bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tracking of tumor-derived exosomal PD-L1 for cancer diagnosis and surveilance of immunotherapy response by dual-aptamer-encoded nanocatalyst assembly.
Authors: Zeng Tianyu , Shi Hai , Sun Chunxiao , Yang Fan , Li Wei , Liang Yan , Fu Ziyi , Yin Yongmei 
Published: June 2022

e14528 Background: Immunohistochemistry is still the gold standard for identifying suitable populations for ICB therapy by staining PD-L1 in tumor tissue. However, IHC may be frustrated by intratumoral heterogeneity, subject to sampling error, and risk damaging tissue. Application of tumor-derived exosomal PD-L1 (Exo-PD-L1) for searching suitable populations for immunotherapy and monitoring immunotherapy response in breast cancer is often hindered by normal cells-derived Exo-PD-L1and the limitation of existed tools. Methods: We have developed a dual-target-specific aptamer recognition activated in situ hybridization chain reaction (HCR)-weaved nanocatalyst assembly (TRACE) on exosome for visualized tracking of Exo-PD-L1. Leveraging theexcellent selectivity of dual-aptamer recognition, high sensitivity of HCR-encoded nanocatalyst assembly, and high accessibility of color changes-based analysis. The clinical significance of tumor-derived Exo-PD-L1 were evaluated in a small cohort of clinical samples (4 healthy donors (HDs), 20 PD-L1-negative (PD-L1-N) breast cancer patients, and 10 PD-L1-positive (PD-L1-P) breast cancer patients) by using this TRACE system. All serum is collected and CT is scanned at approximately every 2 cycles. Results: The TRACE system can accurately distinguish PD-L1-positive breast cancer patients from healthy donors and PD-L1-negative patients by selectively and sensitively detecting tumor-derived Exo-PD-L1, with the most appropriate cutoff value of 0.6168 and 0.3603, respectively. The receiver operating characteristic (ROC) curve demonstrates the excellent accuracy (AUC: 1) of this TRACE system due to the high sensitivity and specificity. Moreover, the TRACE system provide a quantified and visualized tool for dynamically revealing immunotherapy response based on the levels of tumor-derived Exo-PD-L1, including stable, progressive, and partial response. Conclusions: The TRACE system may have a great potential for supplementing the existing standards and assisting to screen appropriate patients for ICB therapy and explore situable patients from different therapeutic regimenin-depth. As a companion diagnostics tool, the TRACE system may also rise great hope for improving the management of dosage, therapeutic regimen, and efficacy evaluation by providing timely feedback of immunotherapy response.
The mobilization of endogenous bi-specific natural killer T-like cells and independent of glucocorticoid receptor activation related to acute supra-pharmacologic weight-based dexamethasone (AVM0703) and 18 mgs/kg body weight.
