tbuckley/cabot-search huggingface dataset:
THOR-707: Using synthetic biology to reprogram the therapeutic activity of interleukin-2 (IL-2).
Authors: Marcos E Milla, Jerod Ptacin, Carolina E. Caffaro, Hans R. Aerni, Lina Ma, Lilia Koriazova, Ingrid B. Joseph, Laura K. Shawver
Journal: Journal of Clinical Oncology (2019)

2603 Background: Recombinant interleukin-2 (rIL-2; aldesleukin) is an approved immunotherapy in melanoma and renal cell carcinoma based on complete durable remissions. The anti-neoplastic properties of IL-2 are mediated by interactions with the beta-gamma chain (IL-2Rβγ) on naïve CD8+ T cells, which lead to their expansion and differentiation into T effector and T memory cells directed against the tumor. However, the widespread use of IL-2 in oncology is limited by interaction with the high affinity IL-2 receptor alpha chain (IL-2R⍺) on regulatory CD4+ T cells (Tregs), which leads to immunosuppression, and on innate lymphoid cells in the vascular endothelium, which leads to eosinophilic recruitment and activation, and the sometimes fatal complication of vascular leak syndrome (VLS). A rIL-2 biased toward IL-2βγ affinity with no IL-2R⍺interaction could fill unmet needs in oncology. Methods: Using a synthetic biology platform, we have engineered THOR-707, a rIL-2 that contains a novel amino acid encoded in the IL-2 gene via a new DNA base pair (X-Y). The novel amino acid serves as a hook for site specific pegylation that extends half-life, blocks IL-2R⍺ engagement and binds to the IL-2Rβγ. Results: In non-human primates, THOR-707 can be dosed to maximize the level of cytotoxic CD8+ T lymphocytes without elevation of VLS-inducing eosinophils. In murine tumor models, THOR-707 induced the expansion of peripheral and intratumoral CD8+ T cells without expansion of suppressive Tregs. Single-agent dose-dependent anti-tumor efficacy was observed in two syngeneic mouse models. In combination with a PD-1 inhibitor, survival of tumor-bearing mice was longer than either agent as monotherapy. Efficacy in tumor models was durable, suggesting activation of CD8+ memory T cell populations. Conclusions: THOR-707 is a reprogrammed, site-directed, singly-pegylated rIL-2 that changes the pharmacologic profile of IL-2, potentially providing a favorable risk-benefit profile. First-in-human studies are expected to begin this year evaluating THOR-707 as monotherapy and in combination with a PD-1 inhibitor. Based on preclinical evidence to-date, THOR-707 may potentially address existing and emerging unmet needs across multiple solid tumors.
Abstract P164: Ideal Cardiovascular Health and Vascular Aging
Authors: Bamba Gaye, Marie C Perrier, Frédérique Thomas, Catherine Guibout, Bruno Pannier, Pierre Boutouyrie, Xavier Jouven, Jean P Empana
Journal: Circulation (2016)

Background: Arterial stiffness is a robust subclinical marker of cardiovascular disease (CVD). Furthermore, under the vascular aging concept, arterial stiffness also reflects the cumulative exposure to environment over life. Studying whether and how cardiovascular health (CVH) at a given point in time correlates with arterial stiffness may help identifying asymptomatic subjects who are at high risk for future CVD and who could benefit the most from interventions. Here, we hypothesized that ideal CVH would be inversely associated with arterial stiffness. Methods and results: Common Carotid Artery IMT (CCA-IMT), carotid stiffness (Elastic Young’s modulus) and carotid distensibility were measured by three trained technicians certified in vascular echography using high-precision echotracking device in 6457 participants attending a health check up in a large health center in France between 2008 and 2012. Participants were categorized as having poor, intermediate and ideal cardiovascular health if they had 0-2, 3-4 and 5-7 ideal health metrics (smoking, physical activity, body mass index, diet, blood glucose and total cholesterol, blood pressure). Carotid parameters were dichotomized according to their median value and multivariable logistic regression analysis was performed to examine the relationship between ICVH (exposure variable) with each carotid parameter (outcome). Mean age was 59.4 (SD 6.2) years and 38.2 % were females. Poor, intermediate and ideal cardiovascular health was present in 39.93%, 49.75% and 10.32% of study participants. Mean CCA-IMT was 654.47 (SD 117.77) and 612.45 (SD 113.86) micrometers in subjects with a poor and an ideal CVH respectively, corresponding to an absolute difference of 42 micrometers. After multivariable adjustment and compared to poor ICVH, ideal CVH was associated significantly with lower CCA-IMT (odds ratio = 1.76; 95% CI: 1.46;2.11) and carotid stiffness (odds ratio = 2.19; 95% CI: 1.83;2.63), and higher carotid distension (odds ratio = 2.81; 95% CI: 2.34;3.39). Theses associations were stronger in magnitude with the biological as compared to the behavioral component. Conclusion: In asymptomatic subjects aged 50-75, an ideal cardiovascular health was associated with significantly less arterial stiffening. The absolute difference in CCA-IMT beteween ideal and poor CVH corresponds to a 4.2 years difference in vascular aging. This dramatic difference supports the promotion of ideal cardiovascular health. Key words: Cardiovascular disease prevention, epidemiology, Carotid intima-media thickness, Vascular aging.
