IL21+ IFNG+ TPH phenotypes (p &lt; 0.0001). The differentiation involved an upregulation of IL21, CD40LG, BCL6, and CXCR5 genes within CD4 T cells. Differential gene analysis showed enrichment of Tertiary Lymphoid Structure (TLS) gene sets in B and TFH cell clusters indicative of TLS formation within which CD8 T, CD4 T TFH, and GC B cells interact. CD8 T cell analysis indicated a dominant expansion and differentiation towards a CXCL13+ IFNG+ FASLG+ phenotype in Dual ICI therapy compared to PD1/PDL1 monotherapy (p &lt; 0.0001). Cell interaction analysis showed up-regulated TFH-mediated IL21 signaling and CD8 T cell-mediated CXCL13 signaling to BANK1 B cells in Dual ICI therapy. Conclusions: Dual ICI therapy led to up-regulation of activation markers and preferential differentiation of CD4 T cells towards TFH cells in addition to upregulation of TLS signature genes and signaling pathways in TFH, CD8 T, and B cells. Given the previously established association between TFHs and the pathogenesis of autoimmune diseases and irAEs, their increased numbers and activity in Dual ICI therapy may explain the greater toxicities seen.
Gender scores in epidemiological research: methods, advantages and implications
Authors: Aranka V Ballering, Tim C Olde Hartman, Judith G M Rosmalen
Journal: The Lancet Regional Health - Europe (2024)

Sex and gender-related factors are strongly associated with patients' illness trajectories, underscoring their essential role in epidemiological research and healthcare. Ignoring sex and gender in research and health inevitably results in inequities between women and men in terms of detection of disease, preventative measures, and effectiveness of treatment. Historical influences, including ideas of female inferiority and conservative notions of women's health only comprising reproductive health, reinforced the perceived irrelevance of sex and gender to health. Currently, these ideas are largely abandoned and epidemiology is becoming increasingly sensitive to sex. Gender-sensitivity, however, is lagging behind. This is potentially due to lacking knowledge and awareness about the relevance of both sex and gender to health and challenges in operationalizing gender in epidemiological research. Here, we thoroughly discuss the relevance of sex and gender to health, and pay special attention to the time, place, and culture-dependent embodiment of gender. We also discuss the operationalization of gender via composite gender scores in epidemiological studies. We argue to move beyond solely using these. Rather we should consider sex and gender in the initial stages of designing a study, to facilitate relevant, reproducible, and person-centric research.
In Situ Fabrication of Electrospun Magnetic Film Under Laparoscopic Guidance for Preventing Postoperative Recurrence of Hepatocellular Carcinoma
Authors: Luyao Xiang, Jinlong Hu, Xu Yan, Huai Yang, Chaofei Ji, Yunjun Xu, Haojie Lu, Chaowei Lu, Qingbing Hou, Yonghong Song, Dongquan Liu, Baoqiang Cao, Yang Lu
Journal: Advanced Healthcare Materials (2024)

Despite laparoscopic-guided minimally invasive hepatectomy emerging as the primary approach for resecting hepatocellular carcinoma (HCC), there is still a significant gap in suitable biomaterials that seamlessly integrate with these techniques to achieve effective hemostasis and suppress residual tumors at the surgical margin. Electrospun films are increasingly used for wound closure, yet the employment of prefabricated electrospun films for hemostasis during minimally invasive HCC resection is hindered by prolonged operation times, complexity in implementation, limited visibility during surgery, and inadequate postoperative prevention of HCC recurrence. In this study, montmorillonite-iron oxide sheets are integrated into the polyvinylpyrrolidone (PVP) polymer framework, enhancing the resulting electrospun PVP/montmorillonite-iron oxide (MI) film (abbreviated as PMI) with robustness, hemostatic capability, and magnetocaloric properties. In contrast to the in vitro prefabricated electrospun films, the electrospun PMI film is designed to be formed in situ on liver wounds under laparoscopic guidance during hepatectomy. This design affords superior wound adaptability, facilitating meticulous wound closure and expeditious hemostasis, thereby simplifying the operative process and ultimately alleviating the workload of healthcare professionals. Moreover, when exposed to an alternating magnetic field, the film can efficiently ablate residual tumors, significantly augmenting the treatment efficacy of HCC.