bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation of circulating EBV-targeted cytotoxic T lymphocyte precursors (EBV-CTLp) and clinical response following tabelecleucel (tab-cel) infusion in patients with EBV-driven disease.
Authors: Aftab Blake T. , Munson Daniel , Rasor Kevin , Foubert Philippe , Tsai Donald Edward , Weng Wen-Kai , Ghobadi Armin , Van Besien Koen , Sun Yan , Hiremath Minoti , Navarro Willis H. , Prockop Susan 
Published: May 2019

2532 Background: EBV is implicated in a variety of diseases. Tab-cel is an investigational off-the-shelf, allogeneic T-cell immunotherapy utilizing endogenous T cell receptors targeting EBV antigens. We hypothesized the clinical activity of tab-cel is mediated by expansion and persistence of EBV-specific T cells. Therefore, we quantified circulating EBV- CTLp after tab-cel administration and examined the correlation between expansion and clinical response. Methods: Samples from 10 patients with EBV+ post-transplant lymphoproliferative disease (PTLD) and other EBV-associated diseases enrolled in an multicenter expanded access protocol (EAP) study ( NCT02822495 ) were analyzed. To evaluate CTLp frequencies, limited dilution analysis was performed on samples taken at baseline and day 34 post first tab-cel dose (end cycle 1). The day 34 persistence of circulating EBV-CTLp from best overall response to initial tab-cel product was tested using the two-tailed Mann-Whitney test. Changes in inflammatory cytokines were also measured. Results: Responders represented in this sampling (n=6; 2 PR and 4 CR) showed a median 5.8-fold increase in circulating CTLp between baseline and day 34 (range: 0.8 to 133-fold). Five of 6 responders showed an increase in EBV-CTLp at day 34 of ≥ 3.8-fold while 1 pt showed no change in CTLp (0.8-fold change). In contrast, the 4 non-responders (3 SD; 1 PD) showed a median 0.3-fold decrease in EBV-CTLp from baseline (range: 1.2 to 0.02-fold; ns). Cumulative analyses revealed a statistically significant correlation between the fold-change of circulating CTLp at day 34 and clinical response (p=0.038) which did not appear to correlate with the type of the EBV-associated disease. Inflammatory cytokines showed no meaningful change from baseline. The safety profile remains consistent with previously reported data. Conclusions: These data support the correlation of clinical activity of tab-cel with the expansion and persistence of EBV-specific T-cells at day 34 post-treatment, as well as the use of circulating CTLp as a biomarker for response in clinical studies. Clinical trial information: NCT02822495.
Safety and efficacy of adoptive cell transfer using autologous tumor infiltrating lymphocytes (LN-145) for treatment of recurrent, metastatic, or persistent cervical carcinoma.
Authors: Jazaeri Amir A. , Zsiros Emese , Amaria Rodabe Navroze , Artz Andrew S. , Edwards Robert P. , Wenham Robert Michael , Slomovitz Brian M. , Walther Axel , Thomas Sajeve Samuel , Chesney Jason Alan , Morris Robert , Matsuo Koji , Gaillard Stephanie , Rose Peter Graham , Donas Jesus Garcia , Tromp Jacqueline Maria , Tavakkoli Fatemeh , Li Huiling , Fardis Maria , Monk Bradley J. 
