bluuebunny/crossref_metadata_2025_split huggingface dataset:
In-depth immune and molecular profiling of melanoma patients receiving adoptive T-cell therapy reveals biomarkers of efficacy in ATATIL study.
Authors: Orcurto Angela , Chiffelle Johanna , Ghisoni Eleonora , Barras David , Crespo Isaac , Navarro Rodrigo Blanca , Ochoa de Olza María , Imbimbo Martina , Rusakiewicz Sylvie , Tissot Stephanie , Gannon Philippe O , Dafni Urania , Zimmermann Stefan , Kandalaft Lana E. , Michielin Olivier , Bassani-Sternberg Michal , Dangaj Denarda , Trueb Lionel , Harari Alexander , Coukos George 
Published: June 2021

2533 Background: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has demonstrated a curative potential for patients with metastatic melanoma (MM). Nevertheless, activity remains unsatisfactory in many patients, requiring development of biomarkers that predict therapeutic efficacy. We report results of a single-center phase I study to assess feasibility, safety and efficacy of TIL-ACT in MM patients (NCT03475134). Methods: Patients with MM refractory to at least one prior line of therapy received TIL therapy with lymphodepleting chemotherapy before T-cell infusion, followed by high-dose interleukin-2. RDG- and FDG-PET imaging was performed before and after TIL infusion. Multispectral immuno-fluorescence (mIF) imaging and bulk-RNA sequencing (Seq) were performed on tumor samples pre-ACT and post-ACT (day+30 and upon progression). Single-cell RNA-Seq and TCR-Seq were performed on pre-ACT tumor and ACT product, as well as on tumor-reactive and neoantigen-specific TILs and on longitudinal blood samples. Results: As of 02/02/2021, thirteen patients (enrolled between March 2018 and December 2020) have successfully completed TIL-ACT therapy, with a median follow-up of 9.5 months (IQR 3.0 -24.6). Median age was 53 years (range 20-69) and all were previously treated with PD-1 based blockade. Median number of TILs infused was 55.0 x109 cells (range 12.8-84.7). The best overall response rate by RECIST 1.1 and disease control rate in evaluable patients was 41.7% (5/12) and 50% (6/12) respectively at 3 months. Two patients have an ongoing near-complete response at 3 years. Up to data cut-off, 10 patients have progressed by RECIST v1.1, with median PFS of 4.8 months (95% CI 1.5 - 9.6), while median OS is not reached. mIF revealed biomarkers of response, which may allow proper identification of patients in subsequent studies. In addition, deep sequencing of bulk and neoepitope-specific TIL clonotypes highlighted transcriptomic signatures revealing cell programs regulating in vitro expansion, in vivo blood persistence as well as tumor infiltration post-ACT. RGD-PET data will also be presented. Conclusions: We demonstrate reproducibility of TIL-ACT in our center, consistently with previous reports. Comprehensive translational studies reveal immune correlates of clinical responses that contribute to the understanding of mechanisms of TIL potency and will guide the development of next-generation cell products. Clinical trial information: NCT03475134.
Progression prediction model for solid tumors with clinical and immunological parameters.
Authors: Novik Aleksei Viktorovich , Girdyuk Dmitrii Viktorovich , Nekhaeva Tatyana Leonidovna , Emelyanova Natalia Viktorovna , Semenova Anna , Teletaeva Gulfiya Midhatovna , Latipova Dilorom Khamidovna , Protsenko Svetlana , Baldueva Irina Alexandrovna 
Published: June 2021

2539 Background: The immune system has well-known relation to tumor progression. Numerous immune-related parameters exist, but only a minor part could be used as biomarkers, especially dynamic ones. We trained a progression prediction model based on clinical features and peripheral immune system assessments. Methods: Patients with immunogenic (melanoma, 295, kidney cancer, 81), non-immunogenic (soft tissue sarcoma, 47, colorectal cancer, 26) and multiple primary tumors (29) with immunologic assessments before treatment (23.5%), on therapy (58.3), and in follow-up after the treatment (18.2%) were randomly divided in 7:3 ratio to the training and test groups. Counts of lymphocytes, T-, B, NK cells, cytotoxic lymphocytes, T-helpers were used as immunologic parameters. Age, sex, disease, stage, therapy, mutational status, last response on treatment, disease and therapy duration, previous treatments were used as clinical ones. The model was trained to predict disease progression in the next three months using “Catboost” gradient boosting. We used ROC AUC to test model performance and Yoden’s index for optimal cutoff calculation. We also studied the influence of model prediction on overall survival (OS) and time to progression (TTP) on the test dataset using the Kaplan-Meyer method and Cox regression. Results: We used 1682 assessments of immune parameters (immune status, IS) done in 354 patients (average 5 per patient) to train the model and 616 IS in 124 patients for validation. All IS of one patient were in the same group. The ROC AUC value of the model was 0.801. The model prediction of progression increased the probability of progressive disease from 37.5 to 62% and decreased the response rate from 37,5% to 8.4% (p = 0.016). The model prediction did not add information over known prognostic factors for OS in the multifactorial model but was an independent prognostic factor for TTP (HR 2.204, p = 0.011). False-positive results separate the group of patients with poor prognosis (OS 16 months, TTP 6 months) among patients with clinical benefit from patients with favorable prognosis (OS 61 months, TTP 18 months, p < 0.001), who had a truly negative model prediction. The possibility of prognosis improvement with therapy change was an essential factor for OS and TTP prediction (р < 0.001). The model was useful in predicting higher OS in patients with disease progression (p = 0.033) and shorter response duration in patients with clinical benefit (р = 0.03). Conclusions: Our progression prediction model provides clinically useful information and can be used for decision making in several clinical situations. Its utility should be tested in a prospective trial.
