bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct immunogenomic properties of melanomas with stable disease as best response to immune checkpoint blockade (ICB).
Authors: Vokes Natalie , Margolis Claire , Liu David , Schilling Bastian , Schadendorf Dirk , Van Allen Eliezer Mendel 
Published: May 2019

2515 Background: ICB has improved survival in melanoma. Patients with stable disease (SD) as best treatment response represent an intermediate response phenotype whose biology has been incompletely characterized. Methods: Whole exome and transcriptome sequencing from pre-treatment tumors in melanoma patients treated with ICB (anti-CTLA-4 and/or anti-PD-1) were assembled and uniformly analyzed (WES n = 293; WES+RNA-seq n = 159). RECIST (v1.1) was used to determine complete or partial response (CR/PR; n = 94), SD (n = 42), or progressive disease (PD; n = 157). Gene set enrichment analysis (GSEA) was performed on 50 “hallmark” gene sets to identify pathways differentially expressed in patients with SD. CIBERSORT was used to infer relative proportions of 22 immune cell types in each sample. Mutation antigenicity was determined by calculating patient-specific mutation affinity for MHC class I peptides. Results: GSEA identified enrichment of multiple immune-related gene sets in SD tumors, including TNF-α signaling and interferon-ɣ response (FDR q < 0.1, SD vs CR/PR and SD vs PD). SD tumors had higher HLA and antigen presentation pathway expression, and increased cytolytic T cell activity compared to CR/PR and PD. CIBERSORT analysis identified higher total immune infiltrate in SD patients compared to CR/PR and PD (Mann-Whitney U p = 0.03 and p < 0.001, respectively) but not in patients with CR/PR vs PD (p = 0.124). However, checkpoint expression, including PD-1, PD-L1, and LAG3, was also higher in SD patients. Mutation load did not differ between SD and CR/PR or PD patients (SD median 2.87 vs CR/PR median 7.98, Mann-Whitney U p = 0.104; PD median 3.42, p = 0.210). However, SD patients had more antigenic passenger mutations (SD vs CR/PR, p = 0.001; vs PD, p < 0.001); there was no difference in antigenicity of driver mutations. Conclusions: Pre-treatment melanomas from patients with SD contain more antigenic passenger mutations and demonstrate a global increase in immune signaling. This may describe a subset of patients with pre-existing dysfunctional immune response that is minimally responsive to ICB. Further characterization of the tumor-immune interaction in these patients may inform improved interventions.
Impact of bridging chemotherapy on clinical outcome of CD19 CAR T therapy in adult ALL.
Authors: Perica Karlo , Flynn Jessica , Curran Kevin Joseph , Wang Xiuyan , Halton Elizabeth , Diamonte Claudia , Pineda John , Bernal Yvette , Gonen Mithat , Riviere Isabelle , Sadelain Michel , Brentjens Renier J. , Park Jae Hong 
Published: May 2019

2520 Background: Autologous chimeric antigen receptor (CAR) T cell therapy has shown to be effective in CD19+ relapsed or refractory (R/R) B-ALL but requires a 2-4 week period of cell processing and manufacture. During this “bridging period,” patients are vulnerable to disease progression and complications. We sought to characterize bridging strategies in our published study of CD19 CAR T cell therapy in adults with R/R ALL (Park et al., NEJM, 2018). Methods: We performed a retrospective review of adult patients with R/R ALL treated with 19-28z CAR T therapy at MSKCC. Bridging therapy was defined as any therapy given from trial enrollment to cell infusion and classified as either high intensity (remission-inducing or myelosuppressive regimens, eg hyper-CVAD or high-dose cytarabine based regimens) or low intensity (maintenance and/or less myelosuppressive regimens, eg POMP, Blinatumomab, TKI). Results: Of 53 patients who received CAR T cell infusion, 19 were bridged with a high intensity regimen and 34 with a low intensity regimen. There was no difference in number of prior therapies, pre-bridging chemotherapy disease burden, and prior transplant status between groups. High intensity therapy was associated with a higher rate of Gr3-4 infectious complications during the bridging period (78% vs 32%, p < 0.002 by Fisher’s Exact) but not with response to bridging or CAR T cell therapy, relapse free survival, post-CAR Gr3-4 cytokine release syndrome (CRS) or neurotoxicity (NT). Patients in both groups who converted from morphologic to molecular disease during bridging (n=9) had a decreased rate of eventual severe CRS (0% vs 41%, p=0.01) or NT (0% vs 55%, p <0.01) compared to patients with persistent morphologic disease. In all patients enrolled on trial (n=83), use of high compared to low intensity bridging was not associated with higher rates of successful CAR T cell infusion (63% vs 79%, p>0.05) or a combined endpoint of CAR T cell infusion or alternative therapy including transplant (80% vs 86%, p> 0.05). Conclusions: High intensity bridging therapy is associated with a high risk of infectious complications without a clear benefit in outcome in R/R ALL receiving CD19 CAR T cells. Selection of bridging regimen therefore requires consideration of previous treatments and patient status to maximize the efficacy and safety. Clinical trial information: NCT01044069.
A phase I study to assess safety, pharmacokinetics (PK), and pharmacodynamics (PD) of JNJ-64457107, a CD40 agonistic monoclonal antibody, in patients (pts) with advanced solid tumors.
Authors: Calvo Emiliano , Moreno Victor , Perets Ruth , Yablonski-Peretz Tamar , Fourneau Nele , Girgis Suzette , Guo Yue , Hellemans Peter , Hokey David , Pendas Franco Natalia , Xia Qi , Geva Ravit 
Published: May 2019

