bluuebunny/crossref_metadata_2025_split huggingface dataset:
Baseline peripheral T-cell composition in relation to radiographic phenotypes of immune-related pneumonitis.
Authors: Henick Brian S. , Bukhari Shoiab , Winchester Robert , Lin Ziyan , Khodadad-Jamayran Alireza , Tsirigos Aristotelis , Lerrer Shalom S. , Adam Kieran , Salvatore Mary M. , Lagos Galina , Pabani Aliyah , Maniar Rohan , Reiner Steven L. , Dallos Matthew , Mathew Matthen , Rizvi Naiyer A. , Mor Adam 
Published: June 2022

2545 Background: Pneumonitis is one of the most morbid complications from immune checkpoint inhibitor (ICI) treatment, but pathogenic mechanisms are unclear and no biomarkers permit pre-treatment risk assessment. We sought to characterize peripheral T cell subsets of pneumonitis patients on the single cell level. Methods: Blood was collected before and during ICI treatment in 24 patients. Cells were processed for single cell RNA sequencing (scRNAseq) employing CITEseq methodology using multiplexed cell surface markers labelled with a cocktail of oligonucleotide-tagged Total-Seq anti-human antibodies against CD4, CD8, CD45RA and CD27 followed by Chromium 10X sequencing. Principal Component Analysis was performed with iCellR, K-nearest-neighbor-based Network graph drawing Layout, and PhenoGraph clustering to assign cell types. CT scans were performed per standard of care and were reviewed by an experienced thoracic radiologist. Results: Seven of 24 patients developed pneumonitis; 9 did not experience an immune-related adverse event, and the remainder experienced arthritis (4), thyroiditis (3), or neurotoxicity (1). Pneumonitis patients had expanded proportions of TH2 TCF7+ T cells at baseline as compared to the other patients. Radiographically, two patients’ pneumonitis manifested as Chronic Hypersensitivity Pneumonitis (CHP), and four had Organized Pneumonia (OP). At baseline, CHP patients had significantly lower levels of CD8+ TCM cells (CXCR3+), double-positive T cells, gamma-delta T cells, and higher levels of naïve-like CD4+ TN TCF7+LEF1+ and CD4+ TH1/2 CXCR3+GATA3+ cells compared to OP. Gene expression levels also distinguished between these radiographic phenotypes. Conclusions: The peripheral T cell composition of patients who developed pneumonitis was distinct from those who did not in our cohort and unique by radiographic manifestation, suggesting potential pathogenic mechanisms and a prelude to circulating predictive markers of ICI toxicity.
LAG3 transcriptomic expression correlates with high levels of PD-1, PD-L1, PD-L2, and CTLA-4 checkpoints and with high tumor mutational burden across cancers.
Authors: Adashek Jacob J. , Kato Shumei , Pabla Sarabjot , Nesline Mary , Conroy Jeffrey M. , Subbiah Vivek , DePietro Paul , Kurzrock Razelle 
Published: June 2022

2561 Background: Lymphocyte Activation Gene 3 (LAG3) or CD223 is an immune checkpoint that can be found on various T cells: CD4+, CD8+, regulatory T cells (Tregs), natural killer T cells, natural killer cells, and plasmacytoid dendritic cells. The expression of LAG3 molecule acts to increase T-cell exhaustion, leading to decreased tumor killing as well as an increase in immune suppressive cytokine release. Many clinical trials of LAG3 inhibitors have had modest effects, but recent data suggests that the LAG3 antibody relatlimab together with nivolumab (anti-PD1) provided greater benefit than nivolumab alone in patients with melanoma. Methods: The RNA expression levels of 397 genes in various types of solid tumors from 514 patients seen at the UCSD Moores Cancer Center were analyzed at a CLIA-licensed laboratory, OmniSeq (https://www.omniseq.com/). Following removal of germline variants, synonymous variants, indels and SNVs with < 5% VAF, TMB is reported as mutations/megabase. Transcript abundance was normalized to internal housekeeping gene profiles and ranked (0-100 percentile) in a standardized manner to a reference population of 735 tumors spanning 35 histologies. Odds ratio for high LAG3 expression was calculated and Bonferroni corrected for multiple genes and cancer histologies with > 40 samples. Results: A total of 116 (22.6%) tumors had high LAG3 (≥75) across 32 different histologies. Cancers with the highest proportion of LAG3 were neuroendocrine (47%), uterine (43%), sarcoma (33%), breast (31%), ovarian (30%), pancreatic (24%), lung (20%), stomach (16%), and colorectal (15%). There was significant association for high LAG3 with high PD-L1 (adj P < 0.001), high PD-1 (adj P < 0.0014), high PD-L2 (adj P < 0.0014), high CTLA-4 (adj P < 0.0014), TMB ≥10 mt/mb (adj P = 0.0504). There was no significant association between histologies colorectal (adj P = 0.1834), breast (adj P = NS), ovarian (adj P = NS), pancreatic (adj P = NS), or gender (adj P = 0.272). Conclusions: High LAG3 was found in almost a quarter of tumor samples and significantly associated with other immune checkpoints with FDA-approved drugs. Ongoing studies combining LAG3 inhibitors and specific immune checkpoint inhibitors may yield more clinical benefit if individualized immunomic transcript interrogation is undertaken, rather than population-based approaches without employment of rationally combined agents matched to each patient’s cancer.