Single-Cell Analysis of the Normal Mouse Aorta Reveals Functionally Distinct Endothelial Cell Populations
Authors: Aditya S. Kalluri, Shamsudheen K. Vellarikkal, Elazer R. Edelman, Lan Nguyen, Ayshwarya Subramanian, Patrick T. Ellinor, Aviv Regev, Sekar Kathiresan, Rajat M. Gupta
Journal: Circulation (2019)

Background: The cells that form the arterial wall contribute to multiple vascular diseases. The extent of cellular heterogeneity within these populations has not been fully characterized. Recent advances in single-cell RNA-sequencing make it possible to identify and characterize cellular subpopulations. Methods: We validate a method for generating a droplet-based single-cell atlas of gene expression in a normal blood vessel. Enzymatic dissociation of 4 whole mouse aortas was followed by single-cell sequencing of &gt;10 000 cells. Results: Clustering analysis of gene expression from aortic cells identified 10 populations of cells representing each of the main arterial cell types: fibroblasts, vascular smooth muscle cells, endothelial cells (ECs), and immune cells, including monocytes, macrophages, and lymphocytes. The most significant cellular heterogeneity was seen in the 3 distinct EC populations. Gene set enrichment analysis of these EC subpopulations identified a lymphatic EC cluster and 2 other populations more specialized in lipoprotein handling, angiogenesis, and extracellular matrix production. These subpopulations persist and exhibit similar changes in gene expression in response to a Western diet. Immunofluorescence for Vcam1 and Cd36 demonstrates regional heterogeneity in EC populations throughout the aorta. Conclusions: We present a comprehensive single-cell atlas of all cells in the aorta. By integrating expression from &gt;1900 genes per cell, we are better able to characterize cellular heterogeneity compared with conventional approaches. Gene expression signatures identify cell subpopulations with vascular disease–relevant functions.
Long-term neurotoxicity in women with breast cancer.
Authors: Fahad Ahmed Faruqi, Charles L. Loprinzi, Kathryn Jean Ruddy, Fergus Couch, Nathan Staff, Janet E. Olson
Journal: Journal of Clinical Oncology (2019)

e23089 Background: Taxanes (paclitaxel and docetaxel) are commonly administered as part of chemotherapy for breast cancer, but long-term data on chemotherapy-induced peripheral neuropathy (CIPN) are limited in this population. We aimed to assess CIPN approximately three years after an initial exposure to paclitaxel or docetaxel. Methods: In a cross-sectional observation study, which surveyed consented enrollees annually after receipt of care at Mayo Clinic for a new breast cancer diagnosis over age 18, we collected patient-reported EORTC CIPN20 data by mailed questionnaire at baseline and three years after a breast cancer diagnosis. We then confirmed patient-reported chemotherapy data by chart abstraction and only included those who had received a standard course of docetaxel-based or paclitaxel-based chemotherapy, but had not had other neurotoxic treatment for cancer. CIPN20 overall and sensory scale raw scores were converted to a 0-100 linear scale with lower scores indicating more severe symptoms. Results: 84 women who received a taxane for breast cancer completed the survey. 82 were treated in the adjuvant or neo-adjuvant setting, while 2 received a taxane for metastatic breast cancer. 67 women received paclitaxel, while 17 received docetaxel. The median age at diagnosis was 51.5 years (range 31-86). 37 had estrogen receptor (ER) and/or progesterone receptor (PR) positive and human epidermal growth factor receptor-2 (Her2) negative, 31 Her2 positive, and 16 triple negative breast cancer. The median CIPN20 score was 92.98 (range 33.33-100). The median sensory CIPN score was 92.59 (range 25.94-100). 81% of women had an overall CIPN20 score of less than 100, and 68% had a sensory score of less than 100. Conclusions: The majority of women who received a taxane based chemotherapy regimen for breast cancer reported at least mild neuropathic symptoms three years out from treatment. Additional research is needed to help tailor chemotherapy decisions to toxicity risks and to reduce the likelihood of long-term CIPN, which can impair quality of life.
