bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor responses and early onset cytokine release syndrome in synovial sarcoma patients treated with a novel affinity-enhanced NY-ESO-1-targeting TCR-redirected T cell transfer.
Authors: Ishihara Mikiya , Kitano Shigehisa , Hattori Hiroyoshi , Miyahara Yoshihiro , Kato Hidefumi , Mishima Hideyuki , Yamamoto Noboru , Funakoshi Takeru , Kojima Takashi , Sasada Tetsuro , Sato Eiichi , Okamoto Sachiko , Tomura Daisuke , Chono Hideto , Nukaya Ikuei , Mineno Junichi , Ikeda Hiroaki , Watanabe Takashi , Kageyama Shinichi , Shiku Hiroshi 
Published: May 2019

2530 Background: Adoptive transfer of TCR-redirected T cells has been reported to exhibit efficacy in some of melanoma and sarcoma patients. However, there have not been well known about cytokine release syndrome (CRS) or its relations to tumor responses. This study evaluates clinical responses in association with the cell kinetics and CRSs after transfer of high-affinity NY-ESO-1 TCR-gene transduced T cells in NY-ESO-1-expressiong cancer patients (NCT02366546). Methods: We developed a novel-type affinity-enhanced NY-ESO-1-specific TCR and an originally-developed retrovirus vector that encodes siRNA to silence endogenous TCR creation. The NY-ESO-1/TCR sequence is mutated for high affinity with replacements of G50A and A51E in CDR2 region. This is a first-in-man clinical trial of the novel NY-ESO-1-specfic TCR-T cell transfer to evaluate the safety, in vivo cell kinetics and clinical responses. It was designed as a cell-dose escalation from 5 x108 to 5 x109 cells. NY-ESO-1-expressing refractory cancer patients were enrolled, with 3+3 cohort design. Cyclophosphamide (1,500mg/m2) were administered prior to the TCR-T cell transfer as pre-conditioning. Results: 9 patients were treated with the NY-ESO-1/TCR-T cell transfer. The TCR-T cells expanded in peripheral blood with a dose-dependent manner, associated with rapid proliferation within 5 days after the cell transfer. 3 patients receiving 5x109 cells developed early-onset CRSs, with elevations of serum IL-6, IFN-γ. The CRSs developed on day1 or 2 after the cell transfer. They were well managed with tocilizumab treatment. 3 synovial sarcoma patients exhibited tumor shrinkages of partial responses, and they all had high-expression of NY-ESO-1 in the tumor samples, namely, 75% or more. Exploratory analysis revealed that multiple chemotactic cytokines including CCL2 and CCL7, and IL-3 increased in the serum from the patients with CRS. The proportions of effector-memory phenotype T cells in the infused cell-product were significantly associated with CRS development. Conclusions: The affinity-enhanced NY-ESO-1/TCR-T cell transfer exhibited early-onset CRS in association with in vivo cell proliferation and sequential tumor responses in the patients with high-NY-ESO-1-expressing synovial sarcoma. Clinical trial information: NCT02366546.
Effect of minimal lymphodepletion prior to ACT with TBI-1301, NY-ESO-1 specific gene-engineered TCR-T cells, on clinical responses and CRS.
Authors: Butler Marcus O. , Saibil Sam , Bonilla Luisa , Franke Norman , Hakgor Sevan , Boross-Harmer Sarah , Majeed Habeeb , Nelles Megan , Ohashi Pamela S , Ross Kendra , Sacher Adrian G. , Scheid Elizabeth , Sotov Valentin , Trang Aileen , Vakili Koosha , Van As Brendan , Takahashi Shuichi , Tanaka Shinya , Nguyen Linh T. , Hirano Naoto 
Published: May 2019

