tbuckley/cabot-search huggingface dataset:
Diversity in B7-H3/CD276 expression across cancer types: Exploring a dynamic novel immune checkpoint.
Authors: Brigid Larkin, Daisuke Nishizaki, Hirotaka Miyashita, Suzanna Lee, Mina Nikanjam, Mary K Nesline, Sarabjot Pabla, Jeffrey M Conroy, Paul DePietro, Jason K. Sicklick, Razelle Kurzrock, Shumei Kato
Journal: Journal of Clinical Oncology (2024)

3133 Background: The resistance encountered in immune checkpoint blockade has persistently impaired the achievement of robust, durable antitumor immune responses in most cancer patients, prompting the search for additional immune targets. B7 homolog 3 (B7-H3)/CD276 is an emerging immune biomarker whose contrasting immune functions challenge conventional immune marker classifications, making it a compelling target. The present study aimed to characterize the expression of B7-H3/CD276 in a pan-cancer setting, analyze its co-expression patterns with potentially co-targetable immune checkpoints, and discuss implications for ongoing clinical trials. Methods: We conducted a focused analysis of B7-H3/CD276 expression in 514 cancer patients with diverse tumor histologies evaluated under the PREDICT protocol at the University of California San Diego. RNA sequencing of tissue specimens was performed, and results were used to characterize the RNA expression levels of B7-H3/CD276 and its correlation with key cancer immunity markers including PD-1, PD-L1, PD-L2, CTLA4, LAG3, BTLA, TIM3, VISTA, ADORA2A and IDO1. Results: Elevated expression levels of B7-H3/CD276 were observed in 41.6% [214/514] of the 514 tumor samples analyzed. When stratified by cancer type, the highest rates of elevated expression were found in sarcomas (58.30%, 14/24), followed by pancreatic (58.20%, 32/55) and liver and bile duct cancers (52.60%, 10/19). The independent association with pancreatic cancers was statistically significant on multivariate analysis (odds ratio 2.20, 95% confidence interval 1.09 – 4.45, p = 0.027). Ninety-three unique patterns of immune co-expression were observed among the 214 patients with high B7-H3/CD276 expression levels. Among them, the most commonly observed pattern was high expression of B7-H3/CD276 alone (26.2%, 56/214) followed by co-expression with high VISTA (7.0%, [15/214]) and high ADORA2A (5.6%, [12/214]). Of note, there was significant heterogeneity observed in the patterns of co-expression in cancer immunity markers, with 72.04% (67/93) in the cohort being unique to one patient. Conclusions: We have observed immunomic diversity in our analysis of B7-H3/CD276 expression levels across varied tumor types as well as in its co-expression patterns with other immune markers. Our findings suggest that leveraging immune profiling to build customized therapeutic regimens may be pertinent to optimizing response rates and minimizing toxicity to B7-H3/CD276 targeting therapies.
The gut microbial characteristics and underlying mechanisms of patients with different clinical prognoses from immunotherapy by landmark analysis.
Authors: Xinyu Liu, Bo Lu, Xinmiao Jia, Hao Tang, Qingyang Zhou, Yanlin Zeng, Xiaoxing Gao, Minjiang Chen, Yan Xu, Mengzhao Wang, Jiaming Qian, Bei Tan
Journal: Journal of Clinical Oncology (2024)

2606 Background: A subset of cancer patients could benefit long-termly from immune checkpoints inhibitors (ICIs), which was called smearing effect. Gut microbiota was widely found to be associated with the initial ICIs efficacy and immune-related adverse event (irAE). This study aimed to identify the baseline gut microbiota characteristics of long-benefit patients and explore the possible underlying mechanisms. Methods: Lung cancer patients initially treated with anti-PD-1/PD-L1 therapy were consecutively enrolled from May 2020 to September 2022. All patients were classified into Benefit group, Resistance group and Severe irAE group based on the long-term prognosis. The baseline gut microbiota characteristics were identified by metagenome sequencing. MelonnPan was used to predict the abundances of 79 metabolites. The sequences of autoantigen, lung cancer antigen and anticancer peptides (ACPs) from IEDB and CancerPPD databases were aligned against the scaftigs of fecal samples. Results: 54 patients were enrolled with 24 in Benefit group, 13 in Severe irAE group and 17 in Resistance group. The microorganism composition