First-in-human dose escalation of ALPN-202, a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies.
Authors: Moser Justin C , Voskoboynik Mark , Lakhani Nehal J. , Millward Michael , Davar Diwakar , Harb Wael A. , Yang Jing , Means Gary , Manjarrez Kristi , Tercero Almudena , Zayed Hany , Hillson Jan , Dela Cruz Christine , Perez Graciela Noemi , Peng Stanford L. 
Published: June 2021

2547 Background: Strong preclinical rationale has emerged for combining checkpoint inhibition (CPI) with T cell costimulatory agonists, particularly CD28, a critical T cell costimulatory molecule recently recognized as a key target of checkpoint inhibition. ALPN-202 is a variant CD80 vIgD-Fc fusion that mediates PD-L1-dependent CD28 costimulation and inhibits the PD-L1 and CTLA-4 checkpoints. It has demonstrated superiority to CPI-only therapies in tumor models, while demonstrating favorable safety in preclinical toxicology studies. Methods: This is a cohort-based, open-label dose escalation and expansion study of ALPN-202 in adults with advanced solid tumors or lymphoma (NCT04186637). Subjects with cancers refractory to standard therapies (including approved CPIs), or cancers without available standard or curative therapy are eligible. After two planned single-subject cohorts, a standard 3+3 dose escalation has been implemented with two dose schedules in parallel, Q1W and Q3W. Objectives include evaluation of safety and tolerability, PK, PD and preliminary anticancer activity of ALPN-202. Disease assessments are evaluated by RECIST v1.1 for solid tumors or by Lugano Classification for lymphoma. Results: As of January 2021, 20 subjects with advanced malignancies have received ALPN-202. Dose-dependent PK and target saturation have been preliminarily observed. So far, ALPN-202 has been well tolerated at dose levels ranging from 0.001 to 1 mg/kg weekly, with no DLTs. Low-grade skin toxicities (grade 1-2 rash) have been observed in 4 subjects (20%). Among 11 evaluable subjects, an unconfirmed partial response has been observed in one subject with colorectal carcinoma, while stable disease has been observed in 5 subjects with colorectal carcinoma, mesothelioma (2), cholangiocarcinoma, and renal cell carcinoma -- for a preliminary clinical benefit (PR+SD) rate of 100% (4/4) at dose levels of 0.3 mg/kg and higher, or 54% (5/11) overall (table). The meeting presentation will update this data, which is expected to include the conclusion of Q1W dose escalation, as well as immune correlates. Conclusions: First-in-human dose escalation with ALPN-202 has been well tolerated at doses capable of engaging CD28 costimulation in vivo in association with dual PD-L1/CTLA-4 checkpoint inhibition, with early signs of anti-tumor activity. These findings suggest that CD28 agonism can be safely achieved in humans, and further suggest that dose expansion with ALPN-202 is warranted to assess the relevance of controlled CD28 costimulation as a novel approach to cancer immunotherapy. Clinical trial information: NCT04186637. [Table: see text]
Resetting the tumor microenvironment to favor anti-tumor immunity after local ablation.