2527 Background: JNJ-64457107 (JNJ-107) is an agonistic human monoclonal (IgG1) antibody targeting CD40, a novel target for anti-tumor immunotherapy with a central role in adaptive and innate immunity. Methods: JNJ-107 was administered intravenously Q2W in treatment cycles of 28 days. Dose escalation was pursued with (w) and without (wo) pre-infusion steroids for mitigation of infusion related reactions (IRRs). Dose-limiting toxicity (DLT), safety, PK, PD and antitumor activity were evaluated. Results: 95 pts of age 18-80 years (median 59) were enrolled in 7 cohorts (n = 50, 75µg/kg – 2000 µg/kg) w/steroids and 5 cohorts (n = 45, 75 µg/kg – 1200 µg/kg) wo/steroids and received 1-26 (median 3) cycles of JNJ-107. Two DLTs occurred: Grade (G) 3 headache lasting 5 days at 1200 µg/kg w/steroids and G3 ALT/AST + G2 bilirubin increase at 1200 µg/kg wo/steroids. Most frequent adverse events (≥20%) were pyrexia (41%), fatigue (39%), pruritus (39%), headache (26%), chills (26%), nausea (22%) and rash (21%). IRRs were reported in 51% of pts (G1-G2 50%, G3 1%). Most commonly reported IRRs (≥10%) were pruritus (31%), rash (15%), chills (13%) and flushing (12%). Cetirizine and Montelukast premedication during dose escalation wo/steroids significantly reduced IRRs. Preliminary PK of JNJ-107 suggest target mediated drug disposition with rapid decline in serum concentrations (half-life of ~13h at 600 µg/kg and ~ 24h at doses ≥1200 µg/kg). Dose proportional increase in Cmax and AUC(last) was observed at doses ≥1200 µg/kg and more than dose proportional increase was seen at lower doses. PD of JNJ-107 demonstrated dose-independent reduction in peripheral blood B cells recovering in a dose-dependent manner. MCP-1, IP-10, MIP-1a, and MIP-1b cytokines showed high-level responses with cytokine/chemokine secretion kinetics consistent, but not confirmatory, for activation of antigen presenting cells. IFNg, TNF, and IL-8 showed moderate responses reflecting downstream T cell activation. Other tested cytokines were at low levels. A partial response lasting 9.2 months was observed in 1 pt with renal cell cancer. 13 (14%) and 10 (11%) pts showed stable disease lasting ≥3 months and ≥ 6 months, respectively. Conclusions: The CD40 agonist JNJ-107 has a manageable safety profile with favorable PK and PD properties. Future clinical development will require combination with either chemotherapy, or other immunotherapies such as antitumor vaccines or checkpoint inhibitors. Clinical trial information: NCT02829099.
Ramucirumab (Ram) and durvalumab (Durva) treatment of metastatic non-small cell lung cancer (NSCLC), gastric/gastroesophageal junction (G/GEJ) adenocarcinoma, and hepatocellular carcinoma (HCC) following progression on systemic treatment(s).
Authors: Bang Yung-Jue , Golan Talia , Lin Chia-Chi , Dahan Laetitia , Fu Siqing , Moreno Victor , Geva Ravit , Reck Martin , Wasserstrom Heather Ann , Mi Gu , Laing Naomi , Goff Laura Williams 
Published: May 2019