was significantly different between Benefit group and Resistance group ( P=0.03), while no difference between Benefit group and Severe irAE group ( P=0.93). The co-occurrence network showed the Benefit group patients had the most compact microbiota network. Metabolites prediction analyses showed the short chain fatty acids propionate ( P=0.005) and butyrate/isobutyrate ( P=0.03) were significantly enriched in Benefit group than Resistance group, wherein the acetyl-CoA pathway ( P=0.04) accounted for the largest proportion of butyrate-production ability difference. The beneficial species had more positive correlations with butyrate-producing enzymes ( P&lt;0.001). The microbiota of irAE patients had abundant aligned sequences with antigen epitopes of multiple autoimmune diseases. The total counts of systemic lupus erythematosus-related epitopes were significantly more enriched in patients with immune-related colitis ( P=0.04), especially FDNGRRGRPVTGP ( P=0.02) and IDNGRRGRPITGP ( P=0.02). Likewise, the microbiota of patients with good ICIs efficacy tended to have more abundant cancer-related antigen counts ( P=0.07) and ACPs counts ( P=0.06). Strain-level analysis revealed Escherichia coli and Faecalibacterium prausnitziishowed a centralized trend of genomic variations based on different clinical phenotypes. Conclusions: Long-term benefit patients had converging characteristics of gut microbiota, which coevoluted a compact microbial community with high butyrate-producing ability. The microbiota molecular mimicry of autoimmune and tumor antigen might contribute to irAE and ICIs efficacy. The strain-level genomic variations of specific species may also play a role in clinical phenotypes.
FCN-159, a MEK1/2 inhibitor, in patients with advanced melanoma harboring <i>NRAS</i> or <i>NF1</i>mutations: A phase 1B dose-expansion study.
Authors: Junjie Gu, Lili Mao, Jun Guo, Yu Jiang, Lingjun Zhu, Xiaoshi Zhang, Wangjun Yan, Yu Chen, Chang Tan, Weiyou Zhu, Jian Zhang, Jie Liu, Jing Lin, Zhuli Wu, Xingli Wang, Yuchen Yang, Ben Li, Lu Si
Journal: Journal of Clinical Oncology (2024)

3095 Background: In phase 1A dose-escalation study, preliminary anti-tumor activity of FCN-159 was observed in advanced melanoma patients harboring NRAS mutations (ORR: 19.0%, mPFS: 3.8 months) with tolerable safety profile, which was posted during AACR 2022 (No.: 22-LB-7398-AACR). Here, we report the results from phase 1B dose-expansion study in advanced NRAS- or NF1-mutant melanoma patients at RP2D predetermined at 12 mg. Methods: This open-label, dose-expansion, phase 1B study (NCT03932253) consists of two cohorts, which enrolled patients with unresectable stage III/IV melanoma harboring NRAS or NF1 mutations, respectively. Patients received FCN-159 orally at 12 mg once daily (QD) continuously in 28-day cycles. The primary endpoint was anti-tumor activity. Results: As of July 17, 2023, 46 patients (32 patients with NRASmutations in Cohort 1 and 14 patients with NF1mutations in Cohort 2) were enrolled and received 12 mg FCN-159 QD. The median follow-up time was 8.6 months. Among 25 patients who failed in previous anti-PD-1 therapy in Cohort 1, 6 had confirmed partial responses (ORR, 24.0%; 95% confidence interval [CI], 9.4–45.1). Median DOR was 6.5 months (95% CI, 2.7–NE). Median progression-free survival (mPFS) was 3.6 months (95% CI, 1.8–5.5). Among 14 patients in Cohort 2, 1 had PR (ORR, 7.1%; 95% CI, 0.2-33.9) and mPFS was 2.8 months (95% CI, 1.8-5.5) (Table). Grade≥3 FCN-159-related treatment-emergent adverse events (TEAEs) were reported in 10 (21.7%) patients in both cohorts; the most common was blood creatine phosphokinase increased (13.0%). FCN-159–related serious AEs (SAEs) were reported in 3 (6.5%) patients, which were edema lower limb, cellulitis and pneumonia. Two (4.3%) patients discontinued treatment due to FCN-159 related TEAEs, including serous retinal detachment and herpes zoster. No FCN-159-related TEAEs led to death. Conclusions: FCN-159 showed encouraging efficacy data with well tolerated safety profile in patients with NRAS-mutant advanced melanoma, especially those who failed in previous anti-PD-1 therapy. Clinical trial information: NCT03932253 . [Table: see text]
Correlations between first cycle toxicity and overall survival in patients with rare cancers treated with immune checkpoint inhibitors (NCI/SWOG S1609).