Authors: Nief Corrine A. , Agudogo Júlia Sroda , Gonzales Alana , Previs Rebecca A. , Nair Smita K , Ramanujam Nimmi 
Published: June 2021

2561 Background: Percutaneous tumor ablation is a non-surgical method of tumor destruction that leaves necrotic tumor debris in situ. Tumor associated antigens released after ablation have the potential to initiate a systemic anti-tumor immune response, however the hostile tumor microenvironment hinders antigen presentation and T cell activity. We hypothesized that resetting the tumor microenvironment with oral sodium bicarbonate to decrease tumor acidity and low-dose cyclophosphamide to deplete pro-tumor immune cells would improve the ability of ablation to initiate anti-tumor immunity. Methods: Tumor growth, overall survival, and metastatic burden was assessed in orthotopic tumor models of triple-negative breast cancer (67NR, 4T1, and E0771). Tumor ablation was performed on palpable tumors using percutaneous ethanol injection (PEI) with 6% ethylcellulose to improve retention in the tumor. Surgical excision was used as a negative control to test the role of in situ tumor debris. Before ablation mice were placed on 200 mM of sodium bicarbonate (SB) in their drinking water and received a single intraperitoneal injection of 200 mg/kg of cyclophosphamide (CP). Mice surviving to 60 days after tumor implant without a primary tumor or signs of metastases were considered "cured" and re-challenged with 50e5 tumor cells in the contralateral mammary pad. T cell dependance was assessed with in vivo CD8 depletions. Results: The combination of PEI+SB+CP produced a potent anti-tumor response, curing a majority of mice (5/7 of E0771, 8/12 of 67NR, 7/12 of 4T1). No mice were cured using PEI alone, SB alone, CP alone, or any combination of two therapies (0/51 of E0771, 0/73 of 67NR, 0/75 of 4T1,). Re-challenge tumor growth was hindered in mice cured with PEI+SB+CP. Mice receiving PEI+SB+CP had significantly less metastases and lived longer than mice receiving surgical excision alone or surgical excision with SB+CP. Additionally the anti-metastatic response of PEI+SB+CP was undone when CD8+ T cells were depleted. Conclusions: Here the anti-tumor response of local ablation produced by PEI was enhanced by priming the tumor with low-dose CP and oral SB in metastatic breast cancer. These results suggest that tumor ablation with CP and SB can create a T cell dependent, personalized immune response to a tumor using only low-cost, easily accessible supplies, and the host’s own tumor.
Phase 2 study of retifanlimab (INCMGA00012) in patients (pts) with selected solid tumors (POD1UM-203).
Authors: Maio Michele , Schenker Michael , Medioni Jacques , Mandziuk Slawomir , Majem Margarita , Gravis Gwenaelle , Cornfeld Mark J. , Ranganathan Sulabha , Yao Yubing , Yeh Howard Su-Hau , Csőszi Tibor 
Published: June 2021

2571 Background: Checkpoint inhibitors (CPIs) are an effective treatment (tx) for many tumor types. Retifanlimab, an investigational humanized anti–PD-1 monoclonal antibody, has shown safety, pharmacology, and clinical activity consistent with the class. POD1UM-203 (NCT03679767) assessed efficacy and safety of retifanlimab in pts with selected solid tumors where CPI monotherapy is highly active. Methods: Eligible pts (≥18 y) had tx-naïve metastatic non-small cell lung cancer (NSCLC) with high PD-L1 expression (tumor proportion score ≥50%), cisplatin ineligible locally-advanced/metastatic urothelial cancer (UC) with PD-L1 expression (combined positive score ≥10%), unresectable/metastatic melanoma, or tx-naïve locally advanced/metastatic clear-cell renal cell carcinoma (RCC). Measurable disease (RECIST v1.1) was required. ECOG PS >1 and prior PD-1/PD-L1 directed tx were exclusions. Retifanlimab was administered as an IV infusion at 500 mg every 4 wks over 30 min. Primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival, overall survival, safety, and pharmacokinetics. Results: A total of 121 pts (35 melanoma, 23 NSCLC, 29 UC, 34 RCC) received ≥1 dose of retifanlimab and were included in the analyses. Median duration of tx was 169 d (range, 1–442). The efficacy cut-off for the primary analysis occurred once all pts had been followed for at least 6 mo from the time of initial tx. Confirmed RECIST v1.1 responses were observed in all tumor types (Table) and were consistent with published ORR for other CPIs; median DOR was not reached for any tumor cohort and tx was ongoing at the time of data cutoff for 17, 11, 9, and 15 pts with melanoma, NSCLC, UC, and RCC, respectively. The most common tx-emergent AEs (TEAEs, >10% incidence) were asthenia (17.4%), arthralgia (14.9%), decreased appetite (14.0%), pruritus (12.4%), rash (10.7%), and urinary tract infection (10.7%); majority of TEAEs were low grade (≤ grade 2) and none led to tx discontinuation. Immune-related AEs occurred in 23 pts (19.0%), most common (>1% incidence) were hypothyroidism (7.4%), rash (4.1%), hyperthyroidism (2.5%), and pruritus (1.7%). Immune-related AEs led to dose delay in 5 pts (4.1%), but none led to tx discontinuation and/or dose interruption. Conclusions: Retifanlimab demonstrated antitumor activity and was generally well-tolerated in pts with melanoma, NSCLC, UC, or RCC comparable with approved CPIs for these tumor types. These results support ongoing further development of retifanlimab. Clinical trial information: NCT03679767. [Table: see text]
Phase Ia/Ib dose-escalation study of IBI110 (anti-LAG-3 mAb) as a single agent and in combination with sintilimab (anti-PD-1 mAb) in patients (pts) with advanced solid tumors.