2537 Background: Adoptive transfer of T cell receptor (TCR) gene-engineered T cells can induce durable anti-cancer responses. Post-infusion cytokine release syndrome (CRS) has been associated with clinical utility. Pre-infusion lymphodepletion (LD) may influence CRS, graft persistence, and clinical responses. While the optimal LD regimen is not yet defined, most include both cyclophosphamide (CY) and fludarabine (FLU). TBI-1301 is a novel gene therapy produced by engineering autologous lymphocytes to express an NY-ESO-1-specific TCR using a retrovirus vector that encodes siRNA to silence endogenous TCR. Since less intensive LD may be sufficient with the use of this novel vector, we are conducting a study where patients are treated with TBI-1301 following LD with CY alone. Methods: Eligibility includes informed consent, HLA-A*02:01 or A*02:06 haplotype, and NY-ESO-1 expression by immunohistochemistry. Eligible patients undergo harvest of PBMC which are then processed locally to generate engineered TBI-1301 cells. The study design is to infuse 5x109 cells (day 0) to patients following LD with CY (750 mg/m2 on day -3 and -2). Endpoints include safety, efficacy, and biological correlates for persistence of NY-ESO-1-specific T cells post infusion. Results: Thus far, 9 patients have been treated, and 8 have received the target dose. To date, 8 patients are evaluable for response and toxicity, and no DLTs have been observed. Despite LD with CY alone, all 4 patients with synovial sarcoma and 1 with melanoma experienced clinical and laboratory evidence of grade 1-2 CRS with increased CRP, ferritin, and IL-6 levels. CRS resolved spontaneously in all but one patient who required tocilizumab due to grade 2 nausea/vomiting. Two subjects experienced grade 3 tumor-associated pain. Other treatment-associated grade 3 or 4 toxicities included neutropenia and hypophosphatemia. Best overall response by RECIST is as follows: 2 partial responses, 5 stable disease, and 1 progressive disease. Biomarker analysis demonstrates persistence of transferred TBI-1301 cells, > 100 days in some patients. Conclusions: TBI-1301 appears to be safe and to possess anti-tumor activity. Despite LD with CY alone, grade 1-2 CRS is induced. Additional cohorts to this study will examine the role of repeat infusions to enhance anti-tumor activity. Clinical trial information: NCT02869217.
Comprehensive report of anti-CD19 chimeric antigen receptor T cells (CAR-T) associated non-relapse mortality (CART-NRM) from FAERS.
Authors: Anand Kartik , Burns Ethan , Sano Dahlia , Pingali Sai Ravi , Westin Jason , Nastoupil Loretta J. , Lee Hun Ju , Samaniego Felipe , Parmar Simrit , Wang Michael , Hawkins Misha , Adkins Sherry , Fayad Luis , Steiner Raphael , Nair Ranjit , Ahmed Sairah , Fowler Nathan Hale , Neelapu Sattva Swarup , Iyer Swaminathan Padmanabhan 
Published: May 2019

2540 Background: CAR-T cells targeting CD19 positive B-cells have improved outcomes for relapsed/refractory non-Hodgkin lymphoma (NHL) and B-cell acute lymphoblastic leukemia (B-ALL). CAR-T emergent toxicities for FDA approved therapies leading to non-progression related death have been reported in the pivotal studies. However, they are underreported and there remains a need to obtain a comprehensive report of NRM emergent with anti-CD19 CAR-T. Methods: We retrospectively searched FDA adverse events reporting system (FAERS) for all adverse events (AE) related to “Tisagenlecleucel(T)” and “Axicabtagene ciloleucel(AC)” reported from 2013-2018. FAERS contains AEs from clinical trials and standard of care patients. All cases with the outcome of death were analyzed. Results: Total numbers of anti-CD19 CAR-T pts reported were 636, out of which 288 cases received “T” and 348 received “AC”. Out of total 129 total deaths, 95 died due to non-disease progression. Patient characteristics are summarized in Table. CART-NRM for entire cohort was 15%; 21% for “T” and 10% for “AC”. Major toxicities reported include CRS, hematological, cardiovascular, neurological and infectious. Difference in mortality is likely related to different patient population, diagnoses and the CAR-T construct. Conclusions: CART-NRM remains considerably high at 15%. Our analysis highlights the major toxicities and informs the potential opportunities for interventions to reduce mortality. We will present updated data with comparative analysis of published clinical studies at the upcoming ASCO Meeting in Chicago. [Table: see text]
ctDNA analysis for personalization of consolidation immunotherapy in localized non-small cell lung cancer.
Authors: Moding Everett J , Liu Yufei , Nabet Barzin , Chabon Jacob J. , Chaudhuri Aadel , Hui Angela B. , He Jianzhong , Qiao Yawei , Heymach John , Tsao Anne S. , Liao Zhongxing X. , Gomez Daniel Richard , Ramchandran Kavitha , Neal Joel W. , Wakelee Heather A. , Loo Billy W. , Lin Steven H. , Alizadeh Ash A. , Diehn Maximilian 
Published: May 2019