A phase II study to evaluate the safety and efficacy of radiotherapy combined with irinotecan liposome followed by camrelizumab and apatinib for advanced solid tumors that failed standard treatments.
Authors: Shen Jie , Li Rutian , Yan Jing , Du Juan , Wei Jia , Zhu Sihui , Liu Ying , Li Huajun , Liu Baorui 
Published: June 2022

2567 Background: Liposomes deliver the drug to tumors based on enhanced permeability and retention (EPR) effects. Radiotherapy further prompts the distribution of liposomal drugs to tumor sites receiving radiotherapy by altering the tumor microenvironment. In addition, radiotherapy might enhance systemic antitumoral responses to immunotherapy. Herein, we aimed to explore safety and efficacy of radiotherapy in combination with irinotecan liposome, immunotherapy, and antiangiogenic therapy in advanced solid tumors patients (pts) that failed standard treatments. Methods: Anopen single-arm, multi-center, phase II study was conducted to enroll solid tumors pts who have failed standard treatments. Eligible pts would receive radiotherapy combined with irinotecan liposome followed by camrelizumab and apatinib. Radiotherapy of 24 Gy/3 fractions/3-10 days was given to the targeted lesions. Irinotecan liposome (80mg/m2 i.v.) was administered once within 48 hours after radiotherapy and followed by camrelizumab (200mg i.v. q3w) and apatinib (250mg po qd) until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR) of the irradiated lesions evaluated by the investigators as per RECIST V1.1. The secondary endpoints were disease control rate (DCR) and treatment-related adverse event (TRAE). Results: As of Dec 2021, 55 pts were enrolled includin 9 with biliary tract cancer, 8 with pancreatic cancer, 8 with sarcoma, 5 with lung cancer, 2 with liver cancer, 2 with cervical cancer, 2 with gastric cancer, and 22 with other cancer types. 26 (47.3%) pts failed at least 3 lines of therapy before enrollment. The median follow-up was 41 weeks and 42 pts can be evaluated. 15 partial response, 26 stable disease, and 1 progressive disease were achieved. The ORR and DCR of irradiated target lesions were 35.7% and 97.6%, respectively. The ORR and DCR of every cancer type are listed in table. TRAEs (all grades) occurred in 87.3% (48/55) pts. The most common grade 3-4 related TRAEs were lymphocyte count decreased (29.1%), white blood cell count decreased (10.9%), and anaemia (10.9%). Conclusions: The combination of radiotherapy, irinotecan liposome, camrelizumab, and apatinib demonstrated promising anti-tumor activity and well tolerance in various advanced solid tumors that failed standard treatments. Clinical trial information: NCT04569916. [Table: see text]
Breath biopsy early detection of lung cancer using an EVOC probe targeting tumor-specific extracellular β-glucuronidase.
