bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase IB study of the combination of selumetinib (AZD6244, ARRY-142886) and cyclosporin A (CsA) in patients with advanced solid tumors with an expansion cohort in metastatic colorectal cancer (mCRC).
Authors: Krishnamurthy Anuradha , Dasari A. , Noonan Anne M. , Mehnert Janice M. , Lockhart Albert C. , Stein Mark N. , Sanoff Hanna Kelly , Lee James J. , Hansen Aaron Richard , Malhotra Usha , Rippke Sarah , Davis Sarah Lindsey , Messersmith Wells A. , Eckhardt S. Gail , Lieu Christopher Hanyoung 
Published: September 2018

2587 Background: MEK inhibition is of interest in cancer drug development. However, better strategies are needed to overcome acquired resistance to MEK inhibitors. Preclinical studies have shown Wnt pathway overexpression in KRAS mutant cell lines resistant to the MEK inhibitor, selumetinib. The combination of selumetinib and cyclosporin A (CsA), a non-canonical Wnt pathway modulator, demonstrated antitumor activity in patient-derived xenograft (PDX) models. We conducted an NCI CTEP-approved Phase I/IB trial (NCI # 9571/COMIRB # 13-2628/NCT02188264) of selumetinib and CsA combination. Biomarkers of response are being co-developed. Methods: Patients with advanced solid tumors were treated with the combination of selumetinib and CsA in dose escalation followed by an expansion cohort in patients with irinotecan and oxaliplatin-refractory mCRC (n = 20). The expansion cohort utilized a selumetinib “run-in” to evaluate efficacy in RAS-WT and RAS-MT mCRC to identify those patients most likely to respond to the combination. Results: As of January 2017, 18 patients were enrolled in the dose escalation phase and 20 patients were enrolled in the dose expansion phase. The most common adverse events and grade 3/4 toxicities were rash, hypertension, and edema. Three DLTs - Grade 3 hypertension, rash and increased creatinine were reported. The maximum tolerated dose was identified as selumetinib 75 mg BID and CsA 2 mg/kg BID on a 28-day cycle. The selumetinib “run-in” did not favor a specific RAS type. Two partial responses were noted. Sixteen patients had stable disease, and 6 patients had progression of disease as their best response to therapy. Conclusions: Selumetinib in combination with cyclosporin A appears to be well tolerated with evidence of activity in mCRC. Tumor response data are currently being updated. FZD will be evaluated as a potential biomarker of response. Clinical trial information: NCT02188264.
Open label, non-randomized, multi-cohort pilot study of genetically engineered NY-ESO-1 specific NY-ESO-1c259t in HLA-A2+ patients with synovial sarcoma (NCT01343043).
Authors: Mackall Crystal , Tap William D. , Glod John , Druta Mihaela , Chow Warren Allen , Araujo Dejka M. , Grupp Stephan A. , Van Tine Brian Andrew , Chagin Karen , Van Winkle Erin , Kari Gabor , Trivedi Trupti , Norry Elliot , Holdich Tom , Bartlett-Pandite Arundathy N. , Amado Rafael G. , D'Angelo Sandra P. 
Published: September 2018

3000 Background: NY-ESO-1 is expressed in ~70% of synovial sarcomas (SS). NY-ESO-1c259T cells recognizing an NY-ESO-1 derived peptide complexed with HLA-A*02 are being studied in SS. Methods: Eligible patients (pt) are HLA-A*02:01, 02:05 or 02:06, with unresectable, metastatic or recurrent SS expressing NY-ESO-1. Primary endpoint of ORR (CR+PR) is evaluated in high (≥ 50% tumor cells express 2+/3+) and low (≥ 1+ in ≥ 1% cells, not exceeding 2+/3+ in ≥ 50% cells) NY-ESO-1 expressers with different lymphodepleting regimens. Secondary endpoints are safety, DOR, PFS, OS, and gene-marked cell persistence. Lymphocytes are obtained by leukapheresis, isolated, activated, transduced to express NY-ESO-1c259T, and expanded. Target dose is 1–6 × 109cells. Disease is assessed at wk 4, 8 and 12 post-T-cell infusion, and then every 3 months. Results: 34 pt have been enrolled with 24 treated. 50% are male; median age is 30 yr (range 15 – 73). 12/15 pt in cohort 1 were treated. ORR was 50% (1 CR; 5 PR). Time to response was 6 wk (range 4-9) and median DOR 31 wk (range 13-72). Cohort 3 was closed due to only 1 PR out of 5 pt. Evaluation is ongoing in cohorts 2 (6 enrolled; 5 treated) and 4 (8 enrolled; 2 treated) as of 1/9/17. The most common AE are leukopenia (96%), nausea and pyrexia (88%), neutropenia (88%), lymphopenia (83%), anemia (79%), and thrombocytopenia (79%). 11 events of CRS were reported (3 G3; 1 G4), with no events of seizure, cerebral edema or fatal neurotoxicity; all resolved with supportive therapy. One fatal SAE (bone marrow failure) occurred in cohort 2; investigations have not identified a mechanism by which NY-ESO-1c259T may have caused this event. Conclusions: NY-ESO-1c259T has promising efficacy and acceptable safety. CRS is not associated with severe neurotoxicity and appears manageable with appropriate supportive care. Cohort 3 data indicate that Flu may be important for efficacy. Efficacy and safety data will be further evaluated and presented. Clinical trial information: NCT01343043. [Table: see text]
CX-1158-101: A first-in-human phase 1 study of CB-1158, a small molecule inhibitor of arginase, as monotherapy and in combination with an anti-PD-1 checkpoint inhibitor in patients (pts) with solid tumors.
Authors: Papadopoulos Kyriakos P. , Tsai Frank Yung-Chin , Bauer Todd Michael , Muigai Lucas , Liang Yu , Bennett Mark K. , Orford Keith W. , Fu Siqing 
Published: September 2018