2547 Background: Detection of molecular residual disease via circulating tumor DNA (ctDNA) analysis after chemoradiation (CRT) in localized non-small cell lung cancer (NSCLC) predicts risk of relapse. We explored the hypotheses that (1) patients with undetectable ctDNA after CRT may not require consolidation immunotherapy (CI) and (2) ctDNA analysis could monitor the effectiveness of CI in patients with residual ctDNA after CRT. Methods: We applied CAPP-Seq ctDNA analysis to 88 plasma and matched leukocyte samples collected pre-CRT, post-CRT but pre-CI, and mid-CI in 22 patients with Stage IIB-IIIB NSCLC treated with CRT followed by CI. Identification of patient-specific tumor variants was performed using tumor tissue or pretreatment plasma, and ctDNA was quantified using a tumor mutation-informed bioinformatic strategy. Freedom from progression (FFP) defined radiographically by RECIST 1.1 criteria was compared in patients with ctDNA detected or not detected at pre-CI and mid-CI landmarks. Results: Median follow up from the start of CRT was 11 months. ctDNA detection was associated with inferior rates of FFP when compared to patients with ctDNA not detected both pre-CI (12-month 33% vs. 76%, P = 0.015, HR 7.51, 95% CI 1.47-38.24) and mid-CI (12-month 0% vs. 86%, P < 0.0001, HR 123.3, 95% CI 16.21-937.8). In patients with undetectable ctDNA after CRT, FFP was similar to a historical cohort of patients with undetectable ctDNA after CRT alone (12-month 88% vs. 87%, P = 0.56, HR 0.55, 95% CI 0.07-4.18), suggesting that such patients may not benefit from CI. All patients with detectable ctDNA pre-CI in whom ctDNA increased mid-CI developed progressive disease. Finally, in 2 patients with ctDNA detected after CRT, CI led to elimination of ctDNA at the mid-CI timepoint. One of these patients developed an isolated local recurrence 22 months after CRT and the other patient is currently disease free at 11 months, suggesting clinical benefit from CI. Conclusions: Our results suggest that ctDNA analysis may allow personalization and response monitoring of CI following CRT for NSCLC. Validation in more patients followed by prospective testing in clinical trials will be required to establish clinical utility of such an approach.
Re-evaluating eligibility criteria: Analysis of factors leading to nonparticipation and outcomes of patients (pt) with advanced cancer who signed consent but were not treated in early-phase immunotherapy (IO) trials.
Authors: Carmagnani Pestana Roberto , Subbiah Ishwaria Mohan , Hess Kenneth R. , Huang Le , Liu Shuang , Beltran Kimberly , Harrison Holly , Bryant Angela , Eshon Jennifer , Yap Timothy A , Pant Shubham , Naing Aung , Hong David S. , Meric-Bernstam Funda , Subbiah Vivek 
Published: May 2019

2552 Background: Eligibility criteria protect the safety of trial pt and delineate the study population. Excessively restrictive criteria, however, can negatively impact accrual and prevent access to beneficial investigational treatments. Recently, ASCO issued a statement on the need to broaden eligibility criteria and make trials more representative. We aim to characterize the factors leading to non-participation and the outcomes of pt who signed consent for phase I IO trials but ultimately did not receive any therapy on that trial. Methods: We identified 696 consecutive pt w/ advanced cancer who consented to participate on IO phase I trials from 10/2015-12/2017, and collected pt characteristics as well as clinical outcomes, and compared participants (P) to non-participants (NP). Results: Among the 696 pt who initially consented to participate on IO phase I trials, 178 (25.6%) were never treated. Median age was 60 in both groups, and there were no differences regarding median number of metastatic sites (n = 2 vs 2 ) or sex distribution (F 53% vs 54%); NP had received less lines of therapy (median = 3 vs 4, p = 0.016). Reasons for non-participation were: 48 (26%) alternate therapy (for 18, geography was the main reason), 29 (16%) clinical progression/ decline in PS, 14 (8%) did not have enough biopsy tissue, 13 (7%) new lab abnormality, 11 (6%) new brain mets, 63 (35%) had other reasons (death, concurrent medications, financial factors). Median time from signature of consent to final exclusion of trial was 19 days (0-82). 54 of NP eventually enrolled in other trial, including 29 in immunotherapy trial. Median overall survival (OS) was significantly lower for NP vs P (median 6.9 vs 18.0, HR 0.5; p < .0001). Conclusions: One quarter of patients who signed consent for early-phase immunotherapy trials were unable to start on study. NP had significantly decreased OS. Detailed examination of these reasons can lead to recognition of modifiable factors and streamline the pretrial period, to guarantee this vulnerable population has maximal access to start therapy on study.
Preliminary results with tislelizumab, an investigational anti-PD-1 antibody, in Chinese patients with nasopharyngeal cancer (NPC).
Authors: Wang Siyang , Huang Xiaoming , Bai Yu-Xian , Yuan Ying , Li Jian , Wang Zuobai , Wei Chenlu , Li Xin , Liu Tianshu 
Published: May 2019