2528 Background: A Phase 1b study (NCT02572687) was conducted to examine the combined effects of Ram (anti VEGFR2) and Durva (anti PD-L1). Methods: Patients (pts) with previously-treated, advanced NSCLC (Cohort [CH] A), G/GEJ adenocarcinoma (CH B), HCC (CH C), ECOG PS 0-1, and no prior Ram or IO therapy, received Ram (10 mg/kg) + Durva (1125 mg) Q3W (CH A) or Ram (8 mg/kg) + Durva (750 mg) Q2W (CH B, C). Primary objective was to assess safety; efficacy was also examined. PD-L1 expression of tumor cells (TC) +/- immune cells (IC) in pretreatment tumor biopsies were assessed using SP263 immunohistochemistry. “High” PD-L1 is ≥25% TC for NSCLC and ≥25% TC or IC for G/GEJ, HCC. Results: CH A, B and C enrolled pts with ECOG PS 1 (%) of 43, 66, 68; and average of 2, 2, 1 prior regimens, respectively. The most common grade 3/4 treatment-emergent adverse events (AE) are hypertension (HTN) (14.3, 17.2, 17.9%), anemia (3.6, 24.1, 21.4%), and fatigue (10.7, 10.3, 10.7%). Grade 3/4 AEs of special interest ( > 5% total pts) for Ram: HTN, bleeding events (3.6, 10.3, 10.7%), Venous thromboembolic events (0, 10.3, 7.1%); for Durva: increase in lipase (10.7, 3.4, 10.6%) and AST (3.6, 3.4, 17.9 %). Data from CH B,C suggest a trend toward increased efficacy in pts with high PD-L1 expressing tumors. Conclusions: Ram + Durva generated no unexpected toxicities and demonstrated antitumor activity. Results in pts with high PD-L1 HCC and G/GEJ cancer warrant further evaluation. Clinical trial information: NCT02572687. [Table: see text]
Clonal expansion of tumor infiltrating lymphocytes (TILs) in the peripheral blood of metastatic melanoma patients is significantly associated with response to CTLA4 blockade-based immunotherapy.
Authors: Khunger Arjun , Rytlewski Julie , Yusko Erik C. , Tarhini Ahmad A. 
Published: May 2019

2541 Background: Patients with metastatic melanoma were treated on a clinical trial with tremelimumab and High Dose Interferon-Alfa (HDI) (Tarhini. J Clin Oncol. 2012). We previously reported that patients who achieved disease control and clinical response had significantly greater T-cell clonality (p = 0.0008) and T-cell fraction (p = 0.044) respectively in their pretreatment tumor biopsy samples (Tarhini. J Clin Oncol. 2017). In this study, we further characterize T-cell repertoire clonality and clonal expansion in the peripheral blood at different time points to evaluate the association between repertoire features and clinical response. Methods: Patients received tremelimumab 15 mg/kg I.V. every 12 weeks and HDI was given concurrently. Responses were assessed by RECIST as complete (CR) or partial (PR), stable disease (SD) or progression (PD). Peripheral blood mononuclear cells (PBMCs) from treated patients (N = 33) were obtained at baseline, day 29, and day 85 (following tremelimumab-HDI treatment); tumor samples at baseline were also obtained (N = 18). The T-cell receptor beta chain (TCRB) repertoire of PBMCs and tumor samples was immunosequenced using the immunoSEQ assay (Adaptive Biotechnologies), and repertoire clonality was assessed at baseline, day 29, and day 85. Differential abundance analysis was used to detect and quantify peripheral clonal expansion pre- versus post-treatment and identify the subset of peripheral clones also detected in the tumor repertoire. The Morisita Index of repertoire similarity was also calculated to compare global repertoire changes between pre- and post-treatment PBMC samples. Results: T-cell repertoire turnover, as measured by the Morisita Index, showed a trend towards responders (CR/PR) having greater turnover (lower Morisita Index) post-treatment than non-responders (SD/PD). Similarly, the total number of clones expanding in the peripheral repertoire varied over time within an individual (p = 0.034) but was not significantly affected by response to therapy (p = 0.275) or by on-treatment time point (p = 0.768). When the analysis was restricted to peripherally expanded clones that were also found in the tumor repertoire, responders had significantly more TILs expanded in the periphery at day 29 than non-responders (p = 0.036). Conclusions: Our analysis of the peripheral T-cell repertoire following treatment showed that detection of TILs in early peripheral clonal expansion correlates with response to therapy.
Molecular circulating tumor DNA response to identify long-term survival in patients receiving immunotherapy with initial radiologic stable disease.
Authors: Hellmann Matthew David , Zhang Qu , Abdullah Shaad Essa , Chaft Jamie E. , Segal Neil Howard , Gao Chen , Dennis Phillip A. , Higgs Brandon W. 
Published: May 2019

