bluuebunny/crossref_metadata_2025_split huggingface dataset:
T cell engager (TCE) score in patients treated with bispecific CD3 TCE in phase I clinical trials.
Authors: Herbel Noé , Goldschmidt Vincent , Michot Jean-Marie , Laparra Ariane , Geraud Arthur , Ouali Kaissa , Danlos Francois-Xavier , Vuagnat Perrine , Bernard-Tessier Alice , Gazzah Anas , Bahleda Rastilav , Hollebecque Antoine , Marabelle Aurelien , Postel-Vinay Sophie , Loriot Yohann , Massard Christophe , Ribrag Vincent , Ponce Aix Santiago , Champiat Stephane , Baldini Capucine 
Published: June 2023

2573 Background: Immune prognostic scores, such as the Gustave Roussy Immune (GRIM) score have been investigated in patients (pts) treated with immune check-point blockers. We aimed to determine whether we could improve the selection of pts that could benefit from new immunotherapies such as bispecific CD3 T cell engagers (TCE) antibodies in pts treated in phase I clinical trials (CT), by building a new prognostic score. Methods: All patients treated with bispecific CD3 TCE in phase I CT from July 2018 to February 2023 at the Drug Development Department at Gustave Roussy were enrolled in the study. Univariate and multivariate analyses (UVA and MVA) were conducted on demographic, clinical and biological data to assess their prognostic value on progression free survival (PFS). MVA results were used to build a new prognostic score (TCE score). This score was then validated on overall survival (0S). The predictive ability (on PFS and OS) of the TCE score was assessed using Harrell’s C index. It was compared with the GRIM and Royal Marsden Hospital (RMH) scores predictive ability on PFS and OS. Results: A total of 67 patients (47 men, 20 women) with metastatic solid cancer or advanced hematological cancer were included. Median age was 62 years old. The most represented tumor types were prostate cancer (33%), lymphoma (25%) and small cell lung carcinoma (24%). UVA on PFS showed that elevated C-reactive protein (CRP) (HR: 2,36; 95%CI: 1,35-4,16; p = 2.10-3) and lactate dehydrogenase (LDH) (HR: 3,00; 95%CI: 1,63-5,53; p = 2.10-4) were associated with a worst PFS. In MVA, LDH (HR: 2,49; 95% CI: 1,30-4,74, p = 1.10-4) and CRP levels (HR: 1,92; 95% CI: 1,1-3,46; p = 1.10-4) were independent negative prognostic factors for PFS. The TCE score was based on MVA results (CRP>10g/l: +1; LDH > 250U/l: +1). It showed that pts with a high score (1-2) had a shorter PFS (median PFS: 2,8 months) and OS (median OS: 9,9 months) than low score (0) pts (median PFS: 5,8 months; median OS: not reached). TCE score’s Harrell’s C index for PFS was 0,63 and 0,64 for OS. For GRIM and RMH scores, Harrell’s C index for PFS were respectively 0,60 and 0,55. For OS it was respectively 0,58 and 0,53. Conclusions: To select patients for Bispecific CD3 TCE phase I CT, we built a new prognostic score, based on LDH and CRP levels, that can be used as prognostic of PFS and OS. TCE score is more reliable than GRIM and RMH scores to prognose PFS and OS.
Use of proteomimetic polymers for delivery of tumor antigens and adjuvants through formation of stable electrostatic complexes with small molecule STING agonists.