Published: May 2019

2538 Background: There is a high unmet medical need for effective treatments for patients with recurrent, metastatic, or persistent cervical cancer. Most patients are young and survival rates are poor. ORR for second line therapies is between 4 and 14% for chemotherapy and recently approved immunotherapy. Adoptive cell transfer using tumor infiltrating lymphocytes (TIL) have demonstrated durable responses in some patients with recurrent cervical cancer thus offering the potential for long-term disease control. Methods: Study C-145-04 is an ongoing, open-label, multicenter Phase 2 clinical trial evaluating the safety and efficacy of LN-145 TIL therapy in patients with advanced cervical cancer who have undergone at least one prior line of chemotherapy. Prior checkpoint inhibitor therapy is an exclusion criterion. The primary endpoint is ORR per RECIST 1.1; secondary endpoints include duration of response (DOR), disease control rate (DCR), and LN-145 safety. Tumors surgically harvested at local institutions are shipped to central GMP facilities for TIL generation in a 22-day manufacturing process. Final LN-145 TIL product is cryopreserved and shipped to sites. Patients receive one week of preconditioning lymphodepletion (cyclophosphamide, fludarabine), a single LN-145 infusion, followed by up to 6 doses of IL-2 (600,000 IU/kg). Results: As of 4 Feb 2019, 27 efficacy-c patients have received Gen 2 of LN-145, with a mean age of 47 years and 2.6 mean prior lines of therapy. Preliminary efficacy results: ORR was 44% (1 CR, 9 PR, 2 uPR), DCR was 89% at 3.5-month median study follow-up with 11/12 patients maintaining their response. Improved responses were observed in 4 patients with longer follow-up. Mean TIL cells infused was 28x109. Median IL-2 doses administered was 6.0. The adverse event profile was generally consistent with the underlying advanced disease and the profile of the lymphodepletion and IL-2 regimens. Conclusions: LN-145 results in 44% ORR in previously treated cervical cancer patients with acceptable safety and efficacy profile. LN-145 offers patients a viable therapeutic option warranting further investigation. Clinical trial information: NCT03108495.
Development of a baseline prognostic cytokine signature that correlates with nivolumab (NIVO) clearance (CL): Translational pharmacokinetic/pharmacodynamic (PK/PD) analysis in patients with renal cell carcinoma (RCC).
Authors: Wang Rui , Shao Xiao , Zheng Junying , Ishii Yuko , Pak Irene , Roy Amit , Bello Akintunde , Lee Richard , Zhang Joshua , Wind-Rotolo Megan , Feng Yan 
Published: May 2019

2544 Background: CL of checkpoint inhibitors has been identified as a predictive covariate of overall survival (OS) in several tumors. Determination of CL requires post-treatment samples, which negates its utility as a baseline prognostic biomarker. This study aims to identify a baseline composite cytokine signature that correlates with NIVO CL in patients with RCC using translational PK/PD analysis. Methods: Peripheral serum PK (NIVO CL) and serum biomarkers to assess PD (Myriad Rules-Based Medicine customized inflammatory cytokine panel) were analyzed from 985 patients with RCC enrolled in 3 clinical trials. CheckMate (CM) 009 (NCT01358721) and CM 025 (NCT01668784) of NIVO (n = 481) were used for model development (training dataset). CM 010 (NCT01354431) of NIVO and a cohort treated with everolimus in CM 025 were included in model application (test dataset; n = 504). PK/PD analyses were conducted using a machine learning algorithm with performance assessed by receiver operating characteristic (ROC) curve and accuracy by confusion matrix. Results: The model selected the top-10 baseline inflammatory cytokines to form a composite cytokine signature, which predicted NIVO CL (high vs low) that was significantly associated with OS (p < 0.001) across all 3 studies (training and test datasets). The same cytokine features were associated with OS of everolimus (p < 0.01), suggesting the potential prognostic nature of the composite signature. The PK/PD analysis provided a robust description of the association between selected cytokines and CL (ROC = 0.71). Identified cytokines (eg, serum C-reactive protein known to reflect immune cell modulation) have been shown individually to be associated with RCC prognosis. A multivariable approach resulting in tumor-specific composite signatures may provide more accurate prognostic value. Conclusions: The baseline composite cytokine signature could serve as a clinically useful biomarker for patients with RCC, pending further evaluation, as it may provide improved prognostic accuracy for long-term clinical outcome compared to individual cytokines.
CD4+ T-cell immunity predicts long-lasting antitumor immunity after PD-1 blockade therapy.