Authors: Megan Othus, Sandip Pravin Patel, Young Kwang Chae, Eliana Dietrich, Howard Streicher, Elad Sharon, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2024)

2655 Background: Associations between immune-related adverse events (irAEs) from checkpoint inhibitor therapy and outcomes have been previously evaluated, with most prior research finding a positive association between toxicity incidence and overall survival. This prior research has generally reported on more common tumor types. We use a unique data resource of a federally funded basket trial (NCT02834013) for patients with rare cancers to evaluate associations between irAEs and overall survival (OS) and progression-free survival (PFS) in a cohort of patients treated with combination checkpoint inhibitor therapy. Methods: We evaluated irAEs observed in the first cycle (6 weeks) of therapy that were possibly, probably, or definitely related to treatment; irAE grade was based on CTCAEv5. Patients received ipilimumab [1mg/kg intravenously (IV) every 6 weeks] plus nivolumab (240mg IV every 2 weeks). Landmarks methods were used to avoid immortal-time bias; PFS and OS were analyzed from day 43 with patients who died or progressed before that date excluded from analyses. Cox regression analyses were used to evaluate covariate associations. Results: We found that grade 1-2 treatment-related irAEs in the first cycle of therapy were associated with longer OS (multivariable hazard ratio, 95% confidence interval, p-value: 0.61, 0.49-0.75, p&lt;0.001) compared to no treatment-related irAE in the first cycle, while grade 3-4 irAEs were associated with shorter OS (HR=1.41, 95% CI=1.04-1.90, p=0.025). Similar, but weaker, associations were observed with PFS, grade 1-2 treatment-related irAEs: HR=0.83, 95% CI=0.67-1.01, p=0.067 and grade 3-4: HR=1.35, 95% CI=1.02-1.78, p=0.037 compared to no treatment-related irAE in the first cycle. Grade 1-2 dermatologic toxicity were associated with improved OS compared to other grade 1-2 toxicities (HR=0.67, 95% CI=0.52-0.85, p=0.002). There were no significant differences between OS among patients with Grade 1-2 gastrointestinal, metabolic, hepatic, endocrine, and thyroid toxicities and fatigue and other Grade 1-2 toxicities. Conclusions: In this large cohort of patients with rare tumors receiving ipilimumab and nivolumab grade of irAE in the first cycle of therapy was prognostic for survival.
An evaluation of novel oncology approvals with a PMR/C for assessing data in racial and ethnic populations underrepresented in premarket clinical trials
Authors: Grace Collins, Hillary S. Andrews, Brittany McKelvey, Carrigan Rice, Jeff D. Allen, Mark D. Stewart
Journal: Clinical Cancer Research (2024)

Clinical trials supporting oncology drug approvals frequently underrepresent diverse racial and ethnic populations. Recent policies have focused on ensuring premarket clinical trials are more inclusive and representative of racial and ethnic diversity in the general U.S. population or intended patient population; however, recent U.S. Food and Drug Administration (FDA) guidance on postmarketing approaches to collecting data in underrepresented populations demonstrates that, in certain circumstances, postmarketing requirements and/or commitments (PMR/Cs) may be issued to conduct more representative studies if there are remaining questions about safety or efficacy. This analysis demonstrates that prior to 2020, no drugs had PMR/Cs to further characterize use in a more representative population, and in the last 3 years, more than half of novel oncology approvals have had such a PMR/C (21/40, 53%). In addition, this analysis helps to identify characteristics, such as single-arm pivotal trial design, U.S. enrollment, and results of safety subgroup analyses based on race and ethnicity, that may contribute to decisions to issue a PMR/C to conduct a study that is more representative of the racial and ethnic diversity of the U.S. or intended patient population. These results can inform efforts to improve premarket clinical trials to ensure they are representative and able to characterize use in any patient who may need the drug.
Ipatasertib in patients with <i>AKT1/2/3</i> mutation-positive (<i>AKT</i>mut) tumors: TAPISTRY study.