Authors: Deisher Theresa , Jarzyna Peter , Poulin Kendra , Zahid Yumna , Ashok Arya , Sawas Spencer , Pathak Manisha , Rylatt Colleen , Parthasarathy Vaishnavi 
Published: June 2022

e14545 Background: Glucocorticoids (GC) are a common component of blood cancer regimens, at doses 40 mg or lower due to concerns of pancreatitis and hepatotoxicity (Walasik-Szemplińska et al. Thyroid Research (2019) 12:13; Ataallah et al. Cureus. 2020 Jul; 12(7)) and neuropsychiatric effects. AVM Biotechnology has developed a high concentration, high volume, preservative-free, patent pending formulation of dexamethasone (Dex) (AVM0703), allowing administration up to 21 mg/kg (1470 mg for 70 kg) in one-hour IV infusion. Prophylactic use of physiologic hydrocortisone reduces the risk of GC neuropsychiatric side-effects (Warris, L. T. et al. J. Clin. Oncol. (2016) 34:2287; Meijer & de Kloet Endocrinology (2017) 158:448). At supra-pharmacologic doses (>6 mg/kg) AVM0703 mobilizes endogenous bispecific gamma delta invariant TCR+ Natural Killer T-like cells (AVM-NKT) (PCT/US21/19773), via a non-GC receptor, that rapidly home to cancer in tumor models and are directly related to tumor killing. GCs have been reported to induce biological responses independent of GCRs: corticosterone has been shown to bind a G-protein coupled receptor that does not bind either Dex or aldosterone (Mitre-Aguilar, et. Al International Journal of Clinical and Experimental Pathology (2015) 8:1; Powell, C. E., et. Al. Endocrine (1999) 10: 271) and the non-GCR mineralocorticoid receptor has high affinity for prednisone but not Dex. Methods: a) Mouse splenocytes or human whole blood were incubated with Dex from 1nM to 1mM. Apoptosis was measured for human whole blood by CBCs and for mouse splenocytes by flow cytometry 4 to 6 hours later. RU486 was used to block expected transmembrane (tm)GCR activity. b) Naïve, tumor bearing and humanized mice were dosed with AVM0703 at human equivalent doses (HED) >18 mg/kg. Depending on the disease state of the mice, novel AVM-NKT were observed in the blood between 3 and 96 hours later, determined by flow cytometry. Results: a) Apoptosis via the tmGCR was observed at expected concentrations between 10nM and 100uM and was blocked by the GCR antagonist RU486. At concentrations above 250uM, which correspond to in vivo peak blood levels from acute 7mg/kg and greater, no Dex-induced apoptosis was observed. b) Acute supra-pharmacologic AVM0703 induced the appearance of CD3+, CD56+, gdTCR+, invariant TCR+ bi-specific Natural Killer T-like cells, that in a cancer setting also expressed activation markers like CD16 and NKp44. Intriguingly, the AVM-NKT also express B220 in certain settings, and CD3+ B220+ DP has been indicative of IL-2 or IL-12 lymphoma killing (Masztalerz, A, et. Al. Anticancer Res (2004) 24(5A):2633). Conclusions: CBC’s and clinical chemistries from enrolling clinical trial confirmed the in vitro non-GCR findings.
Efficacy of the novel treatments of BCC with bone metastasis.
Authors: Esmaeil Pour Mohammad Ali , Mohebtash Mahsa , Amin Ali , Khayyat Azadeh , Khalili-Toosi Amir-Reza , Mousavi Seyedreza , Guo Mengni , Liu Jieying 
Published: June 2022

e14547 Background: Eighty percent of nonmelanoma skin malignancies are basal cell carcinomas (BCC). Metastasis in BCC is about 0.0028 to 0.55. Diagnosis and treatment of metastatic BCC is challenging due to its rarity. In approximately 85% of metastatic BCC, the most common metastatic organs are lymph nodes. Methods: We reviewed 31 skin BCCs with bone metastasis in the past 60 years and 10 observation studies on the efficacy of Sonic hedgehog inhibitors (SHHis). We focused on treatment and outcome of 31 metastatic BCC. Results: The main treatment option was surgery and radiotherapy is a palliative option. Among chemotherapeutic and immunotherapeutic agents, SHHis (e.g. vismodegib and sonidegib) appear to be effective, with reported ORR of 43-100%, and CRR range of 3%-54%. In locally advanced BCCs, vismodegib shows 10 times higher CRRs compared to sonidegib, although ORRs were similar. In metastatic BCC, overall response to vismodegib was three times higher. The common adverse effects of SHHis limit their administration. Conclusions: BCC is a common skin neoplasm that rarely demonstrates metastasis. Among the chemotherapy agents administered, vismodegib appears promising.[Table: see text]
Drug-free biodegradable nanoparticles alleviate myeloid cell-induced immunosuppression and inhibit metastasis.