Worse outcomes associated with public insurance at sarcoma diagnosis in adolescent and young adults (AYAs).
Authors: Elysia Marie Alvarez, Frances Maguire, Helen M. Parsons, Cyllene Morris, Arti Parikh-Patel, Marcio H. Malogolowkin, Ted Wun, Theresa Keegan
Journal: Journal of Clinical Oncology (2019)

e18143 Background: Studies have shown that having public or no insurance at sarcoma diagnosis is associated with higher stage disease and poor survival. However, previous studies have not differentiated sarcoma patients who enrolled in Medicaid at diagnosis from those previously insured, groups with differing access to care. Therefore, we examined the impact of insurance on stage at diagnosis and overall survival for AYAs with soft tissue sarcoma (STS), osteosarcoma (OS) and Ewing sarcoma (EWS). Methods: Using Medicaid enrollment data linked to the California Cancer Registry, we identified AYAs with STS (n = 1782), OS (n = 458), and EWS (n = 348), diagnosed during 2005-14. Insurance was classified as Medicaid [1. Continuous (≥5 months prior to diagnosis), 2. Discontinuous, 3. At diagnosis (no coverage prior to diagnosis)], private, and uninsured. Logistic and Cox proportional hazards regression determined the association of insurance with metastatic stage (vs localized) and overall survival, respectively adjusting for sociodemographic factors, baseline comorbidities, type of facility, treatment (survival) and stage (survival). Results: Only 17.5% of sarcoma patients had continuous Medicaid prior to diagnosis, with 11% of STS, 17% of EWS and 19% of OS patients obtaining Medicaid at diagnosis. AYAs with Medicaid at diagnosis [Odds Ratio (OR) 3.03, 95% Confidence Interval (CI) 2.27-4.03; vs private] and discontinuous Medicaid (OR 2.25, CI 1.48-3.41) had a higher likelihood of metastatic disease. STS patients with Medicaid at diagnosis [Hazard Ratio (HR) 1.83, CI 1.44-2.33; vs private) and discontinuous Medicaid (HR 1.45, CI 1.01-2.08) had worse survival. Medicaid at diagnosis (HR 1.68, CI 1.07-2.63) also was associated with worse survival in OS patients, but this association was not observed in EWS patients. Conclusions: Lacking insurance prior to diagnosis is associated with metastatic disease at presentation and worse survival in AYA patients with sarcoma. Health insurance remained associated with worse survival even after adjusting for stage, highlighting the importance of continuous health insurance to improve outcomes for this patient population.
AB1123 SHOULDER PAIN: ARE THERE PREDICTIVE FACTORS OF RESPONSE TO TREATMENT AND OF ULTRASOUND FINDINGS?
Authors: Soraia Azevedo, Joana Rodrigues, Daniela Faria, Joana Neves, Joana Silva, Daniela Peixoto, Sérgio Alcino, José Tavares-Costa, Carmo Afonso, Filipa Teixeira
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Shoulder pain is a common cause of consultation in Primary Health Care, and may correspond to up to 30% of the reasons for consultation. Pathology of the rotator cuff is the most common cause of pain. Ultrasound is a valuable diagnostic tool in assessing shoulder disorders; it can be as effective as magnetic resonance imaging. <h3>Objectives</h3> To determine the predictive factors of response to treatment and ultrasound findings in shoulder pain. <h3>Methods</h3> We performed an analysis of the patients' cases sent to the rheumatology consultation with shoulder pain, every patients had an echography shoulder evaluation, and the rheumatologist decided treatment based on the guidelines for the treatment of shoulder tendinopathies. The use of nonsteroidal anti-inflammatory drug (NSAIDs) and muscle relaxant medications as well as the following techniques: corticosteroids local injection, barbotage, capsular distension and physiotherapy programs were some of the variables assessed. Posteriorly, the patients were clinically assessed in a follow-up visit. <h3>Results</h3> A total of 119 patients were evaluated. Men presented a higher risk of distension of the subscapular bursa. There was a statistically significant relationship between the time from the beginning of the