Authors: Kaira Kyoichi , Yamaguchi Ou , Yoshimura Kenichi , Mouri Atsuto , Shiono Ayako , Nishihara Fuyumi , Miura Yu , Shinomiya Shun , Hashimoto Kosuke , Murayama Yoshitake , Kitano Shigehisa , Kobayashi Kunihiko , Kagamu Hiroshi 
Published: May 2019

2545 Background: Patients treated with programmed cell death 1 (PD-1)-blockade therapy fall into 3 distinct subgroups: non-responders presenting early disease progression, long survivors who achieve durable disease control, and the remaining short-term responders. We reported that the prediction formula comprised of the percentages of CD62L-downregulated (CD62Llow) and CD25+FOXP3+CD4+T cells in the peripheral blood predicted non-responders of non-small cell lung cancer patients (n = 50) scheduled to receive anti-PD-1-antibody (nivolumab) therapy in the 2017 ASCO meeting. In this study, we included 171 patients with NSCLC who were scheduled for nivolumab treatment after obtaining written informed consent. Peripheral blood mononuclear cells (PBMC) were examined before and after Nivolumab therapy up to 2 years to investigate the differences between long survivors and short-term responders. Methods: The patients received Nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks. Tumor response was assessed with the use of the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, at week 8 and every 8 weeks thereafter. PBMCs were analyzed with a 18-color microfluorometer, LSR Fortessa and a masscytometer, CyTOF. Results: The responder-type patient group whose prediction formula values were greater than 192 showed significantly longer PFS ( P< 0.0001) and OS ( P< 0.0001). The long survivors who consisted of tail plateau of PFS exhibited significantly more CD62LlowCD4+T cells than the short-term responders as pre-existing immunity. The remaining responders kept significantly higher percentages of CD62LlowCD4+T cells ( P= 0.0088) and prediction formula values ( P= 0.017) than the patients with acquired resistance. Conclusions: The pre-existing CD4+T cell balance between primed effector and regulatory T cells correlated with anti-PD-1 therapy response. Further, CD62Llowcell-dominant CD4+T cell immunity was required to maintain durable antitumor reactivity induced by anti-PD-1 antibody therapy. These results have important clinical implication, as they support anti-PD-1 therapy provision to all potentially responding patients and pave the way for new treatment strategies for patients with distinct CD4+T cell immune statuses. Clinical trial information: UMIN000020719.
Severe immune-related adverse events in anti-PD-1-treated patients are clustered into distinct subtypes by peripheral blood T-cell profiles.
Authors: Kim Kyung Hwan , Cho Jinhyun , Hur Joon Young , Ku Bo Mi , Koh Jiae , Sun Jong-Mu , Lee Se-Hoon , Ahn Jin Seok , Park Keunchil , Ahn Myung-Ju , Shin Eui-Cheol 
Published: May 2019

2564 Background: Although anti-programmed death-1 (PD-1) treatment has shown remarkable anti-tumor efficacy, immune-related adverse events (irAEs) develop with heterogeneous clinical manifestations. Immunological understanding of irAEs is currently limited. In the present study, we analyzed peripheral blood T cells obtained from cancer patients who received anti-PD-1 treatment to determine the immunological characteristics of severe irAEs. Methods: This study included 31 patients with refractorythymic epithelial tumor (TET) who were enrolled in a phase II trial of pembrolizumab (NCT02607631) and 60 patients with metastatic non-small cell lung cancer (NSCLC) who received pembrolizumab or nivolumab. T-cell profiling was performed by multi-color flow cytometry using peripheral blood obtained immediately before treatment and 7 days after the first dose of anti-PD-1 antibodies. Results: Severe irAEs (≥ grade 3) occurred in 7 TET patients (22.6%) and 6 NSCLC patients (10.0%). Patients with severe irAEs exhibited a significantly lower fold increase in the frequency of effector regulatory T (eTreg) cells after anti-PD-1 treatment, higher ratio of T helper-17 (Th17) and T helper-1 cells at baseline, and higher percentage of Ki-67+cells among PD-1+CD8+T cells post-treatment. In clustering analysis, patients with severe irAEs were grouped into four distinct subtypes: Th17-related, TNF-related,Treg-related, and CD8-related. Conclusions: Severe irAEs after anti-PD-1 treatment were clustered into four immunological subtypes, indicating that development of severe irAEs is not attributed to a single mechanism. Further investigations in larger cohorts are needed to validate our current findings.