Authors: Labuschagne Christiaan Frederick , Smith Rob , Kumar Neelam , Allsworth Max , Boyle Billy , Janes Sam , Crosbie Phil , Rintoul Robert 
Published: June 2022

2569 Background: Lung cancer is a leading cause of mortality with 5-year survival less than 20%, largely a result of many cases being diagnosed late. Early detection can increase cancer survival up to 13-fold underscoring the need for effective screening. Targeted Low dose computed tomography (LDCT) has been shown to be effective but its impact to date has been limited due to slow adoption and variable uptake in high-risk populations. Breath analysis represents a non-invasive screening approach either alone or alongside LDCT. Numerous studies have investigated potential endogenous breath biomarkers of lung cancer. Many have produced promising results but to date, no validated biomarkers with clear connections to cancer metabolism have been revealed. We have explored an alternative, probe-based approach based around Exogenous Volatile Organic Compound Probes (EVOC Probes). The probes target tumour associated extracellular b-glucuronidase, a glycosidase enzyme that normally resides within lysosomes. Methods: We use a hydrophilic non cell permeable substrate probe D5-ethyl-βD-glucuronide (D5-EtGlu) that upon hydrolysis by the target enzyme releases D5-ethanol, a unique volatile reporter molecule detectable on breath. This provides a readout of tumour associated enzyme activity using breath analysis. Results: Administering D5-EtGlu to mice resulted in tumour specific release of D5-ethanol, enabling discrimination between healthy and tumour bearing animals. Increased expression of b-glucuronidase in lung cancer tissue and the tumour microenvironment was confirmed with immunohistochemistry (IHC) in clinical samples. A phase 1a clinical trial administered D5-EtGlu to healthy individuals in a single ascending dose study to establish safety and background D5-ethanol levels in healthy individuals. This resulted in no adverse events and low/no D5-ethanol signal verifying the inaccessibility of D5-EtGlu to intracellular b-glucuronidase. The next stage, currently ongoing, is a proof of mechanism in humans. D5-EtGlu is administered intravenously to confirmed lung cancer patients followed by breath analysis. D5-ethanol breath levels will be compared to cancer free individuals receiving the same dose of D5-EtGlu. Conclusions: Non-invasive breath testing has great potential to contribute to diagnosis for lung cancer including a potential role in screening. Our current work is evaluating the use of an administered probe to stimulate tumour-specific enzyme activity and produce a marker detectable on breath. Continued success could result in a sensitive and highly specific method for lung cancer early detection.
Phase I study of epacadostat in combination with sirolimus in advanced malignancy.
Authors: Huang Chao Hui , Komiya Takefumi , Kasi Anup , Williamson Stephen K. , Baranda Joaquina Celebre 
Published: June 2022

2575 Background: Epacadostat (E) is an inhibitor of Indoleamine 2,3 dioxygenase-1 (IDO1) which is a rate-limiting enzyme in the catabolism of tryptophan to kynurenine. The inhibition of IDO1 leads to increase tryptophan and reversal of immunosuppression by increasing the proliferation of T cells, suppression of regulatory T cells (Tregs) and activation of mTOR which suppresses autophagy. Sirolimus (S) can reverse the mTOR activation induced by E, suppress the expression of PD-L1 and function of Tregs. We initiated a phase I trial to test the safety and tolerability of SE combination in patients with advanced solid tumors, with plans for an expansion phase II study in patients with advanced recurrent lung cancer once maximum tolerated dose (MTD) was defined. Methods: The phase I trial portion of the study used a modified 3+3 design in which the dose transition rule was similar to standard 3+3 design with the modification based on sirolimus PK data. S had a lead-in of 3mg/day(d) at day -7 followed by 1mg/d with E added on day 1 of Cycle 1 starting at 300mg bid in a 28d cycle at dose level 1; then S is escalated to 6mg/d followed by 2mg/d maintenance with E at 300mg bid at level 2. An additional level 3 was added with S at 6mg/d followed by 2mg/day with E at 400 bid based on results of E at 400-600 mg bid in combination with a checkpoint inhibitor with improved control of peripheral kynurenine and intra-tumoral kynurenine reductions. Enrollment continued until Dose limiting toxicity (DLT) which was defined as grade 3 hematologic toxicities or grade 3 or 4 non-hematologic toxicities up to Cycle 2 day 1. MTD was defined as DLT not exceeding 33% of subjects. Results: The phase I study enrolled 15 patients, with 9 patients evaluable. The types of cancers were non-small cell lung ca (1), colorectal (5), esophagus (1), gallbladder (1) and sarcoma (1). DLT was not observed up to level 3. Adverse events attributed to SE were Grade 1 Diarrhea (2), stomach pain (1); elevated liver enzymes (ELE) (1), decreased white blood cell (1), anorexia (1), hypokalemia (1), dizziness (1), skin rash (1); Grade 2 ELE (1), Anemia (1), Vertigo (1), Constipation (1), Nausea (2); Grade 3: Diarrhea (1), serotonin syndrome (1), dyspnea (1). The best response observed was stable disease in 3 patients, 5 patients had disease progression and 1 patient was not assessable for response due treatment discontinuation related to side effect of serotonin syndrome. The Expansion Cohort (Part 2) did not proceed since the sponsor decided to discontinue further development of E. Conclusions: The combination of SE is feasible, tolerable with mostly grade 1 and 2 toxicities. There were few grades 3 toxicities. SE produced stable disease as best response in 33% of patients. Research using the combination of SE as an immunomodulatory therapy in patients with lung cancer resistant to checkpoint inhibitor is worth additional exploration. Clinical trial information: NCT03217669.