Authors: Ma Jeffrey , Raghani Ravi , Zhang Yining , Orbach Sophia , Murthy Tushar , Podojil Joseph , Elhofy Adam , Shea Lonnie 
Published: June 2022

e14555 Background: Metastasis is responsible for most cancer-related deaths and depends on the formation of a metastatic niche at distal sites. The metastatic niche consists primarily of immunosuppressive myeloid cells, such as neutrophils and monocytes. These cells are recruited to distal sites in response to cancer-induced immune dysregulation and promote the recruitment and survival of disseminated tumor cells. We have employed drug-free poly(lactide-co-glycolide) (PLGA) nanoparticles, ONP-302, to modulate myeloid cell phenotypes and trafficking to disrupt the formation of the metastatic niche. The anti-metastatic efficacy of ONP-302 nanoparticles was evaluated in a translationally relevant mouse model of orthotopic triple-negative breast cancer. Methods: ONP-302 nanoparticles were evaluated in the syngeneic 4T1 model of triple-negative breast cancer in female BALB/c or RAG1KO BALB/c mice. ONP-302 nanoparticles intravenously injected into tumor-bearing mice every 3 days starting 1 day after tumor inoculation. Lungs were extracted 14 and 21 days after inoculation for analysis by single cell RNA sequencing and quantification of metastases by luminescent imaging, respectively. In resection studies, primary tumors were resected 11 days after inoculation and tissues were extracted 42 days after resection for quantification of metastases. Results: ONP-302 nanoparticles significantly reduced primary tumor growth and completely inhibited the formation of lung metastases. ONP-302 was also effective at suppressing metastasis when applied following surgical resection. In mice which received ONP-302 after surgical resection, lung metastases were undetectable up to 42 days after resection, while 44% of control mice developed metastases. These findings suggest that ONP-302 targets both primary tumor growth and metastatic colonization. Single cell RNA sequencing was employed to analyze ONP-302 modulation of the lung metastatic niche. The lungs of ONP-302 treated mice had lower neutrophil infiltration and a higher proportion of monocytes and dendritic cells compared to control mice. Gene expression pathways associated with inflammatory interferon and tumor necrosis factor responses were upregulated in neutrophils, monocytes, and dendritic cells from ONP-302 treated mice. The upregulation of these pathways suggests that ONP-302 treatment prevents the formation of an immunosuppressive niche and promotes anti-tumor cytotoxicity. Adaptive immunity was essential for ONP-302 efficacy, as T and B cell deficient RAG1KO mice demonstrated complete loss of ONP-302 efficacy both in slowing primary tumor growth and preventing metastasis. Conclusions: Our findings demonstrate that our drug-free PLG nanoparticles, ONP-302, impede cancer metastasis as a monotherapy by inhibiting the accumulation of immunosuppressive myeloid cells.
Severe irAEs in patients with immune checkpoint inhibitor therapy: Experience in a Mexican cancer center.
Authors: Bonilla Molina Diana , Nehmad Cecilia , Tovar Cabrera Juan Manuel , Enciso López Ervin Saúl , Camarin Sanchez Efrain Isaias , Shveid Gerson Daniela , Rodriguez Benigno , Serrano Villamayor Omar , López Zepeda Lorena , Blanco Vazquez Yazmin Carolina , Camacho Limas Christian Patricio , Martínez-Herrera José Fabián , Olivares Guillermo , Gerson Cwilich Raquel 
Published: June 2022

e14559 Background: A relationship has been found between a better response to treatment and the presence of irAEs. Different potential factors for developing them have been described, including the type of immunotherapy and their combination. Rare (< 1%) and potentially life-threatening irAEs have been reported, which due to severity lead to treatment discontinuation, and a prolonged effective response is seen in these patients if they survive the irAE. Methods: Observational study in patients with solid tumors who received treatment with immune checkpoint inhibitor and their characteristic, that presented irAEs grade 3 and 4 using the CTCAE version 4, from January to December 2021 in a Mexican cancer center. Results: irAEs grade 3 or 4 were observed in 7 (5.6%) of 125 patients, with an age range of 60 to 69 years, most of the patients had a diagnosis of metastatic melanoma (43%) and secondly urothelial carcinoma with 29%. The predominant treatment was pembrolizumab monotherapy (56%), with an average of 5 applications after those who presented irAEs. The rare irAEs presented were myocarditis (2.4%), myositis (1.6%), myasthenia gravis and interstitial nephritis, both with 1%. 70% of these patients were managed with three boluses of methylprednisolone and subsequently prednisone 1 mg/kg as maintenance. The median appearance of these irAEs was 72 days. Myocarditis and myositis had an earlier onset with an average of 32 days. One of the seven patients presented myasthenia gravis, myositis and myocarditis concomitantly, with complete response of the neoplasia, however, due to the prolonged use of immunosuppressants to control irAEs, the disease recurred at 7 months. Two of the three patients with myocarditis had a complete response and remain disease free. 57% survived more than 90 days, of which 75% are still alive. Conclusions: Among the 125 patients who received an immune checkpoint inhibitor in our cancer center in 2021, the most prevalent serious irAE was myocarditis, with a higher incidence than that reported by other centers, and a prolonged therapeutic response was found in the patients who presented it.