Authors: Wang Max Mu , Gattis Brayley , Choi Mi Ran , Zhang Bin , Gianneschi Nathan 
Published: June 2023

2583 Background: Utilizing tumor antigens for the development of patient-specific cancer vaccines has been a promising therapeutic strategy. However, significant challenges remain in delivering subunit vaccine components to elicit antitumor immune responses. To overcome these, we developed rationally designed cancer vaccines using a new nanoplatform called the Protein-Like Polymer (PLP) with unique characteristics that allow for sustained delivery of tumor antigens in conjunction with immunomodulatory compounds. Methods: PLPs containing antigens were synthesized via ring-opening metathesis polymerization (ROMP) and characterized using HPLC, LC-MS, NMR, and GPC. A library of compounds were generated with different sidechain linkage chemistries (amide, ester, or disulfide linkage), DPs, and inclusion of PEG side chains. In vitro assays using gp100-specific T Cells were conducted with fluorescently labeled and non-labeled polymers. In vivo experiments were done using B16 murine melanoma transplanted tumor models. Ability of PLPs to co-deliver immunomodulatory compounds was tested using a small molecule STING agonist 2’3’ cGAMP. Results: Conjugating antigens to the polymer backbone using a cleavable disulfide linkage, designed to be reduced intracellularly, resulted in the best subcellular localization and immune activation (higher levels of immune cell proliferation, cytokine production, and expression of activation markers). Incorporating a diluent amount of PEG side chains increased resistance to enzymatic degradation while improving bioactivity and cell uptake. In vivo studies using PLPs conjugated with melanoma-associated antigen gp100 showed the reductions in tumor size with increased immune cell proliferation and activation in a B16 melanoma model. Additionally, increasing the degree of polymerization, and therefore the density of antigen side chains per unit polymer, improved vaccine efficacy and resistance to proteolysis. Mice treated with STING agonists electrostatically coupled to PLPs showed significantly smaller tumors vs no-treatment at day 14 (0.038g vs 0.76g; p <0.0001) and allowed for subcutaneous administration of the small molecule, which normally must be injected intratumorally. Conclusions: Our work demonstrates the potential of PLPs to overcome inherent difficulties associated with developing cancer vaccines. The modularity of the platform allows for complex nano-architectures including systems capable of delivering challenging compounds, ie small molecule STING agonists, subcutaneously through electrostatic coupling. This technology has the potential to revolutionize cancer vaccinology.
Patient-derived skin MicroOrganoSpheres and clinical response to immunotherapy.
Authors: Chakraborty Rikhia , Fagan-Solis Katerina , DeVilla Jessica , Recaldin Timothy , Bscheider Michael , Gjorevski Nikolche , Fullerton Aaron , Prell Rodney , Khan Zia , Wang Zhaohui , Ding Shengli , Glass Carolyn , Jeck William , McCall Shannon J. , Beasley Georgia , Mohindra Rajat , Hsu Shiaowen David , Chandler G Scott , Shen Xiling , Roth Adrian B ,   ASCO Authors' Group
Published: June 2023

2588 Background: Immunotherapies, including immune checkpoint inhibitors (ICI), have revolutionized the treatment of many cancers, producing significant improvements in survival in patients with many different cancers. However, the intended anti-tumor effects also result in a unique form of autoimmunity, known as immune-related adverse events (irAEs), which have emerged as a limiting factor for many immunotherapies. Cutaneous irAEs (cirAEs), the most frequently occurring ICI–related toxicities, have been associated with improved efficacy and survival but, in their severe forms, require systemic steroids and have in cases led to premature ICI discontinuation and fatality. There is a need for both robust biomarkers and adequate models that effectively predict which patients who develop irAEs may have improved outcomes. Methods: Using a microfluidic droplet technology that generates "mini" patient-derived organoids called MicroOrganoSpheres (MOS), we successfully generated skin MOS from skin biopsy samples in both healthy skin and tumor-involved skin that sustain the original patient skin immune microenvironment over three weeks. Using this model, we assessed skin cell toxicity and cytokine release in response to ICI and targeted therapies. Results: Clinical responses were largely consistent with the skin and tumor MOS assay readouts, indicating that MOS recapitulates the potential association between skin irAEs and efficacy. Matched pairs of patient melanoma and skin MOS showed good concordance with patient outcome indicating that MOS recapitulates the potential association between skin irAEs and efficacy. Enrichment of genes associated with atopic dermatitis, vitiligo, and psoriatic dermatitis were observed in MOS generated from skin of an ICI-sensitive patient compared to the MOS generated from skin of an ICI-resistant patient. These results indicated that the skin MOS platform can potentially predict the dermatological toxicity of ICI. As the MOS assay can be completed within 12 days after biopsy acquisition, this novel technology may enable personalized medicine approaches by prediction of cirAEs and efficacy for individual patients. Conclusions: This is the first study to date demonstrating the application of a patient-derived immune competent skin model deployable for assessing ICI efficacy and toxicity response. Matched tumor skin MOS from the same patients recapitulated the clinically observed association between ICI efficacy and toxicity and may provide key indicators for prospective irAE-predicting clinical trials.
Retrospective analysis on association of ABO blood type and immune checkpoint inhibitor response.