2556 Background: Epidemiology of NPC is characterized by a unique geographic distribution, with China having one of the highest incidence rates of NPC worldwide. Tislelizumab is an investigational monoclonal antibody with high affinity and specificity for PD-1. Tislelizumab was engineered to minimize binding to FcɤR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Previous reports from this phase 1/2 study (CTR20160872) have shown that single-agent tislelizumab was generally well tolerated and demonstrated preliminary antitumor activity in Chinese patients (pts) with advanced solid tumors. In the dose-verification part of this study, the recommended dose was established as 200 mg IV Q3W. Here we present preliminary results from the NPC cohort of this study. Methods: Chinese pts with advanced or metastatic, histologically or cytologically confirmed WHO type II-III NPC were enrolled in the indication-expansion phase of this study. Enrolled pts received tislelizumab 200 mg IV Q3W until unacceptable toxicity, consent withdrawal, or no evidence of continued clinical benefit. Antitumor activity (per RECIST v1.1) and safety/tolerability (per NCI-CTCAE v4.03) were assessed. Results: As of 11 May 2018, 20 NPC pts (median age 49 yr [range 35–61]) were enrolled. Most pts were male (85%) and non-smokers (65%). All pts received prior radiotherapy; 19 pts (95%) received ≥1 line of systemic treatment and the median number of prior lines of systemic treatment was 2 (range 0–10). At the cut-off date, 15 pts remain on treatment and the median study follow-up was 5.5 mo (range 0.46–9.0). Of 15 response-evaluable pts, 3 achieved a confirmed partial response (PR) and 9 achieved stable disease; 1 patient had an unconfirmed PR. Seven patients experienced ≥1 treatment-related AE (TRAE); hypothyroidism (n = 3) was the only TRAE that occurred in ≥2 pts. No grade ≥3 TRAEs or serious AEs were reported. Furthermore, no AEs led to either treatment interruption or discontinuation. Conclusions: Tislelizumab was generally well tolerated and demonstrated antitumor activity in previously treated pts with advanced NPC. Clinical trial information: CTR20160872.
Understanding contribution and independence of multiple biomarkers for predicting response to atezolizumab.
Authors: Shah Parantu K. , Kaczmarczyk Jan , Myronov Alexander , Gruba Katarzyna , Stępniak Piotr , Rolfe P. Alexander 
Published: May 2019

2567 Background: No biomarker satisfactorily predict response to anti-PD-L1 therapies. Biomarker studies suffer from small sample size, presence of disease subtypes, and lack of simultaneous measurement of multiple biomarkers. The IMvigor210 dataset (Mariathasan et al., Nature 2018) provides baseline measurements for multiple biomarkers of response to atezolizumab (n range: 105-298) coupled with genomewide RNAseq profiles. We examined predictive performance of individual biomarkers and combined information from multiple biomarkers to measure changes in predictive performance. Methods: We built classification models (PR/CR vs. PD/SD) using genes and gene sets that provide information on pathways (mSigDB), immune components (xCell, Cibersort), and predictors of response (IMPRES, Immunophenoscore, and TIDE). Prognostic features were removed based on survival association in TCGA. All experiments were done with repeated five-fold double cross validation. Predictions from the gene sets model were used as a single biomarker. PD-L1 expression by IHC in tumor core and immune cells, tumor mutation burden(TMB), neo-antigen burden (NB), location of metastatic disease, immune phenotype and genomic subtypes were then systematically merged with the gene set based model. Results: NB was the best predictor of response (AUC 0.77), while a model combining NB, TMB, ECOG and expression signatures was marginally better (AUC 0.81) with a chance of over fitting. Chi-square tests for independence suggested that examined biomarkers do not provide independent information explaining lack of increase in AUC. Signatures for TP53 mutations, M1 macrophages, CD8+ T effector cell and DNA repair, among others, were present frequently in classification using gene expression information (AUC 0.71), suggesting their independent contributions to response. Adding gene expression information to NB didn’t improve AUC for response but provided better survival stratification. Conclusions: Integration of examined biomarkers with machine learning did not improve response prediction significantly. We are now examining sizes of subgroups defined by combination of low NB/TMB with these biomarkers.
Tumor mutational burden (TMB) and response rates to immune checkpoint inhibitors (ICIs) targeting PD-1, CTLA-4, and combination.
Authors: Osipov Arsen , Popovic Aleksandra , Hopkins Alexander , Frampton Garrett M. , Albacker Lee A. , Azad Nilofer Saba , Laheru Daniel A. , Zheng Lei , Jaffee Elizabeth M. , Yarchoan Mark 
Published: May 2019