2546 Background: Early on-treatment changes in ctDNA may identify responders to immunotherapy and complement radiologic assessment of benefit. Here we investigate how early changes in ctDNA associate with long-term survival following treatment with immunotherapy, and if differential patterns in molecular ctDNA response (MCR) among patients with radiologic stable disease (SD) at first on-treatment scan could identify patients deriving benefit from treatment. Methods: Paired pre- and on-treatment (week 6-8) plasma samples from 3 cohorts of patients treated with durvalumab (D) +/- tremelimumab (D+T) were evaluated (NCT01693562, NCT02087423, NCT02261220). CtDNA was profiled with the 73-gene Guardant 360 assay. Nonsynonymous variants were summarized per patient to calculate variant allelic frequency changes (dVAF) and on-treatment variant allele frequency (pVAF). A combination of dVAF and pVAF was used to define MCR. Results: The reduction of ctDNA (dVAF<0) and undetectable on-treatment ctDNA (pVAF=0) were each associated with improved OS and PFS. An optimal threshold for MCR was determined from one cohort, then applied to the other cohorts. MCR associated with significantly improved PFS and OS across all three cohorts (Table). MCR was then applied to a pooled subgroup of patients with initial radiologic SD from all three cohorts (n=78). Patients with radiologic SD and MCR were significantly more likely than those without MCR to achieve radiologic CR or PR (pooled Odds ratio 12.7, p<0.001), had improved PFS (stratified pooled HR 0.36, p<0.001), and improved OS (stratified pooled HR 0.38, p=0.005). Conclusions: MCR is an early on-treatment tool that may identify patients with improved long-term survival and patients with radiologic SD who derive clinical benefit from immunotherapy. MCR may be a supportive endpoint in prospective clinical trials. MCR and survival benefit. [Table: see text]
Community and academic partnerships: Moving a new generation of clinical trials in NCI Community Oncology Research Program (NCORP) into community oncology practices.
Authors: McCaskill-Stevens Worta J. , Geiger Ann M. 
Published: May 2019

2551 Background: NCORP is a model program that bridges academic and community oncology practices and research. Over the past decade, community cancer investigators have adopted new technology, encountered new treatment sequalae, and faced rising cost of care with its financial toxicity imposed upon individuals seeking care. Opportunities are abundant for community investigators to assess feasibility and uptake of research advances into community practice settings, yet these opportunities are met with the challenges of dynamic changes in types of organizations delivering cancer care and diversity of populations within their catchment areas. Little information is shared about how and to what extent the health environment influences this partnership and the implementation of a broad cancer research portfolio. Methods: This abstract reports on the continued interest and participation of community oncologists in research which is demonstrated by 987 practices with over 4000 investigators in NCORP. Since 2014, over 30,000 individuals enrolled in symptom management, screening, surveillance, quality of life, and treatment trials. An additional 4500 patients and clinicians have enrolled in care delivery studies. Results: NCORP has been central in evaluating the most effective strategies for investigators to effectively communicate to patients the science of genomically-driven trials. It has also provided ways of bringing the pediatric and AYA patients access to the most up-to-date treatment strategies and new therapies in their community. This creates the least disruption on family structure/dynamics, diminished traveling requirements/costs, and reduced the financial burden. NCORP promotes involvement of treating oncologists in research activities. This also improves care for patients not enrolled in clinical trials. Therefore, NCORP serves as a laboratory to determine the most effective strategies for co-management of cancer patients and survivors. Conclusions: Several questions however remain to be addressed using this clinical trial model. These include: how to continue to reduce disparities in cancer care and clinical trial participation; and, what are the best strategies for fostering implementation of cancer care models in community practice.
Association between MDM2/MDM4 amplification and PD-1/PD-L1 inhibitors-related hyperprogressive disease: A pan-cancer analysis.
Authors: Ju Weiqiang , Chen Shiqing , Wang Guoqiang , Cai Shangli , Xiong Jianping , Xiang Xiaojun 
Published: May 2019