Authors: Batra Akshee , Singh Rohit , Schuetz Samantha R , Gandler Helen , Devine Derek , Barker Jacob , Rehman Hibba tul , Ahmed Shahid Sattar 
Published: June 2023

2596 Background: The presence or lack of a collection of antigenic cell surface markers on red blood cells makes up the ABO blood groups that contribute to various immunogenic neoantigens. Variations in the T-cell diversity and HLA haplotype with different blood types might affect a patient's response to Immune checkpoint inhibitors (ICIs). However, the association between the ABO blood type and ICIs is not well studied. Methods: We did a retrospective observational study to investigate the influence of ABO blood groups on patients receiving ICIs at the University of Vermont Cancer Centre. We examined the medical records of people who received ICIs as first-line therapy between January 2017 and June 2022 and collected demographic data, including age, sex, ethnicity, cancer stage, type and metastasis. We looked at overall survival and the occurrence of immune-related adverse events (irAEs) in different blood type subgroups and calculated relative risks. Results: A total of 288 cases were identified, out of which 169 had documented blood type, including 75 with A, 19 with B, 72 with O and 3 with AB blood type. The mean age was 63.71 years (Standard deviation (SD): 11.52), 58.6% were males, and ethnicity was 94.7% White, 1.2% Asian and 0.6% Hispanic. Lung cancer was most commonly identified at 41%, and 60% of total cancers were stage 4. The median ECOG status was 1 and the Charlson comorbidity index was 6. 36% of cases developed irAEs, whereas mortality was 39% during the study period. The relative risk of irAEs with blood type A and B compared to O was 0.89 and 0.83, respectively but wasn't statistically significant. The relative risk of irAEs of AB compared to O blood type was statistically significant at 2.63 (CI: 1.95-3.54). The relative risk of death in A and B blood types compared to O wasn't statistically significant. No patients in the AB blood group died. Conclusions: Clinically significant association wasn't found between different blood types and irAEs or mortality except for the increased risk of irAEs with AB compared to O. With the rapidly growing use of ICIs, prospective trials are needed to better understand the true risk of developing irAEs in patients with AB blood type. [Table: see text]
A phase 1/2 study of retifanlimab (INCMGA00012, Anti–PD-1), INCAGN02385 (Anti–LAG-3), and INCAGN02390 (Anti–TIM-3) combination therapy in patients (Pts) with advanced solid tumors.
Authors: Hamid Omid , Gutierrez Martin , Mehmi Inderjit , Dudzisz-Sledz Monika , Hoyle Paul Edward , Wei Wendy , Powderly John D. 
Published: June 2023

2599 Background: In cancer treatment (tx), loss of T-cell function is associated with progressive expression of checkpoint (CP) molecules, and resistance or relapse following PD-(L)1 inhibitor therapy is a high unmet need. LAG-3 and TIM-3 are key CP pathways implicated in resistance to PD-1 inhibitors and have shown synergistic effects upon triple inhibition with PD-1 in a murine model. This open-label, nonrandomized phase 1/2 study (NCT04370704) aims to determine optimal doses and preliminary safety and efficacy for the monoclonal antibody combinations of INCAGN02385, INCAGN02390, and retifanlimab. Here we report initial safety and efficacy results. Methods: Study consists of 4 parts in phase 1 and 2 expansion cohorts in phase 2. In phase 1, parts 1 and 2 determined safety of INCAGN02385 350 mg Q2W + INCAGN02390 400 mg Q2W and INCAGN02385 350 mg Q2W + INCAGN02390 400 mg Q2W + retifanlimab 500 mg Q4W, respectively; parts 3 and 4 will test additional dosing schedules. Pts enrolled had previously treated (including PD-[L]1) locally advanced unresectable or metastatic solid tumors, with no prior LAG-3– or TIM-3–directed therapy. Results: As of June 28, 2021, 21 pts were enrolled in parts 1 (n=10) and 2 (n=11); 62% of pts were <65 years and 38% were male. Pts had median 3 (range 1-9) prior lines of therapy, including prior anti–PD-(L)1 (part 1, 8 pts; part 2, 11 pts); pt tumor types are listed. Nineteen pts discontinued tx, 1 due to toxicity. Nine pts in part 1 and 10 pts in part 2 had tx-emergent adverse events (TEAEs), most commonly anemia and diarrhea (each 30%) in part 1 and anemia (36%) in part 2 (all tx-unrelated). Serious tx-related TEAEs occurred in 1 pt in part 1 (grade [G] 3 vasculitis) and 1 pt in part 2 (G3 myocarditis and pericardial effusion). Most common G≥3 TEAE was G3 anemia (part 1, 2 pts; part 2, 3 pts); 1 pt in part 1 had a G5 TEAE of sepsis unrelated to tx, with COVID-19 infection. In part 2, 1 pt had an infusion-related reaction, and 1 pt had immune-related TEAEs of pericardial effusion and myocarditis (both G3 and tx-related), which resolved after steroid therapy and tx discontinuation. Best overall response in part 1 was stable disease, and in part 2 was a confirmed and durable partial response in 1 pt with CP therapy–refractory melanoma. Conclusions: Doublet anti–LAG-3 + anti–TIM-3 and triplet anti–LAG-3 + anti–TIM-3 + retifanlimab regimens in the study were generally well tolerated in heavily pretreated pts, with a safety profile consistent with that of CP monotherapy and no novel toxicities. Optimal doses of both combinations are to be further evaluated in the ongoing study in first-line tx of melanoma. Clinical trial information: NCT04370704 . [Table: see text]
A phase 1B dose escalation study of ETC-159 in combination with pembrolizumab in advanced or metastatic solid tumours.