Authors: David Morgan Thomas, Gennaro Daniele, Jeong Eun Kim, Shirish M. Gadgeel, Eugene R. Ahn, Luis G. Paz-Ares, Hans Prenen, David Chen, Junhan Fang, Timothy R. Wilson, Brian P. Simmons, Fabrice Barlesi
Journal: Journal of Clinical Oncology (2024)

3092 Background: AKT1/2/3 point mutations are found in ~1% of all solid tumors, with varying prevalence across different tumor types. Ipatasertib is an inhibitor of the AKT kinase, but its antitumor activity as monotherapy in patients with AKTmut tumors is unknown. We present efficacy and safety data of ipatasertib in patients with advanced/metastatic AKTmut solid tumors from Cohort E of the TAPISTRY trial (NCT04589845). Methods: TAPISTRY is a phase II, global, open-label, multi-cohort trial evaluating the efficacy and safety of different therapies in patients with advanced/metastatic solid tumors. Patients in Cohort E were aged ≥12 years and had solid tumors harboring an AKT1/2/3mutation identified by next-generation sequencing and measurable disease by RECIST v1.1. Oral ipatasertib 400 mg was administered once daily. Tumor assessments were performed at screening, every eight weeks from Day 1/Cycle 1 for one year, and every 12 weeks after that. The primary endpoint was objective response rate (ORR) by independent review committee (IRC). Key secondary endpoints included ORR by investigator, duration of response, progression-free survival, overall survival and safety. Results: At data cut-off (16 Jul 2023), 50 patients were safety evaluable and 48 were efficacy evaluable. In the safety-evaluable population, median age was 59 years (range, 30–79); 98% of patients (n/N = 49/50) had an AKT1 mutation ( AKT1 E17K, n=47) and 2% (n/N = 1/50) had an AKT2 E17K mutation; 41/50 patients (82%) had received ≥2 prior lines of treatment. Efficacy-evaluable patients had 10 different tumor types, the most common being breast cancer (n/N = 21/48; 44%). Key outcomes are summarized in the Table. After a median follow-up of 11.3 months, ORR by IRC in efficacy-evaluable patients was 31.3% (n/N = 15/48; 95% CI 18.7–46.3), driven by responses in three tumor types: breast (n/N = 7/21; 33%), endometrial (n/N = 7/7; 100%), and head and neck (n/N = 1/2; 50%). The most frequent adverse event was diarrhea (n/N = 39/50; 78%). Safety was consistent with the known profile of ipatasertib; no new safety signals were identified. Conclusions: Treatment with ipatasertib led to a marked and durable antitumor activity in some tumor types such as endometrial cancer, but not in the overall tumor-agnostic cohort. Further studies are needed to understand the relevance of AKT inhibition in these tumor types. Clinical trial information: NCT04589845 . [Table: see text]
A phase I open-label study of a novel IL-2Rβ/γ cytokine agonist, LTC004, in patients with advanced or metastatic solid tumors.
Authors: Jifang Gong, Lin Shen, Aimin Zang, Huan Zhou, Jie Tang, Dan Liu, Youchao Jia, Beibei Wang
Journal: Journal of Clinical Oncology (2024)

2652 Background: LTC004, a novel IL-2Rβ/γ cytokine agonist, designed to minimize toxicity with improved potency. It has selective affinity for the receptor IL-2Rβγ subunits, preferentially stimulates CD8 + effector T cells and natural killer cells which are associated with tumor killing, while minimizing the activation of immunosuppressive regulatory T cells. LTC004 has shown significant in vitro and in vivo anti-tumor activity in multiple cell lines and murine models respectively. Methods: This is a first-in-human, multicenter, open-label, dose-escalation and dose-expansion phase I study of LTC004 in advanced solid tumors. Dose escalation part assessed safety and tolerability of intravenous LTC004 with doses ranging from 3.0 to 360 µg/kg. The dose escalation schedule utilized an accelerated titration and Bayesian Optimal Interval (BOIN) design. Eligible pts with advanced solid tumor were required to have received prior standard therapy. LTC004 is administrated intravenously once every 3 weeks. Results: The study completed dose-escalation part (3.0 to 360 µg/kg) as of cutoff date (Jan 10, 2024). 