Authors: Zhou Cai , He Yayi , Ren Shengxiang , Li Wei , Zhu Jun , Yu Jia , Wang Lei , Xiong Anwen , Xu Nong , Mao Chenyu , Pan Beiqing , Liu Ying , Zhou Hui 
Published: June 2021

2589 Background: Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor protein that functions to control T cell response, activation and growth. Dual inhibition of PD-1 and LAG-3 may improve anti-tumor effect synergistically. In this first-in-human dose-escalation study, we report the preliminary safety and anti-tumor activity of IBI110 ± sintilimab in pts with advanced solid tumors. Methods: Enrolled pts, ECOG PS 0-1, had locally advanced, recurrent or metastatic solid tumors for whom standard therapy had failed. Pts received escalating doses of IBI110 (0.01/0.1/0.3/1/3/10/20mg/kg) IV Q3W in phase Ia and escalating doses of IBI110 (0.3/0.7/1.5/3/5 mg/kg) in combination with sintilimab 200 mg IV Q3W in phase Ib. Crossover from mono to combo was allowed at progression. The objectives were safety and tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of IBI110 alone or IBI110+sintilimab (per RECIST v1.1). Results: Phase Ia: 21 pts (median age: 62 yr [range 43-72]; ECOG PS: 0 [n = 11], 1 [n = 10]) were enrolled. Dose escalation has completed and no dose-limiting toxicity (DLT) was observed in all dose cohorts. The most common treatment-related adverse event (TRAE) was anaemia (19.0%). TRAEs ≥G3 included anaemia (4.8%), ascites (4.8%) and hepatic function abnormal (4.8%). By investigator-assessment, best response was 1 confirmed partial response (PR) (ovarian cancer, 3 mg/kg IBI110 single agent) and 5 stable disease (SD) in monotherapy. After crossing from mono to combo at progression, 5 pts were observed to have SD. Phase Ib: 12 pts (median age: 60 yr [range 33-72]; ECOG PS: 0 [n = 7], 1 [n = 5]) were enrolled. All dose cohorts in dose escalation except IBI110 5mg/kg+ sintilimab have completed DLT observation and no DLT was observed. The most common TRAE was AST increased (41.7%). TRAEs ≥G3 included hyperglycaemia (8.3%), bilirubin conjugated increased (8.3%) and hepatic function abnormal (8.3%). By investigator-assessment, best response was 2 PR (small cell lung cancer and endometrial cancer) and 6 SD. Conclusions: IBI110 alone or plus sintilimab has acceptable toxicity and shows preliminary antitumor activity. Clinical trial information: NCT04085185.
Interleukin-1-beta concentration and neutrophil-lymphocyte ratio as possible predicting biomarkers of response to therapy with checkpoint inhibitors.