Authors: Tan David Shao Peng , Ng Matthew C.H. , Subbiah Vivek , Messersmith Wells A. , Strickler John H , diermayr veronica , Cometa Julienne , Blanchard Stephanie , Nellore Ranjani , Pendharkar Vishal , Gan Bong Hwa , Rozaini Nurul Nazihah , Koh Claudia , Sarma Suman , Poh Huay Mei , Lezhava Alexander , SRIRANGAM PRATIVADIBHAYANKARAM VENKATESHAN 
Published: June 2023

2601 Background: ETC-159 is a small molecule porcupine inhibitor, in a prior Phase 1 study was safe as a monotherapy at 16 mg or at 24 mg with the addition of preventive denosumab for bone protection. In this Ph1B open-label trial the safety, MTD, PK and pharmacodynamics (PD) of ETC-159 in combination with pembrolizumab were determined (NCT02521844). Methods: Eligible patients had adequate organ function, advanced or metastatic solid malignancies and had failed standard treatments. Patients’ refractory/resistant to prior PD-1 treatment were allowed and all patients had to have serum β-CTX levels below 600 pg/mL (or <1000 pg/mL and preventive denosumab). Dose escalation followed a 3+3 design with a DLT period of 42 days. ETC-159 was dosed orally QOD in 21-day cycles (8-24 mg); pembrolizumab was dosed IV at 200 mg Q3W. Day 1 and trough PK were determined for ETC-159 and pembrolizumab. Responses were assessed every 6 weeks (RECIST 1.1). Results: 20 patients were enrolled, 6 in the 8 mg cohort and 14 in the 16 mg cohort (50% M and 50% F, mean age of 51.4 y). All patients have been discontinued: 16 due to disease progression; 1 due to AEs, 2 developed contra-indication to denosumab & pembrolizumab, 1 withdrawal of consent. PK parameters of ETC-159 in the first cycle were consistent with prior single agent data. TEAEs were reported in all subjects in the study with most events being grade 1/2, with dysgeusia (65%), β-CTX increase (30%), fatigue (25%), constipation (20%), and nausea (20%) being the most common. DLTs were G3 colitis and G3 immune-related enteritis (16 mg, 2 patients), and pneumonitis and erythema with fever (8 mg, 1 patient). Other drug related SAEs were G2 thyroiditis, hematuria, and thrombocytopenia. No fractures or other drug related skeletal SAEs. Of the 15 evaluable patients, 6 (40%) demonstrated clinical benefit (1 PR, 5 SDs) in combination with pembrolizumab (2 ovarian, 1 lung, 1 pancreatic, 1 urachal, 1 MSS CRC patient with RSPO fusion), at the first assessment, in a predominantly MSS population (65% MSS, 25% unknown, 10% MSI). Pharmacodynamics, (hair follicle Axin2 reduction), was detected at both dose levels and was ≥80% from baseline on D15. Conclusions: ETC-159 + pembrolizumab was well tolerated; 8 mg of ETC-159 in combination with pembrolizumab was determined to be the MTD/RD. Preliminary data suggest Wnt signaling inhibition in combination with checkpoint inhibition may provide clinical benefit in MSS patients. Clinical trial information: NCT02521844 .
The impact of renin-angiotensin-aldosterone system inhibitors on immune checkpoint inhibitor-associated adverse cardiovascular events.