17 pts of multiple tumor types (including non-small cell lung, cervical, colorectal, sarcoma, melanoma, parotid adenocarcinoma, thymic adenocarcinoma, gastric and ovarian cancers) were enrolled and received ≥1 dose of LTC004. At baseline, 12 pts (70.6%) had received ≥2 prior lines therapy, 11 pts (64.7%) had received prior targeted therapy, 10 pts (58.8%) had received prior immune checkpoint inhibitor (ICI) therapy. LTC004 generally well tolerated and no dose-limiting toxicities (DLTs) up to and including 360 µg/kg was observed. The most common TEAEs overall in ≥30% of pts were fever, white blood cell decreased, anemia, AST/ALT increased, neutrophil count decreased, GGT increased, nausea and hypotension. Most of the reported AEs were G1 and G2, all drug related events reversible and responsive to supportive care therapy. Fever can be resolved with standard anti-pyretic treatment or steroids, transient hypotension can be preventable with prophylactic fluid infusion. Of 17 pts enrolled evaluable for efficacy per RECIST v1.1, the ORR were 5.9% (1/17), DCR were 58.8% (10/17). A confirmed PR was achieved in a pMMR/MSS CRC patient with prior therapies including fluoropyrimidines, irinotecan, oxaliplatin, targeted therapy and TKI. The starting dose was 45µg/kg, titration to 90µg/kg after 4 consecutive doses at 45µg/kg Q3W. As of cutoff date, the patient sustained PR for 4.8 months with follow-up ongoing. Conclusions: LTC004 demonstrated encouraging anti-tumor efficacy including cold tumor, and well tolerated in patients with advanced or metastatic solid tumors. The further dose expansion in selected tumor types is ongoing, and evaluations in combination with other agents are being planned. Clinical trial information: NCT05666635 .
The anti-tumor immune response of radiotherapy combined with anti-CD200R1 in hepatocellular carcinoma.
Authors: Siqi Li, Kun Li, Peng Jiang, Hua Li, Yang Yang, Linsen Ye
Journal: Journal of Clinical Oncology (2024)

2525 Background: Various clinical trials demonstrate the efficacy of regional radiotherapy or chemotherapy in augmenting the therapeutic response to PD1/L1 antibody in hepatocellular carcinoma (HCC). However, a significant proportion of HCC patients still exhibit suboptimal responses to these combination therapies. The immune-suppressive tumor microenvironment (TME) poses a formidable barrier to effective immunotherapy. Recent evidences underscore the pivotal role played by myeloid cells in modulating the immunosuppressive TME following regional treatments. Therefore, targeting the myeloid immunosuppressive checkpoint represents a promising strategy for enhancing the efficacy of current local-immune combination therapy. Methods: Initially, single cell RNA sequencing (scRNA-seq) was conducted on tumor infilitrating immune cells (TIICs) of mouse HCC tissues three days post-radiotherapy. Subsequently, the phenotype of tumor-infiltrating CD200 + macrophages was characterized in mouse HCC tissues using flow cytometry. Next, the specific mechanism underlying CD200 up-regulation in tumor-infiltrating macrophages was investigated using wild-type mice and STING KO mice. Furthermore, the chemotactic and interactive mechanisms between CD200 + macrophages and CD200R + myeloid-derived suppressor cells (MDSCs) were investigated through in vitro and in vivo experiments. Finally, the systemic antitumor effect of combined radiotherapy and anti-CD200R treatment was observed in multiple non-immunogenic HCC mouse models. Results: The infiltration level of CD200 + macrophages in HCC tissues significantly increase following local radiotherapy. The accumulation of CD200 + macrophage subset relies on potent STING activation subsequent to radiotherapy. In vitro and in vivo experiments demonstrate the robust capacity of CD200 + macrophages in enhancing myeloid immunosuppression. Mechanistically, CD200 + macrophages recruit CXCR2 + CD200R + MDSC through secretion of CXCL1/3, thereby amplifying the proliferation and immunosuppressive capacity of this specific MDSC subset via interaction between CD200 and CD200R. Targeted blockade of CD200R improve the inhibitory immune microenvironment by suppressing the immunosuppressive capacity of myeloid suppressor cells. Lastly, combined anti-CD200R1 with radiotherapy sensitized the therapeutic effect of PD-1/L1 antibody in multiple non-immunogenic HCC mouse models. Conclusions: Our studies identify CD200 + macrophages as a crucial immune suppressor that is essential for tumor immune resistance following radiotherapy. These findings unveil a novel mechanism of immune evasion mediated by STING activation, thereby offering a potential target for further optimization of local-immune combination therapy in HCC.