Inferior survival outcomes with concomitant immune checkpoint inhibitors and chronic opioid use.
Authors: Varghese Aaron , Gallo Steven , Argentieri Deanna , Harvey Bethany W , Catalfamo Kayla , Attwood Kristopher , Zsiros Emese 
Published: June 2022

e14564 Background: Immune checkpoint inhibitors (ICI) are monoclonal antibodies that promote immune recognition of tumor cells to facilitate their elimination. Opioids are a major facet of pain management in cancer patients. Since chronic opioid use results in immunosuppression, the purpose of this study was to evaluate the survival outcomes of cancer patients on concurrent ICI and opioid therapy. Methods: This single-institute retrospective study from an NCI-designated comprehensive cancer center evaluated all patients in the primary or recurrent setting who underwent ICI therapy (anti-PD-1/PD-L1/CTLA-4) from 1 January 2020 to 18 June 2021. Demographic, clinicopathologic, and co-morbidity data were obtained from electronic medical records and the New York State Cancer Registry data. The New York State Prescription Monitoring Program was used to collect data about opioid prescriptions filled by patients from 30 days prior to and 30 days after the end of ICI therapy. Patient characteristics were analyzed with the Mann-Whitney U or chi-square tests. Survival analyses were performed using the Kaplan-Meier and Cox model regression, adjusting for relevant clinical factors. Results: A total of 869 patients were evaluable based on inclusion criteria and data availability. Most patients (77.15% chronic users and 64.62% occasional users) had stage III/IV disease. The most represented services included: gynecology (11.54%), soft tissue/melanoma (14.13%), thoracic (38.75%), urology (11.9%). Comorbidities did not vary between the two groups. Pre-treatment median opioid consumption was higher in the chronic users compared to occasional users (240 oral morphine equivalents (OME) vs 120, p = 0.03). Total opioid prescriptions filled was significantly higher for chronic users compared to occasional users (4275.0 vs 520.1 OME, p < 0.001). Chronic users were more likely to be on an additional anti-neoplastic agent (64% vs 44.07% for occasional users). Occasional users had significantly longer progression free (44.7 vs 16.0 months, p < 0.001) and overall (42.7 vs 16.2 months, p < 0.001) survival. When controlling for age, stage, and concurrent therapy, chronic opioid use retained a significantly negative association with PFS and OS. Conclusions: Patients on ICI therapy in the primary and recurrent setting who chronically use opioids exhibit significantly decreased PFS and OS compared to the occasional user cohort. This study provides evidence that chronic opioid use during ICI therapy results in inferior clinical outcomes.
An open-label, multicenter, phase II study of RC48-ADC combined with radiotherapy, PD-1/PD-L1 inhibitor sequential GM-CSF and IL-2 for salvage therapy in patients with HER2-expressing advanced solid tumors(PRaG3.0).