2557 Background: Immune checkpoint inhibitors have demonstrated a clear survival benefit in various tumor types. However, accelerated disease progression, documented as hyperprogressive disease (HPD), was reported in a subset of patients treated with PD-1/PD-L1 inhibitors. Until now, the mechanisms underlying HPD have not been elucidated. Previous studies have demonstrated that MDM2/MDM4 amplification were associated with HPD. In the present study, we evaluated the relationship between MDM2/MDM4 amplification and HPD. Methods: We reviewed extensive clinical trials of PD-1/PD-L1 inhibitors in advanced solid tumor patients updated to January 2019, and estimated the incidence of HPD, which was defined as time-to-treatment failure (TTF) < 2 months, and > 50% increase in tumor burden compared with pre-immunotherapy imaging in this study. The proportions of MDM2/MDM4 amplification across different cancer types were obtained from The Cancer Genome Atlas (TCGA) and our own database respectively. Then we plotted the incidence of HPD and the corresponding proportion of MDM2/MDM4 amplification across various cancer types in TCGA. Results: Overall, 19 published clinical trials of 1318 patients treated with PD-1/PD-L1 inhibitors were included for analysis, covering 12 types of solid cancers. The incidences of HPD among these studies were ranging from 1.58% in renal clear cell carcinoma to 24.3% in sarcoma. Correspondingly, the proportions of MDM2/MDM4 amplification for these cancer types in TCGA were 0.74% in renal clear cell carcinoma to 20.38% in sarcoma. In our database, in total, 60 patients with MDM2/MDM4 amplification were identified in 2931 patients with the highest proportion of MDM2/MDM4 amplification in sarcoma (22 of 152, 14.5%). A significant correlation was detected between the incidence of HPD and the corresponding proportion of MDM2/MDM4 amplification in TCGA across various cancer types ( P < 0.001, R2 = 0.67). Conclusions: Our results suggest that MDM2/MDM4 amplification may be associated with rapid disease progression in patients receiving PD-1/PD-L1 inhibitors among various tumor types. The exact mechanisms underlying HPD are needed to be further evaluated.
Family history of cancer as surrogate predictor for immunotherapy with anti-PD-1/PD-L1 immune checkpoint inhibitors: The FAMI-L1 study.
Authors: Cortellini Alessio , Buti Sebastiano , Santini Daniele , Giusti Raffaele , Tiseo Marcello , Zoratto Federica , Marchetti Paolo , Bersanelli Melissa , De Galitiis Federica , Vitale Maria Giuseppa , Rastelli Francesca , Berardi Rossana , Tudini Marianna , Atzori Francesco , Iacono Daniela , Inno Alessandro , Bracarda Sergio , Natoli Clara , Ascierto Paolo Antonio , Ficorella Corrado 
Published: May 2019

2559 Background: In the preliminary analysis of the FAMI-L1 study, we found a significant association between family history of cancer (FHC) and better clinical outcomes with anti-PD1/PD-L1 inhibitors. Methods: We retrospectively evaluated advanced cancer patients treated with single agents PD1/PD-L1 inhibitors. Patients were categorized as follow: FHC-high (in case of at least one cancer diagnoses in both straight and collateral family line), FHC-low (in case of a cancer diagnoses in only one family line) and FHC-negative. FHC was collected till the second degree of relatedness. Results: Between September 2013 and May 2018, 772 consecutive patients were evaluated. Median age was 68 years; male/female ratio was 521/251. Primary tumors were: NSCLC (58.3%), melanoma (22.1%), renal cell carcinoma (16.6%) and others (3%). 114 patients (14.9%) had ECOG-PS ≥ 2. 341 patients (44.3) were FHC-positive: 268 of them (34.75) were FHC-low while 74 (9.6%) were FHC-high. FHC-high patients had a significantly higher incidence of irAEs compared to FHC-negative (55.4% vs 35.6%; p = 0.0012) and to FHC-low (41.4%; p = 0.0323). No significant differences were found in terms of ORR among subgroups (data not shown). At median follow-up of 15.8 months, median PFS was 9.1 months (95%CI: 8.1-10.4; 452 events) and median OS was 19.7 months (95%CI: 15.7-24.4; 436 censored). No significant differences were found regarding PFS (data not shown). Median OS of FHC-high patients was 31.6 months (95%CI: 26.2-31.6; 50 censored patients), which was significantly longer than 18.2 months (95%CI: 14.7-21.3; 229 censored patients) of FHC-negative patients (HR = 0.60 [95%CI: 0.39–0.92), p = 0.0213). No significant differences in terms of OS were found between FHC-high/low patients (data not shown). After adjusting for primary tumor, sex, treatment-line, number of metastatic sites and ECOG-PS, FHC-high was confirmed an independent predictor of longer OS compared to FHC-negative (HR: 0.57 [95%CI: 0.37-0.88], p = 0.0098). Conclusions: FHC-high seems to be an independent predictor for longer OS in cancer patients treated with anti-PD-1/PD-L1. DNA damage and response (DDR) genes alterations may underlie that results.