Organ dysfunction (dys) and clinical outcomes in patients (pts) treated with immune checkpoint inhibitors (ICIs).
Authors: LIU QI , Sharon Elad , Zineh Issam , Xie Diqiong (Joan) , Baxi Shrujal S. , Liu Chao , Zhi Jizu , Torres Aracelis Z. , Gossai Anala , Sridhara Rajeshwari , Booth Brian , Blumenthal Gideon Michael , Huang Shiew-Mei , Khozin Sean 
Published: May 2019

2569 Background: ICIs (anti-PD-L1/PD-1/CTLA-4) are approved in multiple cancers. The impact of organ dys on the pharmacokinetics of ICIs is known, but associated clinical outcomes are not well characterized. We compared real-world (rw) clinical outcomes in ICI-treated pts by liver and renal function. Methods: This retrospective study used longitudinal, patient-level data from community practices in the Flatiron Health electronic-health record (EHR)-derived database. We included pts diagnosed with advanced cancers (NSCLC, renal cell, melanoma, gastric/esophageal, or head and neck) on or after 1/1/2011, treated with an ICI with follow-up through 12/31/2018 and with baseline liver or renal function results in the EHR ≤30 days prior to ICI start. Organ function was stratified as normal, mild, moderate, or severe dys based on NCI CTCAE. We computed unadjusted median estimates for rw time to treatment discontinuation (rwTTD) for any reason and overall survival (OS) across baseline groups using the Kaplan-Meier method. Results: Of 15,979 pts, we identified 12,978/12,840 pts with evaluable renal/liver function, respectively; median follow-up was 5.1 mos and median age was 69.0 yrs (IQR: 61.0, 76.0) for both. Most pts had NSCLC (69.4/69.0%), were men (60.1/60.0%), white (73.5/73.6%), and diagnosed at stage IV (58.7%/58.6%). Most ICI was given in 1st-line (42.3/42.1%) (outcomes in Table). Conclusions: Pts with categorically worse baseline liver function had progressively worse on-treatment outcomes, including shorter OS, which differed from trends in renal dys. Whether baseline dys is prognostic or predictive of ICI outcomes should be further investigated in addition to reasons for discontinuation. Clinical outcomes (unadjusted median times, mos [95% CI]) by organ function. [Table: see text]
Neoadjuvant presurgical PD-1 inhibition in oral cavity squamous cell carcinoma.
Authors: Horton Joshua Dean , Knochelmann Hannah , Armeson Kent , Kaczmar John M. , Paulos Chrystal , Neskey David 
Published: May 2019

2574 Background: Oral cavity squamous cell carcinoma (OCSCC) is a highly prevalent surgically-treated subset of head and neck cancer with frequent recurrence and poor survival. Immunotherapy has demonstrated efficacy in recurrent/metastatic head and neck cancer, but has not been validated in the neoadjuvant presurgical setting. Methods: A Simon two stage design was used in this single-arm, Phase II clinical trial with a preplanned analysis after completion of stage one. The first stage included 9 patients with stage II-IVA OCSCC who received 3-4 biweekly doses of 3mg/kg Nivolumab (anti-programmed death 1 [PD-1]) followed by definitive surgical resection for cure. The primary endpoint was overall response rate to treatment. Secondary endpoints were safety and feasibility. Results: Presurgical Nivolumab therapy resulted in an overall response rate of 44% (95% CI: 14-79%) with four patients having >30% reduction in tumor size consistent with partial response. An additional patient had stable disease while the remaining four patients progressed through treatment. Neoadjuvant Nivolumab was not associated with delays in definitive surgical treatment. There were no grade 3-4 adverse events and no treatment interruptions. At median follow up of 10 months (2-16), there were 4 recurrences in 3 patients and one death. Objective response by RECIST 1.1 criteria on interval imaging predicated eventual pathologic response in 100% of patients. Conclusions: Neoadjuvant presurgical PD-1 blockade is associated with encouraging response rate and demonstrates feasibility and safety for OCSCC. Clinical trial information: NCT03021993.