symptomatology and treatment response. Diabetes <i>mellitus</i>, arterial hypertension and dyslipidaemia were statistically significantly associated with some rotator cuff lesions and distention of the subscapular bursa. <h3>Conclusion</h3> In patients with shoulder pain, early intervention positively influences the response to treatment. Thus, it is important that these patients are evaluated more promptly. Some comorbidities seem to be associated with a higher risk of specific rotator cuff lesions. No relationship was found between response to treatment and age, sex, occupation, previous treatments or type of therapy selected. The associations found in this study seem to have clinical implications. Prevention of rotator cuff disease is a matter of major relevance as well as early institution of treatment. <h3>References</h3> [1] Greenberg D.L. 2014 [2] Rechardt M. et al. 2010 [3] Teunis T, et al. 2014 [4] Armstrong A. 2014 [5] Lenza M, et al. 2013 [6] Middelton WD, et al. 2004 [7] Mathias R, et al. 2018 [8] Gatt DL, et al. 2014 [9] Booker S, et al. 2015 [10] Alfahad N, et al. 2015 [11] Le Goff B. et al. 2010 [12] Lansdown DA, et al. 2012 [13] Mantone JK, et al. 2000 [14] Gialanella B, et al. 2013 [15] Titchener AG, et al. 2014 [16] Namdari S, et al. 2014 [17] Boissonnault WG, et al. 2007 [18] Abboud JA, et al. 2010 [19] Lui PPY, et al. 2017 [20] Gumina S, et al. 2013 <h3>Disclosure of Interests</h3> None declared
Modeling the consequences of recurrences after trastuzumab treatment of HER2+ early-stage breast cancer.
Authors: Quan V. Doan, Miguel Martin, Deepa Lalla, Marc Halperin, Richard Bryce, Mark D. Danese, Beverly Moy
Journal: Journal of Clinical Oncology (2019)

e12032 Background: The study objective was to estimate the long-term consequences of recurrences following treatment with trastuzumab (TRA) among women with HER2+ early stage breast cancer (BC) in the United States (US). Methods: A simulation model was constructed to estimate the following outcomes for each combination of hormone receptor (+/-) and nodal (+/-) status: number of recurrences, direct medical cost and indirect cost attributed to recurrences. The number of women aged ≥18 years with newly diagnosed HER2+ BC between 2018 and 2037 was estimated using SEER incidence rates (assumed constant over time) and from US Census data and accounted for the proportion of women utilizing adjuvant TRA by nodal status and age (assumed constant over time). The recurrence rate to any regional, distant or contralateral site was based on the long-term follow-up of the HERceptin Adjuvant (HERA) trial (expected 20-year recurrence proportions of 27.6% for TRA and 36.7% without TRA). Medical and pharmacy costs due to a recurrence were based on a 3-year study of metastatic BC patients treated with HER2 targeted agents. Beyond year 3, cost increased by 4.5% per year. The indirect costs of recurrences included loss of income from early retirement valued at the mean hourly wage, work absenteeism ($6,960/year), and reduced productivity while at work ($3,456/year). Non-cancer related mortality was estimated using SEER data. Results: We estimated that there would be 411,373 incident cases of early stage BC who would receive adjuvant TRA treatment from 2018 to 2037. Following each annual cohort for 20 years, we estimated that there would be 112,700 recurrences after TRA treatment and 149,674 recurrences without TRA treatment. The 20-year direct medical costs of recurrences were estimated to be $28.2 and $37.5 billion with and without TRA, respectively and the indirect costs were estimated to be $4.1 and $5.6 billion with and without TRA, respectively. Conclusions: Although TRA reduced recurrences by 25% in our 20-year model, there was a substantial number of recurrences. Future research will assess the clinical and economic impact of newer HER2 directed therapies in the adjuvant (pertuzumab, T-DM1) and extended adjuvant (neratinib) setting.
Impact of baseline number of metastases on the efficacy of PD-1 inhibitor monotherapy for non-small cell lung cancer with high PD-L1 expression.
