bluuebunny/crossref_metadata_2025_split huggingface dataset:
Auto-reactive antibodies as predictive markers for immune checkpoint–induced pneumonitis.
Authors: Altan Mehmet , Wang Qi , Li Quan-Zhen , Zhu Chengsong , Tran Hai T. , Sheshadri Ajay , Gandhi Saumil , Antonoff Mara , Swisher Stephen , Vokes Natalie I , Spelman Amy R. , Lee J. Jack , Zhang Jianjun , Heymach John 
Published: June 2022

2554 Background: Certain immune-related adverse events (irAEs) that emerge with immune checkpoint blockade share clinical features of autoimmune conditions. Preexisting auto-reactive antibodies and their contribution to irAEs have not been well defined, and observations are limited. Methods: We longitudinally collected patient plasma samples from a clinical trial that combines immune checkpoint inhibitors, Ipilimumab, and Nivolumab (I+N) with subsequent radiation therapy (Lonestar, NCT03391869). Plasma samples were collected at baseline, after 12 weeks of I+N (induction), and at the time of Grade ≥ 2 pneumonitis (CTCAEv5.0). Auto reactive antibody profiles were analyzed using a fluorescence-based assay system that measures more than 130 antigens and is capable of assaying antibody reactivity for IgG and IgM fractions, including nuclear-cytosolic and tissue-specific antigens. Selected antibodies had a reportable result range, reference intervals, and reproducibility with quality controls. A paired t-test was used to compare the mean of longitudinally collected baseline and toxicity samples. An unpaired t-test was used to compare differences between groups. The False Discovery Rate was used to control the Type I error rate of multiple comparisons. Results: In the study cohort, G≥2 pneumonitis was observed in 11 patients out of 194 (5.6%). Serum was collected at baseline for all 11 patients, and 9 of the 11 patients had a serum sample collected at the time of pneumonitis event. Longitudinal serum samples (baseline and post-induction) collected from 32 patients without any irAEs were used as control. At baseline AChR3 and calmodulin antibodies were elevated in patients who developed pneumonitis, compared with baseline samples from controls (p≤0.05). At the time of pneumonitis IgM antibodies against AChR3, CXCL10, NSE, BAFF, CA242, Cytokeratin 19 were noted to be elevated in serum for pneumonitis cases compared with post induction samples from control (p≤0.005). Conclusions: We identified auto reactive antibodies associated with a higher risk of immunotherapy associated pneumonitis in patients treated with ipilimumab and nivolumab. These included auto reactive antibodies against proteins associated with lung injury (AChR3), lung inflammation (BAFF, CXCL10) and against alveolar epithelium (Cytokeratin 19). Future studies are warranted to determine if auto-reactive antibodies can be used as pre-treatment risk markers or to diagnose pneumonitis and may offer insights into to mechanisms that predispose toward pneumonitis.
Assessment of a 4-chemokine signature in prediction of T-cell inflammation and response to immune checkpoint inhibition across tumor types.
Authors: Romero Joan Miguel , Titmuss Emma , Wang Yifan , Vafiadis James , Pacis Alain , Jang Gun Ho , Zhang Amy , Golesworthy Bryn , Lenko Tatiana , Williamson Laura , Grunwald Barbara , O'Kane Grainne M. , Wilson Julie , Gallinger Steven , Laskin Janessa J. , Zogopoulos George 
Published: June 2022

2558 Background: Immune checkpoint inhibitors (ICI) are highly effective in select cancers. Novel predictors of T cell-inflammation may identify a broader subset of tumors with ICI responsiveness. Our group has identified four chemokines (CCL4, CCL5, CXCL9, CXLC10) able to predict a T cell-inflamed phenotype in primary and metastatic pancreatic tumors. Here, we test whether this 4-chemokine signature can predict T cell-inflammation across additional tumor types and response to ICI. Methods: Using matched genomic and transcriptomic data from 6,455 patients spanning 25 tumor types from The Cancer Genome Atlas, we searched for associations between the 4-chemokine signature and metrics of antitumor immunity. Further, we tested the association of this signature with markers of DNA damage repair deficiency. We also investigated the ability of this signature to predict response to immunotherapy using real-world data from a pan-cancer cohort of 82 patients in the Personalized OncoGenomics Program who had