3005 Background: Arginase is secreted by myeloid-derived suppressor cells (MDSCs) and polymorphonuclear cells (PMNs) in the tumor microenvironment, depleting arginine, an amino acid required for T-cell activation and proliferation. CB-1158 is an oral small molecule inhibitor of arginase. CB-1158 reverses PMN- and MDSC-mediated suppression of T-cells in ex vivo human models, and increases plasma and tumor arginine levels in mouse syngeneic tumor models leading to increased pro-inflammatory markers and activated CD8 T-cells in the tumor. CB-1158 has single agent efficacy in mouse tumor models and synergistically enhances the antitumor efficacy of checkpoint inhibitors. Methods: This is an ongoing phase 1 study to evaluate safety and tolerability of CB-1158 as a monotherapy and in combination with anti-PD-1 in pts with solid tumors. Pharmacokinetics (PK), anti-tumor effects, and biomarkers, including plasma arginine, arginase activity, and effects on immune function in blood and in tumors will be evaluated. CB-1158 was administered BID orally in 28-day cycles. Escalating doses were administered to cohorts for safety evaluation. Additional pts were enrolled at dose levels determined to be safe to support biomarker objectives. Results: Nine pts have been enrolled across two monotherapy dose escalation cohorts (50 and 100 mg) and biomarker cohorts. CB-1158 was rapidly absorbed (Tmax = 4 h) and was cleared with a half-life of 6 h. At doses of 50 and 100 mg, steady-state plasma trough levels were 1.6 and 4.5 µM, sufficient to achieve > 90% arginase inhibition, and plasma arginine levels increased 2.4- and 4-fold, respectively. CB-1158 has been well tolerated with no DLTs or drug-related Grade 3 AEs. Dose escalation is ongoing and updated safety, PK and biomarker data will be presented. Conclusions: CB-1158 is a first-in-class inhibitor of the myeloid-derived immunosuppressive enzyme arginase. CB-1158 has been well tolerated and achieves on-target inhibition resulting in increases in plasma arginine, an amino acid required for T-cell immune responses. Clinical trial information: NCT02903914.
Loss-of-function of PBRM1 to predict response to anti-PD-1/PD-L1 therapy in metastatic renal cell carcinoma.
Authors: Miao Diana , Margolis Claire , Martini Dylan , Mullane Stephanie Anne , Cullen Dana , Horak Christine , Wind-Rotolo Megan , Hellmann Matthew David , Voss Martin Henner , Motzer Robert J. , Norton Craig , Signoretti Sabina , Snyder Charen Alexandra , Van Allen Eliezer Mendel , Choueiri Toni K. 
Published: September 2018