Factors associated with acute kidney injury among patients with cancer treated with immune checkpoint inhibitor therapy: A population-based study.
Authors: Blanchette Phillip S. , Richard Lucie , Shariff Salimah , Raphael Jacques , Earle Craig , Garg Amit , Kitchlu Abhijat 
Published: June 2022

2584 Background: Cancer immune checkpoint inhibitor (ICI) therapy may be associated with kidney immune-related adverse events (IRAEs) and other causes of acute kidney injury (AKI). In clinical trials, the frequency of AKI events was uncommon, however, further real-world study is warranted. Methods: We evaluated the proportion of AKI events among patients with advanced cancer (bladder, head and neck, lung, kidney and malignant melanoma) treated with ICI therapy in Ontario, Canada from 2012 - 2018. AKI was defined by a rise in the concentration of serum creatinine as per Kidney Disease: Improving Global Outcomes (KDIGO) criteria. A multivariable regression model was used to identify predictors of AKI while accounting for the competing risk of death. Results: A total of 4,380 patients received ICI therapy. In follow-up, 1,283 (29%) had recorded AKI event (any stage AKI) and 289 (7%) had a severe AKI event (≥ stage 2). Median time to AKI was 6 months (Interquartile Range 2-16 months) and ≤ 1 % of patients received dialysis therapy. Within 30 days of any observed AKI event, 853 (58%) discontinued ICI therapy, 372 (29%) were hospitalized and 266 (21%) died. Mortality was significantly higher among patients who experiencing a severe AKI event (≥ stage 2) as compared to patients with a less severe AKI event (stage 1) or no observed AKI event. Among patients alive at 30 days following an AKI event, 14% received an outpatient corticosteroid or immunosuppressive therapy prescription, 7% had a visit with a nephrologist. Characteristics associated with a higher risk of AKI included female sex, bladder or kidney cancer (reference malignant melanoma), history of hypertension or diabetes, higher Charlson comorbidity score, a baseline estimated glomerular filtration rate less than 30 mL/min/1.73 m2, or outpatient prescription for either a proton pump inhibitor or non-steroidal anti-inflammatory drug. Among patients with an AKI event and treatment discontinuation, re-challenge of ICI therapy was infrequent (16%) with a significant risk of a recurrent AKI event (57%). Conclusions: In a population-based study among patients with cancer receiving ICI therapy, the rate of AKI was common (29%) but severe AKI was less frequent (7%). Rates of ICI discontinuation, hospitalization and death are substantial following an AKI event. Kidney function should be monitored carefully among patients undergoing ICI therapy who have common risk factors for developing renal disease. Nephrology consultation may be optimized among patients who develop a severe AKI event, especially among individuals who are considered for ICI therapy re-challenge.
Preliminary data from an ongoing phase 1 dose-escalation study of CCX559, an orally administered small molecule PD-L1 inhibitor, in patients with advanced solid tumors.
Authors: Tapia Gonzalo , Lundy Joanne , Richardson Gary Edward , Zhao Niky , Ebsworth Karen , Yue Huibin , Miao Shichang , deGoma Emil , Jain Rita , Schall Thomas J. , Sullivan Kathleen , Zhang Penglie , de Souza Paul L. 