received ICI. Results: The majority of tumor types displayed sub-populations with high expression of the 4-chemokines (4-chemokinehi) and transcriptional hallmarks of the cancer-immunity cycle. Testicular germ cell tumors, cervical squamous cell carcinomas, and head and neck squamous cell carcinomas were the strongest expressors of the signature. Immunomodulatory genes, including PD-L1, PD-1, TIM3, LAG3, TIGIT, CTLA-4, and FASLG, were significantly overexpressed (p<0.05) in the 4-chemokinehi cohorts. Genesets of processes involved in the cancer-immunity cycle, including MHC I expression and cytolytic activity, were upregulated in the 4-chemokinehi cohorts (p<0.05). While a global relationship between tumor mutation burden (TMB) and 4-chemokine expression across tumor histological type was seen (rho=0.42, p=0.02), high TMB was associated with only a subset of 4-chemokinehi tumors. Among patients treated with ICIs, those with 4-chemokinehi tumors had a longer median time to progression (104 versus 71 days, p=0.013) and overall survival (391 versus 195 days, p=0.016). The 4-chemokine signature outperformed TMB for overall survival prediction. Conclusions: Sub-populations of T cell-inflamed patients exist across tumor types and may therefore respond favourably to ICI. The 4-chemokine signature has the potential to select a wider spectrum of patients that may benefit from ICIs. [Table: see text]
LB101, a conditionally tetravalent PD-L1xCD47 bispecific monoclonal antibody (mAb), combines tumor microenvironment (TME) targeted delivery (PD-L1) and a single biological high potency effector (CD47).
Authors: Finlay Jonny , Yver Antoine , Chivers Simon , Grainger David 
Published: June 2022

2562 Background: Anti-PD-L1 antibodies are well-established as potent immune effectors in solid tumors expressing PD-L1 and demonstrate binding to these tumor cells within the TME. By contrast, due to the ubiquitous expression of CD47 on normal cells and tissues, anti-CD47 therapeutic agents with an active antibody Fc can lead to serious dose-limiting toxicities and profound biodistribution problems. To overcome these issues, we have generated LB101, a next-generation conditionally activated PD-L1xCD47 bispecific mAb with two anti-CD47 domains blocked by two further anti-PD-L1 domains, linked by two proprietary IgG-derived hinges, which inhibit CD47 interactions in the periphery, but are degraded in the PD-L1+ TME, thereby activating CD47 blockade to induce antibody-dependent cellular phagocytosis (ADCP). Methods: An IgG1-based, conditionally activated bispecific molecule was examined in binding, phagocytosis, PD-L1 blocking and flow cytometry assays. Efficacy analyses were performed in an hPD-L1+ syngeneic model in hPD-L1+/hPD1+ C57BL/6 mice, and preliminary safety and exposure analyses were completed in monkey. Results: In its intact locked form, LB101 exhibited anti-PD-L1 assay potency similar to atezolizumab. CD47 binding was only observed for LB101 after unlocking by hinge linker cleavage, leading to strongly enhanced ADCP by human CD14+ cells. In monkey, plasma stability of the locked construct was established with a PK profile mimicking that of a typical PD-L1 mAb. In the MC38 mouse model, systemically administered LB101 monotherapy delivered at equimolar dose to atezolizumab, led to no anemia, weight-loss, or overt toxicity. Monotherapy LB101 exhibited greatly improved efficacy and durability of response (14/16 tumors eradicated) over isotype control IgG (0/16) and atezolizumab (1/16). The CD47 naked parent IgG1 mAb was not tolerated in mouse, with 100% lethality above 2mg/kg. In rechallenge experiments, all naïve mice established tumors rapidly while none of the mice from groups with prior LB101-induced regressions exhibited tumor growth. Conclusions: Single agent LB101 immunotherapy delivered systemically in a difficult to treat syngeneic mouse model resulted in PD-L1 directed, local tumor-specific CD47 effector engagement leading to significant tumor regressions as compared to atezolizumab without overt toxicity. Future developments will focus on developing LB101 as a single agent therapeutic and exploring the potential of LockBody technology in improving the therapeutic index of other anti-cancer biological effectors through conditional activation within the TME.
Micro-organospheres retain patient tumor microenvironment for precision immuno-oncology.