Authors: Taichi Miyawaki, Hirotsugu Kenmotsu, Eriko Miyawaki, Nobuaki Mamesaya, Takahisa Kawamura, Haruki Kobayashi, Kazuhisa Nakashima, Shota Omori, Kazushige Wakuda, Akifumi Notsu, Akira Ono, Tateaki Naito, Haruyasu Murakami, Keita Mori, Hideyuki Harada, Masahiro Endo, Toshiaki Takahashi
Journal: Journal of Clinical Oncology (2019)

e20551 Background: Pembrolizumab monotherapy and pembrolizumab combined with platinum-based chemotherapy are the standard therapies for advanced non-small cell lung cancer (NSCLC) patients with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) ≥ 50%. Apart from PD-L1 status, predictive factors for the efficacy of pembrolizumab treatment remain unclear. High tumour burden has been shown to be a negative predictor for the efficacy of PD-1 inhibitors in melanoma. Hence, the purpose of this study was to evaluate the association between tumour burden and efficacy of pembrolizumab in NSCLC patients with PD-L1 TPS ≥ 50%. Methods: This single-center retrospective observational study evaluated patients with advanced NSCLC with PD-L1 TPS ≥ 50% who received pembrolizumab monotherapy as first line therapy between March 2016 and November 2018. The primary endpoint was progression-free survival (PFS). Tumour burden was estimated by the baseline number of metastases (BNM) and the baseline sum of the target lesions’ longest diameters (BSLD; measured according to RECIST criteria). Results: Of 52 patients with target lesions, the median age was 69 years; ECOG-PS 0-1 94%; non-squamous histology 79%; and PD-L1 TPS ≥ 75% was 65%. The optimal cut-off values for predicting PFS were 4 for BNM and 115 mm for BSLD, based on the minimum P-value method for PFS. The low BNM group included 20 (38%) patients, and the low BSLD group 33 (63%). Low BNM was significantly associated with longer PFS (median PFS not reached vs 4.0 months, HR = 0.35, P = 0.021) and with higher response rate (60% vs 31%, P = 0.041) compared to high BNM. There was no significant difference in PFS between low BSLD and high BSLD groups (12.4 vs 4.0 months, HR = 0.52, P = 0.098). Multivariate analysis showed that both low BNM (≤ 4 vs. &gt; 4, HR = 0.32, P = 0.02) and PD-L1 TPS (75-100% vs. 50-74%, HR = 0.41, P = 0.032) were significantly associated with longer PFS. There was no association between PD-L1 TPS and BNM (Spearman’s rho = -0.0985, P = 0.487) Conclusions: BNM may be an independent predictive factor of efficacy of pembrolizumab monotherapy. Patients with low BNM can be candidates for pembrolizumab monotherapy.
Phase Ia clinical trial of adoptively transferring peripheral blood-derived cytotoxic T lymphocytes targeting individual neo-antigens to treat patients with advanced solid tumor.
Authors: Bo Li, Xiaoshi Zhang, Geng Liu, Si Qiu, Zhaoduan Liang, Mingming Liu, Yan Gao, Rui-hua Xu
Journal: Journal of Clinical Oncology (2019)

e14025 Background: Adoptive transfer of tumor infiltrating lymphocytes (TILs) targeting neo-antigens mediates complete and durable regression of solid tumor. However, the limited availability of fresh tumor samples hinders the application of TILs treatment. Based on neo-antigen specific T cells occurring in the circulation, we carried out a phase Ia clinical trial that adoptive transfer of peripheral blood-derived cytotoxic T lymphocytes (CTLs) targeting individual neo-antigens administrated patients with advanced solid tumor. Methods: This phase Ia clinical trial (NCT02959905) is designed to test the safety and objective response of CTL targeting individual neo-antigens treatment. Patients underwent apheresis on day -25, 0, 25, 50, 85 and 110, then CD8 + T cells were isolated from peripheral blood and co-cultured with autologous dendritic cells pulsed with neo-antigens, which generated the infused CTLs targeting neo-antigens. On day 0, 25, 50, 85, 110 and 135, patients received CTLs respectively, which were prepared prior to 25 days. Patients received evaluations on day 55 and 140, and were followed up from day 150 for 32 weeks. The survival of the infused CTLs was analyzed according to the sequence of CDR3 regions of the T-cell receptor. Results: Until October 16 th , 2018, a total of 10 patients were enrolled, 9 patients were infused 0.35-4×10 8 of CTLs for 1-6 times in this trial, in which 8 cases were metastatic melanoma and 1 case was colorectal cancer. Of the 10 participants who were enrolled, 7 participants had been evaluated, in which 1 case was evaluated as partial response (PR), 1 case was evaluated as iPR (evaluated as PR based on iRECIST), 3 cases were evaluated as stable disease (SD), 2 case were evaluated as progression of disease (PD), the objective reaction rate was 28.57%, and the disease control rate was 71.4%. All the subjects had safe tolerance, and the highest grade of adverse events related to adoptive cell transfer was grade 2. Neo-antigen specific CTLs persistently occurred in peripheral blood of 2 participants with PR or iPR for 140 days. Conclusions: Adoptively transferring peripheral blood-derived cytotoxic T lymphocytes targeting individual neo-antigens to treat patients with advanced solid tumor was safe under our current dose and preliminarily efficient. Clinical trial information: NCT02959905.