Published: June 2022

2593 Background: The novel small molecule CCX559 is a highly potent and selective PD-L1 inhibitor that induces the dimerization and internalization of cell-surface PD-L1. CCX559, when orally administered in animal models, demonstrated anti-tumor efficacy, including the ability to induce complete responses (Li C, et al. Cancer Res 2021;81(13_Suppl): Abstract nr 1274). Safety pharmacology and toxicology studies in animals demonstrated an acceptable safety profile for CCX559. Taken together, the preclinical data supports the initiation of human trials in patients with advanced solid tumors. PD-(L)1 therapies have been shown to increase peripheral T cell activation and cytokines such as IFNγ and CXCL9 in patients (Herbst RS, et al. Nature.2014; 515(7528):563–567). Methods: This phase 1, first-in-patient, multicenter, open-label, dose-escalation study evaluates safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of CCX559 in patients with refractory, locally advanced or metastatic solid tumors. CCX559 is dosed orally once daily with a starting dose level of 30 mg. Dose escalation/de-escalation is based on the Bayesian Optimal Interval (BOIN) design. PBMC and plasma samples were collected from patients over the first 2 cycles (6 weeks) of treatment, and PD assays were performed, including measurement of cytokines and T cell proliferation. Results: As of February 1, 2022, one patient per cohort was enrolled at the 30 mg and 60 mg levels, and 9 patients were enrolled in the 120 mg dose cohort. Of the 11 patients enrolled, 5 patients (all 120 mg cohort) remain on treatment. No DLTs, treatment-related SAEs, or severe (Grade 3 or higher) treatment-related AEs have been reported. PD assays have been performed with samples from the 30 mg (n=1), 60 mg (n=1), and 120 mg (n=3) cohorts. Patients in all three cohorts showed increased peripheral CD4 and CD8 T cell proliferation starting in the first cycle (21 days) of treatment, as measured by Ki67 positivity. Increases in plasma IFNγ, CXCL9, CXCL10, and CXCL11 levels were observed, in particular in one patient (120 mg cohort) starting 15 days after treatment initiation. Conclusions: Initial results from the phase 1 dose-escalation study of CCX559 indicate on-target PD effects consistent with PD-L1 inhibition. Updated PD data, together with the safety and PK profile, will be presented. Clinical trial information: ACTRN12621001342808.
Cancer PD1/PD-L1 inhibitor efficacy as stratified by smoking status: A population large database study.
Authors: Urdang Zachary D. , Park SoHye , Philips Ramez , Juon Hee-Soon , Johnson Jennifer Maria , Martinez-Outschoorn Ubaldo E. , Curry Joseph M. 
Published: June 2022

2594 Background: Delineating clinical factors that predict immune checkpoint inhibitor (ICI) cancer therapy response is a pressing need and smoking is a known factor. In this study we leveraged a large international (heavily US) database to perform the largest study to date for all cancers and major cancer sub-sites/types. Methods: Utilizing the TriNetX electronic health records database with 84.3M patients we tested the hypotheses that ICI response stratifies based on smoking, and continued smoking after ICI. Queries were constructed using billing codes for all cancer types treated with an ICI with and without smoking. The smoking cohort was subsequently sub-stratified for continuing vs cessation of smoking after ICI. Next, using ICI therapy as the index event, odds ratios (OR) with 95% confidence intervals for death, and treatment related secondary outcomes were calculated between 0.5-5 years after ICI treatment. Statistics were calculated using TriNetX's integrated statistical platform before and after 1:1 propensity score matching (PSM) for smoking related co-morbidities. Results: The OR for death after ICI therapy for smokers ( n 13336) vs non-smokers ( n 38973) for any cancer type was 1.27(1.21-1.34) and decreased to 1.11(1.04-1.19) after PSM. Further sub-stratifying the smoking cohort for continued vs cessation of smoking yielded ORs of 1.13(1.03-1.24) and 1.12(1.01-1.24) before and after PSM respectively. Secondary outcomes included ablative surgery, chemotherapy, radiation, and secondary neoplasm. ORs for receiving chemotherapy, and developing secondary neoplasm were most consistently statistically significant across comparisons. Conclusions: Smoking adversely potentiates cancer outcomes after ICI therapy. PSM for smoking related comorbid conditions decreased the magnitude of this association although the findings remained clinically and statistically significant. This highlights the key role in smoking related co-morbid conditions as prognostic clinical characteristics. Furthermore, this suggests that smoking affects ICI on a mechanistic/biological level beyond increasing burden of medical comorbidities. Lastly, as smoking cessation also improved outcomes after PSM this further suggests that washout of smoke toxins has a mechanistic/biological effect on ICI activity. [Table: see text]