Authors: Chiang Cho Hung , Chiang Cho Han , HSIA YUANPING , Chiang Cho Hsien , Shiah Her-Shyong 
Published: June 2023

2605 Background: Immune checkpoint inhibitors (ICIs) are associated with adverse cardiovascular events that impair patient outcomes. Previous observational studies showed that renin-angiotensin-aldosterone system inhibitors (RAASi) may mitigate the cardiotoxicity associated with chemotherapeutic agents. However, the effects of RAASi on ICI-associated adverse cardiovascular events are unknown. Methods: We conducted a 1:1 propensity score-matched cohort study involving ICI-treated patients at two tertiary referral centers in Taiwan. The propensity score matching model includes age, sex, hypertension, diabetes mellitus, chronic kidney disease, Eastern Cooperative Oncology Group (ECOG) Performance Scale, cancer stage, and cancer type. The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of myocardial infarction (MI), ischemic stroke, peripheral arterial occlusive disease (PAOD), pulmonary embolism (PE), deep venous thrombosis (DVT), heart failure, pericardial disease, myocarditis, and cardiac arrhythmias. The secondary outcomes were arterial thrombotic events (MI, ischemic stroke, PAOD) and venous thrombotic events (PE and DVT). Results: We identified 684 patients eligible for inclusion, from which 164 patients who received RAASi were matched to patients who did not receive RAASi. Over a median follow-up of 9.1 months, the incidence rate of MACE for RAASi and non-RAASi recipients was 6.5 and 13.9 per 100 patient-years, respectively, resulting in an incidence rate ratio of 0.47 [95% CI: 0.21–1.00] (p = 0.038). In a multivariate Cox proportional hazard model adjusting for cancer therapy, RAASi recipients had an approximately 60% reduction in the risk for MACE (HR, 0.37 [95% CI: 0.16-0.86], p = 0.021). In the secondary analysis, RAASi were associated with a reduction in venous thrombotic events (HR, 0.11 [95% CI: 0.02-0.63], p = 0.013), but not for arterial thrombotic events (HR, 0.47 [95% CI: 0.06-3.38], p = 0.45). Conclusions: In patients receiving ICI therapy, the use of RAASi is associated with a decreased cardiovascular risk, particularly for venous thrombotic events. [Table: see text]
The controversial abscopal effect: A single-center experience about the combination of stereotactic radiotherapy with pembrolizumab in patients with metastatic dMMR/MSI-H colorectal cancer.
Authors: Gandini Annalice , Martelli Valentino , Belgioia Liliana , Puglisi Silvia , Cremante Malvina , Murianni Veronica , Damassi Alessandra , Ricciotti Ilaria , Pirrone Chiara , Catalano Fabio , Grassi Massimiliano , Pessino Anna Maria , Pastorino Alessandro , Sciallero Stefania , Puccini Alberto , Sobrero Alberto F. 
Published: June 2023

2608 Background: Colorectal cancer (CRC) patients with mismatch repair system deficiency (dMMR/MSI-H) have shown impressive responses to immune checkpoint inhibitors in any lines of treatment. However, almost 30% of these patients are primary refractory and another 30% develop secondary resistance. Thus, many treatment combinations are being pursued to overcome resistance. One of the proposed strategies is the addition of radiotherapy to immunotherapy based on the potential abscopal effect and its consequent on-target and off-target activity. Methods: Between November 2019 and April 2021, we conducted a prospective interventional single-institution study to assess the feasibility, disease control and safety of the combination of pembrolizumab with stereotactic ablative radiotherapy (SABR) in a cohort of 14 consecutive dMMR CRC patients. SABR was administered in combination within the second or third cycle of Pembrolizumab 200 mg infused every 21 days. SABR was delivered on one or more targetable metastases with the ablative dose of 15 Gy in the first fraction followed by a second fraction of 5 Gy. Results: Fourteen patients were enrolled and 11 received radiotherapy in combination with Pembrolizumab as per protocol. Three patients who started Pembrolizumab never received radiotherapy due to deterioration of their general conditions, leading to death within two months. Two out of these three patients were BRAFV600E mutated. Five patients (35.7%) received Pembrolizumab as first line, 6 (43%) as second line and 3 (21%) as third or later lines. Six out of 14 patients (42.9%) harboured BRAFV600E mutation, 2 out of 14 (14.3%) RAS mutation and the others were RAS/BRAF wild type. Objective response was observed in 4 out of 14 patients (29%) and disease control was achieved in 7/14 patients (50%). Among these, six patients (42%) achieved a disease control lasting more than 15 months. This regimen caused substantial toxicity, mainly linked to SABR. Any grade TRAEs occurred in 50% of patients, with one patient with G1 event, three patients with G2 events, and two patients with G3 events (pneumonia, bowel perforation); no treatment-related deaths were observed. Conclusions: These data do not show hint of added efficacy of Pembrolizumab by SART in unresectable dMMR/MSI-H mCRC.