A donor-dependent in vivo model for single agent and drug combination cytokine release syndrome safety evaluation.
Authors: Keck James G. , Cheng Mingshan , Brehm Michael , Greiner Dale , Shultz Lenny J. , Rueter Jens , Ye Chunting 
Published: May 2019

2612 Background: Although antibodies and CART cells therapies have been successfully used for cancer therapy, they can have lethal adverse effects such as cytokine release syndrome (CRS). The animal models and in vitro human PBMC assays presently in use can’t reliably predict the CRS in patients. A predictive marker for identifying patients at risk for developing CRS upfront would improve the safety of immune-oncology drug development. Methods: We have developed a rapid, sensitive and reproducible in vivo humanized mouse model for quantitating CRS. The NSG mouse and its derivatives are engrafted with human PBMCs. On day 6 we induced cytokines release with pembrolizumab, avelumab, atezolizumab, ipilimumab, anti-CD28, ATG and OKT3 in single dose; as well as combination treatments involving pembrolizumab, lenalidomide, ATG and anti-CD28. Furthermore, we compared our method versus the in vitro PBMC assay. The cytokine levels were also compared to the dose response. Results: There are about 10-15% CD45+ human cells on day 5 of engraftment; and among of them, there were approximately 70% CD3 T cells and 25% CD56 NK cells. All tested cytokines, human IFN-γ, IL-2, IL-4, IL-6, IL-10 and TNF were upregulated after 2 and 6 hours of OKT3, ATG, anti-CD28, pembrolizumab, avelumab and atezolizumab drug treatment. Mouse’s rectal temperatures dropped from 37-38 °C to about 36 °C at 6 hours’ time point in the treated groups. There is various cytokines release levels, low to high response in different donors with anti-CD28 treatment. All donors showed high response to OKT3. The cytokine release levels were consistent with a dose response or variable PBMC engraftment. The cytokine levels were also higher in some drug combination studies such as pembrolizumab combined with lenalidomide or ATG; anti-CD28 combined with ATG. Our in vivo method was able to determine CRS missed in the in vitro testing method. Conclusions: We have developed a rapid, sensitive and reproducible novel in vivo PBMC humanized mouse model that is able to differentiate human PBMC donors based on individual safety response to single agent and combination therapeutics of immune checkpoint inhibitors and possibly CAR-T therapy. This assay could be employed in future drug development.
Interleukin-6 is potential target to de-couple checkpoint inhibitor-induced colitis from antitumor immunity.