2578 Background: ICIs targeting PD-1/L1 and/or CTLA-4 have activity against many different cancers. We and others have previously shown that a higher TMB, a surrogate for an increased number of expressed tumor neoantigens, is an important biomarker for response to anti-PD-1/L1 monotherapy. Whether the relationship between the TMB and response to ICIs extends beyond anti-PD-1/L1 is unknown. Methods: We identified 30 major solid tumor types for which TMB has been described using a genomic profiling assay performed by Foundation Medicine. We conducted searches of MEDLINE (from Jan 1, 2010 to Jan 20, 2019), as well as abstracts presented at ASCO, ESMO, AACR Annual Meetings 2010-2018 to identify the objective response rate (ORR) for anti-PD-1/L1, anti-CTLA-4 and combination anti-PD-1/L1 plus anti-CTLA-4, in each of these cancer types. We pooled the response data from the largest published studies that evaluated the ORR. We excluded studies that; enrolled < 10 evaluable patients, investigated ICI therapies in combination with other agents, and studies that selected patients based on immune-related biomarkers. Across tumor types, median TMB was compared to ORR utilizing the coefficient of determination (r2) derived from simple linear regressions. Results: TMB is strongly associated with response to anti-PD-1/L1 monotherapy (n = 8798, r2= 0.4704, p < 0.001), and combination anti-PD-1/L1 plus anti-CTLA-4 (n = 2280,r2= 0.4082, p = 0.004). Available ORR data were more limited with CTLA-4 monotherapy and the relationship between ORR and TMB did not meet statistical significance (n = 1377, r2= 0.2606, p = 0.1086). The additional ORR benefit of adding a CTLA-4 inhibitor to anti-PD-1/PDL1 therapy increased with increasing TMB. In tumor types with a lower TMB ( < 10 mutations/MB), combined ICI therapy led to an average improvement of 5.5% in ORR over PD-1/L1 monotherapy, versus 21.8 % ORR improvement in high TMB tumors (≥10 mutations/MB). Conclusions: A strong relationship exists between TMB and clinical activity of both PD-1/L1 monotherapy and combination ICIs with PD-1/L1 plus CTLA-4. The clinical benefit of adding anti-CTLA-4 to anti-PD-1/L1 is greatest in high TMB tumors and limited in low TMB tumors.
Using machine learning algorithms to predict response and toxicity to immune checkpoint inhibitors (ICIs) in melanoma patients.
Authors: Johannet Paul , Coudray Nicolas , Jour George , Donnelly Douglas MacArthur , Bajaj Shirin , Moran Una , Dawood Zarmeena , Nomikou Sofia , Kim Randie H , Pavlick Anna C. , Weber Jeffrey S. , Tsirigos Aristotelis , Osman Iman 
Published: May 2019

2581 Background: There is growing interest in optimizing patient selection for treatment with immune checkpoint inhibitors (ICIs). We postulate that phenotypic features present in metastatic melanoma tissue reflect the biology of tumor cells, immune cells, and stromal tissue, and hence can provide predictive information about tumor behavior. Here, we test the hypothesis that machine learning algorithms can be trained to predict the likelihood of response and/or toxicity to ICIs. Methods: We examined 124 stage III/IV melanoma patients who received anti-CTLA-4 (n = 81), anti-PD-1 (n = 25), or combination (n = 18) therapy as first line. The tissue analyzed was resected before treatment with ICIs. In total, 340 H&E slides were digitized and annotated for three regions of interest: tumor, lymphocytes, and stroma. The slides were then partitioned into training (n = 285), validation (n = 26), and test (n = 29) sets. Slides were tiled (299x299 pixels) at 20X magnification. We trained a deep convolutional neural network (DCNN) to automatically segment the images into each of the three regions and then deconstruct images into their component features to detect non-obvious patterns with objectivity and reproducibility. We then trained the DCNN for two classifications: 1) complete/partial response versus progression of disease (POD), and 2) severe versus no immune-related adverse events (irAEs). Predictive accuracy was estimated by area under the curve (AUC) of receiver operating characteristics (ROC). Results: The DCNN identified tumor within LN with AUC 0.987 and within ST with AUC 0.943. Prediction of POD based on ST-only always performed better than prediction based on LN-only (AUC 0.84 compared to 0.61, respectively). The DCNN had an average AUC 0.69 when analyzing only tumor regions from both LN and ST data sets and AUC 0.68 when analyzing tumor and lymphocyte regions. Severe irAEs were predicted with limited accuracy (AUC 0.53). Conclusions: Our results support the potential application of machine learning on pre-treatment histologic slides to predict response to ICIs. It also revealed their limited value in predicting toxicity. We are currently investigating whether the predictive capability of the algorithm can be further improved by incorporating additional immunologic biomarkers.