Authors: Ding Shengli , Natesh Naveen R. , Spiller Kassandra , Xi Rui , Nelson Daniel , Gjorevski Nikolche , Walz Antje , Marrer-Berger Estelle , Clevers Hans , Hsu Shiaowen David , Shen Xiling 
Published: June 2022

2573 Background: Current patient-derived organoid (PDO) models are largely devoid of immune components. We developed a precision microfluidic and membrane platform to generate patient-derived micro-organospheres (MOS) that retain tumor-resident immune and stromal components for personalized immuno-oncology (IO) assays. Methods: MOS were generated from lung, kidney, and colorectal cancer patients. The composition and function of patient tumor-resident immune cells in MOS were characterized by flow cytometry, single-cell RNA-seq, antibody staining, and TCR-seq. High-content and longitudinal imaging with AI analyses were used to quantify tumor cell death and immune cell dynamics inside MOS in response to IO therapies including checkpoint inhibitors, T cell bispecific antibodies, and adoptive tumor infiltrating lymphocyte (TIL) therapies, followed by single-cell analyses. Results: Tumor and stromal cells quickly form tissue niches inside MOS to sustain the viability and function of encapsulated immune cells. MOS derived from lung and kidney cancer patients respond to Nivolumab, indicated by the Annexin V apoptosis marker. ESK1* (TCB antibody targeting HLA-A2/WT1) induces killing in eight lung tumor patients derived MOS. We further developed a MOS T-cell potency assay as autologous TILs or PBMC efficiently infiltrate MOS from lung, kidney and CRC patients and induce tumor cell apoptosis. Adjunctive therapies combining TCB with TILs enhanced the potency of adoptive cell therapy against lung tumor. Based on the data, three ongoing and upcoming personalize IO clinical trials will further validate the ability of the MOS assay to predict patient response to TCB, checkpoint combinations, and adoptive cell therapy. Conclusions: MOS provide a rapid and scalable personalized platform for developing and testing IO therapies such as checkpoint inhibitors, bispecific antibodies, and T cell therapies on patient tumor models that still retain the original tumor microenvironments.
Preliminary results from an early phase trial of in situ immunization of lymphoma with a virus likeparticle containing a TLR9 agonist combined with anti-PD1 therapy (NCT03983668).
Authors: Farooq Umar , Ayyappan Sabarish Ram , Yin Chaobo , Lemke-Miltner Caitlin , Smith Brian J. , Link Brian K. , Weiner George J. 
Published: June 2022

2639 Background: In situ immunization involves intratumoral (IT) injection of immunostimulatory agents to modify the tumor microenvironment with the goal of inducing an anti-tumor T cell response. Here, we report preliminary results of a clinical trial exploring in situ immunization with a virus like particle (VLP) combined with systemic pembrolizumab (Pembro) in lymphoma. The VLP, known as CMP-001 or vidutolimod (Vidu), is composed of the bacteriophage Qb capsid encapsulating the TLR9 agonist G10. Preclinical studies demonstrated generation of antibodies against the Qb capsid (anti-Qb) is necessary for Vidu to induce an anti-tumor response. In other cancers, early phase clinical trials of in situ immunization with Vidu, with and without systemic anti-PD1 therapy, have revealed early promising results. Methods: This trial included patients with relapsed lymphoma that have failed at least 1 line of therapy. The first dose of Vidu is given subcutaneously to stimulate anti-Qb that opsonizes the VLP. This is followed by IT Vidu administered weekly for seven doses, then at 3-week intervals. Pembro (200 mg fixed dose) is given intravenously every 3 weeks. Subjects continue treatment if they do not experience unacceptable toxicities and in the investigator’s opinion continued treatment is in the subject’s best interest. Fine needle aspirates for flow cytometric analysis are obtained prior to therapy and 4-6 weeks following initiation of therapy. Results: Six patients have enrolled to date (1 CR, 2 PR, 1 SD, 2 PD). The first 3 patients received 5mg Vidu per dose and the second cohort 7.5 mg per dose. Common side effects included chills, rigors, mild headache, and fatigue. These typically resolved within 4 hours after receiving the injection. Conclusions: In situ immunization with Vidu plus systemic anti-PD1 is a promising therapy in lymphoma. The ability to generate anti-Qb that opsonizes the VLP appears to be necessary for Vidu to induce an immune and therapeutic response. Accrual and correlative studies are continuing with the modification that generation of functional-Qb after the first dose of Vidu is required before patients receive IT therapy. Clinical trial information: NCT03983668. [Table: see text]
Comparison of the checkpoint inhibitor pneumonitis incidence between immunotherapy alone or in combination with chemotherapy for lung cancer: An observational, retrospective pharmacovigilance study.