Authors: Orlova Rashida , Zhukova Natalia V. , Malkova Anna , Kaledina Ekaterina , Gubal Anna , Sharoyko Vladimir 
Published: June 2021

3024 Background: One of the discussed predictive markers of the immune therapy efficacy is the index of neutrophils to lymphocytes ratio in peripheral blood (NLr), which reflects the activity of adaptive immunity and correlates with the level of tumor-infiltrating lymphocytes (TILs). High NLr and low TILs are associated with disease progression. Interleukin-1-beta (IL-1β) is one of the main cytokines produced by the tumor microenvironment (TMO). Overexpression of the cytokine leads to a local immunosuppression. For some tumors, elevated serum IL-1β levels have been associated with a poor prognosis. The aim of this work is to analyze the serum IL-1β level as a marker of TMO activity and the NLr as a marker of adaptive immunity activity in relation to the response to therapy with checkpoint inhibitors in patients with various solid tumors. Methods: The study involved 63 patients with various solid tumors who were treated at the City Oncological Dispensary and were prescribed checkpoint inhibitors (nivolumab (n = 33), pembrolizumab (n = 23), ipilimumab + nivolumab (n = 7)). The determination of the level of IL-1β was performed using the ELISA method ("Interleukin-1-beta, ELISA-best", Novosibirsk), a clinical blood test was performed in a dispensary. The response to treatment was assessed 3-6 months after the start of therapy. Statistical analysis was carried out in GraphPad Prism. Results: Among the examined patients 49.21% (31/63) achieved partial regression or stabilization of the process (group I), and 50.79% (32/63) progressed (group II). The mean concentration of IL-1β before treatment in group I was 2.21±0.3 pg/ml, in group II - 0.98±0.2 pg/ml. NLr was increased in 7 patients from group I and in 9 patients from group II, with the mean index level being 2.9±0.39 and 3.2±0.5, respectively. There was no statistically significant difference in the concentration of IL-1β and the NLr between the studied groups. In group II, the number of patients undergoing systemic anticancer therapy before immune therapy (n = 18) was statistically significantly higher than in group I (n = 8), p = 0.033. There was no statistically significant difference in IL-1β concentration and NLr relative to previous treatment. Conclusions: Our study showed that the level of IL-1β corresponds to that of healthy donors and its isolated determination has no prognostic value. The NLr in most patients from the progression group was higher than normal, in contrast to group I, which is confirmed in the literature. The presence of previous systemic anticancer therapy was found to be associated with disease progression. The described feature can be explained by the fact that patients who received therapy before, already have a longer period of illness, a more severe clinical condition. The presence of systemic anticancer therapy does not affect the level of IL-1β and NLr.
Antibiotic use reduces efficacy of tyrosine kinase inhibitors in patients with advanced melanoma and non-small cell lung cancer.
Authors: Tinsley Nadina , Cook Natalie , Zhou Cong , Nahm Sharon Hyo-Eun , Rack Samuel , Tan Grace Chin Lay , Lorigan Paul , Blackhall Fiona Helen 
Published: June 2021

3100 Background: Antibiotic (ABX) use and disruption of the gut microbiome has been demonstrated to reduce the efficacy of immune checkpoint inhibitors and chemotherapeutics in cancer patients. Little is known about the impact of ABX use in patients treated with targeted therapies, such as tyrosine kinase inhibitors (TKI). Methods: Retrospective data analysis was performed on advanced melanoma and non-small cell lung cancer (NSCLC) patients treated with TKIs between January 2015 and April 2017 at The Christie NHS Foundation Trust, UK. Demographics, prior systemic treatment, extent of disease, lactate dehydrogenase level (LDH), presence of brain metastases, performance status, comorbidities, TKI agent and the use of ABX (class, route, duration) were collected. Progression free survival (PFS) and overall survival (OS) were compared between the ABX+ group (defined as patients treated with ABX within 2 weeks of TKI initiation or 6 weeks after) and the ABX – group (patients with no ABX during specified period). Statistical analyses were performed with univariate and multivariable models. Results: In total, 168 patients were included; 89 patients (53%) with advanced NSCLC and 79 patients (47%) with melanoma. Over a third of patients, (57/168, 34%) received ABX in the specified period (ABX+). On univariable analysis, ABX use was associated with shorter PFS (208 days vs 357 days, p = 0.008) and OS (294 days vs 438 days, p = 0.024). Increased age, poorer performance status, and higher LDH were also associated with shorter PFS and OS. On multivariable analysis, ABX use was independently associated with shorter PFS (HR 1.57, 95% CI 1.05-2.34, p = 0.028) and OS (HR 2.19, 95% CI 1.44-3.32, p = 0.0002). The negative impact of ABX on OS was particularly pronounced for patients with worse performance status (HR 3.82, 95% CI 1.18-12.36, p = 0.025). Conclusions: To our knowledge, this is the largest multivariable analysis showing ABX use independently reduces PFS and OS in patients treated with TKIs. It is the first analysis to demonstrate this phenomenon across two distinct tumour sites. The data suggests that ABX use could be an independent predictor of shorter PFS and OS in cancer patients treated with TKIs, and warrants further validation in a larger cohort.