Authors: Johnson Daniel H. , Hailemichael Yared , Foo Wai Chin , Hess Kenneth R. , Haymaker Cara L. , Wani Khalida M , Lazar Alexander J. , Saberian Chantal M , Bentebibel Salah E , Burton Elizabeth M. , Abu-Sbeih Hamzah , Wang Yinghong , Hwu Patrick , Diab Adi 
Published: May 2019

2616 Background: A deep understanding of the immunobiology of checkpoint inhibitor (CPI) induced immune related toxicities, such as immune related enterocolitis (irEC), and how these compare to the immune signatures in tumors could lead to the development of strategies that de-couple autoimmunity from anti-tumor immunity. Methods: Total RNA from patient-matched irEC and normal colon FFPE tissue from patients [n = 12] receiving CPIs were profiled with the 770 gene NanoString nCounter PanCancer Immune Profiling Panel (NanoPCIP). The mean fold change in gene expression from normal vs. irEC inflamed colonic tissue and baseline vs. on-treatment tumor samples from patients responding or non-responding to ipilimumab based therapy were analyzed. C57BL/6 mice with B16.BL6 melanoma tumors were treated with systemic anti-IL-6 + anti-CTLA-4 vs. anti-CTLA4 alone vs. placebo and tumor size was measured. Results: In patients with irEC, the highest significantly upregulated differentially expressed gene (DEG) in inflamed colon tissue encoded for IL-6 (Fold change +24.1). None of the significant and highest upregulated DEGs in the colitis, including IL-6, were significantly upregulated in responding tumors. Interestingly, IL-6 was also the highest upregulated DEG in non-responding tumors numerically. When comparing mean fold changes across these analyses, the gene with the largest difference in upregulatation between colitis and responding tumors was IL-6; the other highest upregulated genes in colitis encoded for neutrophil and monocyte chemotactic molecules. In our mouse models, the addition of IL-6 blockade to anti-CTLA-4 therapy significantly improved tumor shrinkage compared to anti-CTLA-4 alone. Conclusions: Our data demonstrates that IL-6-mediated inflammation may be more prevalent in irEC and tumors not responding to CPIs than in tumors responding, and blocking IL-6 enhances CPI anti-melanoma activity. Targeting IL-6 may ameliorate irEC without hindering anti-tumor immunity.
Frameshift mutations (Fsindel) complement tumor mutation burden (TMB) in predicting survival after immune checkpoint inhibitors (ICI) in a pancancer analysis.
Authors: Florou Vaia , Park Wungki , Hosein Peter Joel , Wilky Breelyn A. , Trent Jonathan C. , Lopes Gilberto 
Published: May 2019

2617 Background: ICI benefit certain patients (pts) with various malignancies and discovering biomarkers for response is an active research field. Recently, higher TMB (top 20% in each histology) based on nonsynonymous single nucleotide variants from MSK-IMPACT was shown to correlate with superior survival in a pancancer cohort. Fsindels may generate more immunogenic neoantigens and robust T cell infiltrates, thus predicting better responses to ICI. We previously demonstrated the clinical implication of fsindel in lung cancer pts on ICI. However, its value in other solid cancers has not been evaluated. Methods: Comprehensive genomic profiling (CGP) of the tumors was performed by FoundationOne to derive fsindel and TMB as previously described. Pts with advanced solid cancers who received ICI and had CGP available were included. We categorized pts into two groups; 0 fsindel (FS-) and more than 1 fsindel (FS+). Also, they were categorized into TMB high (top 20%) and TMB low (bottom 80%) within their own histology. Progression free survival (PFS) and overall survival (OS) were compared. Results: One hundred thirty-one pts excluding lung cancer were included. There were 11 histology groups: 14 soft tissue sarcomas, 19 GU, 23 GI, 23 skin, 10 HEENT, 10 RCC, 9 GYO, 6 pancreas, 5 mucosal melanoma, 4 breast, and 8 others. 74 pts received pembrolizumab, 25 nivolumab, 29 ipilimumab/nivolumab, and 3 atezolizumab. All pts had metastatic disease, mean age was 61 years and 55 (42%) were women. Among the 131 pts, 74 were FS- and 57 FS+. The presence of fsindel (FS+) was significantly correlated with overall response (p = 0.032) and clinical benefit rates (p = 0.025). TMB-high did not show any significant difference in PFS (p = 0.1) or OS (p = 0.28) when compared to the TMB low. However, in a combined model of TMB and fsindel, TMB high and FS+ patients had significantly better PFS compared to patients who had either TMB high or FS+ or neither (TMB low and FS-) (p = 0.021). Conclusions: Combined model of TMB high and fsindel (+) correlated with superior PFS in advanced solid cancer pts on ICI, in concordance with previous report for lung cancer. Validation in a larger cohort is underway.