Authors: Xu Meiling , Kong Yuehong , Xing Pengfei , Chen Rongzheng , Ma Yifu , Shan Chanchan , Zhang Liyuan 
Published: June 2022

e14565 Background: The development of anticancer therapy tends to focusing on pan-cancer analysis, targeted therapy and immunotherapy with the advance of molecular and tumor microenvironment. Radiotherapy produces an immunomodulatory effect that may act synergistically with PD-1/PD-L1 inhibitor in multiple malignancies. Previous phase II trial showed HFRT/SBRT combined with PD-1 inhibitor and GM-CSF (PRaG regimen) has obtained promising results(Yuehong Kong et al. ASTRO 2021). RC48-ADC is a novel HER2-targeting antibody-drug conjugate (ADC). Preclinical studies indicated that ADC elicit immunogenic cell death and selectively radiosensitize to tumours. RC48-ADC combined with HFRT, PD-1/PD-L1 inhibitor sequential GM-CSF and IL-2 (PRaG3.0 regimen) could further improve the synergistic antitumor effects, this precise combination therapy paradigm provides an exploratory path for the treatment of pan-cancer. An exploratory phase II, open-label, multi-centre, single-arm study was conducted to evaluate the initial clinical efficacy and safety of PRaG3.0 regimen for treatment of HER2-expressing advanced solid tumors. Methods: Participants with advanced, confirmed HER2-expressing(IHC3+, 2+ or 1+) solid tumors that had progressed after the standard of care or intolerance were enrolled. In the cycle, those received RC48-ADC(2.0 mg/kg d1, every 3 weeks), then HFRT (2-3 doses of 5-8Gy) was delivered for one metastatic lesion every other day, followed by GM-CSF(200 μg d3-7), sequential IL-2(2million IU d8-12), and PD-1/PD-L1 inhibitor was dosing within one week after completion of HFRT. After RC48-ADC combined with PD-1/PD-L1 inhibitor sequential GM-CSF and IL-2 for at least 6 cycles, then maintenance with PD-1/PD-L1 inhibitor was administered until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). This trial is registered with ClinicalTrials.gov, number NCT05115500. Results: With the cutoff date of 11 February 2022, a total of 8 patients were enrolled. Among 6 patients who had at least one tumor assessment, involved gastric cancer(3/6), breast cancer(1/6), cervical cancer(1/6), pancreatic cancer(1/6). The ORR was 66.7% (4/6) and disease control rate (DCR) was 83.3%(5/6). One cervical cancer and one pancreatic cancer achieved complete remission. The most common treatment-related adverse events (TRAEs) were alopecia (37.5%), fatigue (25%) and hepatic damage(12.5%). No Grade 3 and higher adverse events occurred. Conclusions: The PRaG3.0 regimen manifested manageable safety profile and encouraging efficacy. So PRaG3.0 regimen is considered as a promising salvage treatment for patients with HER2-expressing advanced solid tumors. And the conclusion should be validated in more patients subsequently. Clinical trial information: NCT05115500.
Gastrointestinal adverse effects of combined checkpoint inhibitors: A systematic review and meta-analysis.