Authors: Xu Pei-Hang , Zheng Yi-Fan , Li Zi-mu , Kuang Yu-Kun , Tang Ke-Jing 
Published: June 2022

2655 Background: Clinical trials lack direct cross-comparison in safety between immune checkpoint inhibitor (ICI) as monotherapy and in combination with chemotherapy. The adverse event of checkpoint inhibitor pneumonitis (CIP) is an important factor influencing the treatment decision making. We performed a real-world pharmacovigilance study in the US Food and Drug Administration Adverse Event Reporting System (FAERS) to determine if ICI combination therapy is superior to monotherapy for lung cancer patients in terms of CIP incidence. Methods: The database of lung cancer patients receiving ICI between 2015 and 2020 was extracted for this study. The strategy-specific durations of the pneumonitis event were compared using the Kaplan-Meier method. Reporting odds ratio (ROR), a surrogate measure in disproportionality analysis, was used to assess the signal of CIP between ICI treatment strategies. Results: A total of 27,882 lung cancer patients with reported adverse events were involved. Among them, 1763 (6.3%) CIP after ICIs therapy were identified. In general, ICI usage was associated with over-reporting frequencies of CIP, but this association was no longer significant after adjustment (ROR: 1.14, 95%CI 0.86-1.49). The median times to CIP occurred early after therapy onset, either in ICI monotherapy or in combination with chemotherapy (41 days and 37 days, log-rank p>0.05). Different reporting frequencies emerged when we further compared different ICI strategies. Combination therapy with anti-PD-1 and chemotherapy was associated with a higher CIP incidence compared with anti-PD-1 monotherapy (ROR: 1.86, 95%CI 1.37-2.51), whereas anti-PD-L1/ CTLA-4 medications had lower risks in combination with chemotherapy (ROR: 0.31, 95%CI 0.16-0.56 and ROR: 0.41, 95%CI 0.09-1.22). Subgroup analyses on those with recorded therapy duration also indicated that reports of CIP were significantly lower with combination therapy of PD-L1 and CTLA-4 (ROR: 0.52, 95%CI 0.36-0.74 and ROR: 0.22, 95%CI 0.09-0.51 respectively). Conclusions: Compared with ICI monotherapy, the combination with chemotherapy might have an acceptable risk of CIP. Anti-PD-1 medications with additional chemotherapy could increase the risk of pneumonitis, whereas the risk was lower in the combination strategy with anti-PD-L1/CTLA-4. The combination might be a better therapeutic strategy than ICI monotherapy in treating lung cancer, regarding the CIP incidence. [Table: see text]
Efficacy proof-of-concept from a phase 1 study of a novel therapeutic peptide, ST101, targeting the oncogenic transcription factor C/EBPβ in patients with refractory solid tumors.
Authors: Evans T.R. Jeffry , Lakhani Nehal J. , Arkenau Hendrik-Tobias , McKean Meredith , Symeonides Stefan N. , Iwamoto Fabio Massaiti , Rotolo Jim , Capiaux Gina , Michel Rob , Kaesshaefer Stephen , Bexon Alice Susannah , Falchook Gerald Steven 
Published: June 2022

3014 Background: The oncogenic transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) promotes tumor survival and proliferation and inhibits differentiation. ST101 is a peptide antagonist of C/EBPβ, with anti-tumor activity in prostate cancer (PC), glioblastoma (GBM), breast cancer (BC), melanoma, and other pre-clinical models. Methods: This phase 1 study enrolled patients (pts) with refractory solid tumors with varying histologies. The primary objective was to evaluate safety/tolerability of ST101 and to determine the recommended phase 2 dose (RP2D). Secondary and exploratory objectives included pharmacokinetics (PK), preliminary efficacy (RECIST 1.1), and pharmacodynamic (PD) evaluation. The study used a 3+3 dose-escalation design, with once-weekly IV infusion dosing of ST101 at 0.5, 1, 2, 4, 6, 9 mg/kg or a flat dose of 500 mg. Results: Enrollment in phase 1 was completed in November 2021 with a total of 25 pts with multi-metastatic disease that were refractory to standard therapy. As of February 15, 2022, five pts remain on study with a median treatment duration of 27 weeks’ (16-77). There were no DLTs, dose modifications, or serious adverse events (SAEs) related to ST101. The only AEs of note were G1-2 histaminergic infusion-related reactions (IRRs), largely pruritis and urticaria, managed with antihistamines, montelukast, and interruption/slowing of infusion. IRRs affected 93% of pts on the first dose at ≥4mg/kg and led to prolongation of infusion time. Intensity and frequency of IRRs decrease with repeat dosing. No other AEs were consistently reported. There was no evidence of accumulation upon continued exposure of ST101 and no anti-drug antibodies. Tumor immunohistochemistry showed dose-proportionate staining for ST101 and decreased tumor proliferation in several pts represented by decreased Ki67 expression. Population PK analysis supported flat dosing in phase 2. Five pts continue on treatment with one confirmed partial response in a patient with cutaneous melanoma lasting >42 weeks and four pts with ongoing stable disease. Conclusions: ST101 demonstrated safety at all doses explored and evidence of efficacy across dose levels, particularly higher doses and in pts with melanoma. PK and PD support a dose relationship for efficacy and selection of 500 mg as the RP2D. Pts are now enrolling in phase 2 cohorts to assess response in cutaneous melanoma, GBM, castrate-resistant PC, and HR+ BC. Clinical trial information: NCT04478279. [Table: see text]
VEGF inhibitors (VEGFi) activity in liver metastases (mets) regardless of primary cancer type: Meta-analysis and systematic review.
Authors: Pires Da Silva Ines Esteves Domingues , Lo Serigne N. , Conway Jordan W. , Scolyer Richard A. , Carlino Matteo S. , Menzies Alexander M. , Long Georgina V. 
Published: June 2022

3024 Background: Liver metastasis is a poor prognostic factor in several cancers and is associated with poor response to immunotherapy (IO) in melanoma and lung cancer. VEGFi have activity in hepatocarcinoma (HCC) and is hypothesized to be due the hypoxic microenvironment. Whether this is also true for liver mets is unknown. We sought to assess the efficacy of VEGFi in liver mets utilizing randomized-controlled clinical trials (RCTs) testing the efficacy of VEGFi, regardless of primary cancer site. Methods: Systematic searches of PubMed, Cochrane CENTRAL, and Embase were conducted from January 1, 2000, to January 1, 2022. All RCTs that compared a backbone of systemic therapy (chemotherapy [chemo] and/or IO and/or targeted therapy [TT]) or best supportive care (BSC) with vs without VEGFi in patients (pts) with liver mets from any cancer were selected. HCC trials were excluded. Study design, cancer type, number of pts, lines of treatment, study drugs and hazard ratios (HRs) with 95% CIs for overall survival (OS) and progression-free survival (PFS) were extracted. Pooled effects of VEGFi in pts with liver mets across different cancer types were estimated using random effect model with inverse variance. Heterogeneity between studies was assessed by I2 statistics. Sensitivity analyses were performed considering prespecified subgroups of trials. Results: 3170 pts with liver mets from 19 RCTs were included in this meta-analysis: 8 colorectal cancer, 4 non-small cell lung cancer, 4 renal cell cancer & urothelial cancer, 1 pancreatic cancer, 1 GIST and 1 gastric cancer. Backbone systemic therapy in these trials included: chemo (11), TT (2), IO (2), chemo+IO (1), chemo+TT (1); and 2 BSC trials. Moderate heterogeneity between studies for both PFS (I2= 55%) and OS (I2= 46%) was seen. The addition of VEGFi to standard systemic therapy or BSC was associated with superior PFS (HR = 0.61; 95% CI, 0.50-0.74; p < 0.0001) and OS (HR = 0.86; 95%CI, 0.76-0.99; p = 0.0334) in pts with liver mets, regardless of whether pts had only liver mets or concurrent other sites of mets. In the subset of RCTs with data on pts without liver mets, the benefit with VEGFi was more pronounced in patients with liver mets (HR = 0.56) vs those without liver mets (HR = 0.64) for PFS, but not for OS. Conclusions: The addition of VEGFi to standard management improved survival outcomes in pts with liver mets across different cancer types and warrants further investigation. VEGFi added to IO may be effective in pts with resistant liver mets.