Authors: Karna Rahul , Deliwala Smit , Ramgopal Balasubramanian , Asawa Palash , Mishra Rahul , Mohan Babu P. , Grover Dheera , Kalra Tanisha , Bhalla Jaideep , Saraswati Ushasi , Jayakrishnan Thejus , Monga Dulabh K. , Dhawan Manish 
Published: June 2022

e14591 Background: Combined immune checkpoint inhibitors (ICPI) have revolutionized treatment of solid tumors. Their use can lead to treatment-related adverse events (TRAEs) resulting in hospital admissions, treatment discontinuation and increased morbidity. We aim to evaluate gastrointestinal (GI) TRAEs of different combination ICPI. Methods: A comprehensive search of multiple databases from inception to October 2021 was performed. Phase 2 and 3 trials assessing safety and efficacy of combined ICPI in solid tumors were included. Trials reporting concurrent use of chemotherapy, immunosuppressants, targeted therapy, or sequential ICPI therapy were excluded. Primary outcome was pooled luminal, hepatic and pancreatic TRAEs. A meta-analysis of proportions was done for outcomes using a random-effects model. I2 % was used to assess heterogeneity. Results: Out of 3696 citations screened, 53 trials reporting TRAEs in 6186 patients were included. Data from 41 study arms of 35 trials in nivolumab plus ipilimumab (N+I), 15 study arms of 15 trials in durvalumab plus tremelimumab (D+T), 4 study arms of 3 trials in pembrolizumab plus ipilimumab (P+I). The most common indications for combined ICPI were melanoma (26.4%) and lung cancer (24.5%). Pooled GI TRAE rates from the D+T, P+I and two different dosing combinations of N+I are shown in the table. Conclusions: Our study provides pooled data of TRAEs from different combination ICPI use in solid tumors and demonstrates high incidence of all grades and ≥ 3 GI TRAEs. Combined ICPI related TRAEs should be recognized early, as it may require treatment discontinuation. Further studies are required to assess overall impact of TRAEs on treatment course and outcomes.[Table: see text]
Effects of prophylactic high and low doses of corticosteroid on the efficacy of immune checkpoint blockade in murine hepatocellular carcinoma models.
Authors: Shen Ying-Chun , Yeh Ching-Ping , Jin Lu , Chang Nai-Wen , Hsu Chia-Lang , Ou Da-Liang , Chu Ching-Liang , Cheng Ann-Lii 
Published: June 2022

e14596 Background: Immune-related adverse events (irAEs) are major hurdle to immune checkpoint blockade (ICB). Corticosteroid (CS) is effective in controlling the majority of irAEs. Although recent studies suggested CS use does not jeopardize the anti-tumor efficacy of ICB, prophylactic use of CS remains prohibited with the concerns of attenuating efficacy of ICB. This study aimed to investigate the effects of CS premedication on the efficacy of ICB in murine hepatocellular carcinoma models. Methods: Anti-mCTLA-4 (9D9C, BMS) and anti-mPD-1 antibodies (4H2, ONO) were intraperitoneally (ip) administered to tumor-bearing mice (subcutaneous Hepa 1-6 model and orthotopic BNL 1MEA.7R.1 model) with or without dexamethasone (DEXA) premedication (10 and 200 μg, equivalent to minimal anti-inflammatory dosage and pulse therapy in human, respectively). Efficacy of ICB was evaluated as tumor shrinkage. Tumor-infiltrating lymphocytes (TILs) were isolated for single cell RNA-sequencing and effector function analysis through flow cytometry. Results: In the subcutaneous model, all tumors treated with ICB alone (N=7) or ICB plus DEXA 10 μg (N=5) completely regressed, but 1 out of 7 tumors treated with ICB plus DEXA 200 μg escaped. However, the tumor growth was not significantly different between groups ( P-value >0.05, multiple Mann-Whitney test). In the orthotopic model (N=5/group), the mean (± standard error) tumor weights on day 21 after tumor implantation for isotype control, ICB, ICB plus DEXA 10 μg and ICB plus DEXA 200 μg were 2.45 (± 0.54), 0.73 (± 0.18), 0.98 (± 0.65), and 0.69 (± 0.17) grams, respectively ( P-value >0.05, comparing ICB plus DEXA 10 or 200 μg with ICB). At transcriptomic level, premedication with either dosage of DEXA significantly reduced the percentage of effector memory cells and increased the percentage of exhausted effector cells in the CD8 TIL population, which appeared to counterbalance the effects of ICB. However, at protein level, premedication of DEXA 10 or 200 μg did not reduce the interferon-γ or granzyme B production of CD8 TILs in both models (Table). Conclusions: CS premedication did not attenuate the efficacy of ICB. Our study provides the scientific basis to evaluate the potential of prophylactic CS in preventing ICB-induced irAEs in clinical studies.[Table: see text]