3016 Background: Immune checkpoint inhibitors targeting programmed cell death-1 (PD-1) substantially improve patient survival in clear-cell renal cell carcinoma (ccRCC), but predictive biomarkers for efficacy have not yet been identified. Methods: We analyzed whole exome sequencing (WES) from a clinical trial of anti-PD-1 monotherapy (nivolumab) for ccRCC (N = 34) to discover genomic predictors of response to immune checkpoint therapy, and validated our findings in 28 ccRCC patients from 2 institutions treated with anti-PD-1 or anti-PD-L1 therapies. We defined 3 response groups: clinical benefit (CB) – complete or partial response by RECIST or stable disease with objective decrease in tumor burden and progression free survival (PFS) > 6 months - and no clinical benefit (NCB) – progressive disease with PFS < 3 months, with all other patients in intermediate benefit (IB). We further validated our findings in WES from 212 melanoma patients treated with immune checkpoint therapies in 3 published cohorts. Results: Biallelic loss of the chromatin remodeling subunit PBRM1, mutated in 34/62 (55%) patients across both cohorts and up to 41% of ccRCC overall, was the only gene mutation associated with CB in both the training (p = 0.0064; Pearson’s chi-squared) and validation cohorts (p = 0.043), and predicted both PFS and overall survival (OS) (p = 0.042 and 0.014, respectively; Kaplan-Meier). In 212 melanomas, truncating alterations in ARID2 – a closely related chromatin remodeler - were also enriched in responders after correcting for tumor mutational burden (p = 0.036), and having a truncating alteration in either PBRM1 or ARID2 significantly predicted overall survival (p = 0.022). In this ccRCC cohort, tumor mutational burden and loss of antigen presentation machinery were not associated with CB or NCB. Conclusions: Loss of chromatin remodeling subunits may impact response to immune checkpoint therapy in both ccRCC and melanoma. Further study in larger cohorts of immunotherapy-treated patients and functional characterization of ARID2 and PBRM1 in the context of the tumor-immune microenvironment will help to determine potential for further biomarker development.
Expression quantitative trait loci (eQTLs) as germline determinants of melanoma immunotherapy response.
Authors: Ferguson Robert , Simpson Danny , Martinez Carlos N. , Vogelsang Matjaz , Kazlow Esther , Moran Una , Weber Jeffrey S. , Sullivan Ryan J. , Flaherty Keith , Pavlick Anna C. , Ribas Antoni , Osman Iman , Kirchhoff Tomas 
Published: September 2018

3017 Background: Approximately 40-60% of metastatic cutaneous melanoma (CM) patients do not respond to the current immunotherapy (IT) regimens, pointing to other yet unknown factors conferring IT resistance. Based on our recent findings showing that germline expression quantitative trait loci (eQTLs) in immune pathways associate with overall CM survival, in this study we tested whether germline immune-specific eQTLs also impact IT outcomes in CM. Methods: By interrogating a healthy twin cohort expression dataset (MuTHER), we have identified 50 eQTLs most significantly associated with the expression of 265 immune genes. Using the MassARRAY system, these 50 SNPs were genotyped in 138 anti-CTLA-4 treated patients, 59 PD-1 treated patients and 38 patients from combined (COMBO) treatments collected from multi-institutional collaborations. To test the association of SNPs with IT response, logistic regression was performed for each treatment group adjusting by demographic and clinical covariates. Results: We found significant associations with COMBO IT resistance for rs6673928 (OR = 4.249, p = 0.0167), an eQTL in IL10/IL19 which we have recently identified for association with melanoma survival; interestingly, it is a previously established locus associated with the risk of several autoimmune diseases. Additionally, we also identified eQTLs that are associated with IT sensitivity: rs4848306 in IL1-β with resistance to anti-CTLA-4 (OR = 0.373, p = 0.000733) and rs2071304 in SPI1with resistance to anti-PD-1 (OR = 0.3328, p = 0.0271). Conclusions: In this study we report that rs6673928, an eQTL from the IL19/IL10 locus previously shown to predict autoimmunity risk and CM survival, is also a surrogate marker of response to COMBO IT. The associations of rs6673928 with both IT response and CM survival indicate a strong relationship between interleukin pathways and the level of tumor immunogenicity. In addition to its apparent function in immune response, the putative multi-faceted role of this locus in predicting better survival and IT outcomes indicates high potential as a novel clinical target. Additional genetic and functional validation of these findings is currently underway in a large collaborative setting.
FDA analysis of patients with baseline autoimmune diseases treated with PD-1/PD-L1 immunotherapy agents.
Authors: Weinstock Chana , Singh Harpreet , Maher Virginia Ellen , Kim Geoffrey , Pazdur Richard 
Published: September 2018

3018 Background: With FDA approval of three novel agents targeting the PD-L1/PD-1 checkpoint pathway in multiple tumor types, use of these agents in the clinical setting is becoming increasingly common. However, little is published on their use in patients with a history of autoimmune diseases. We therefore aimed to collect safety data on patients with a history of autoimmune diseases treated with PD-1/PD-L1 immunotherapy agents in a clinical trial setting. Methods: Data on patients with a history of autoimmune disease were collected for four different PD-1/PD-L1 immunotherapy agents. Information collected included name of autoimmune disease, corticosteroid dependency at baseline, duration of dosing, immune-related adverse events (iRAEs) and worsening of underlying autoimmune disease. Results: In total, 552 patients enrolled in 22 clinical trials of PD-1/PD-L1 immunotherapy agents were identified with a history of autoimmune disease. None were known to be dependent on systemic corticosteroids at baseline. The most common autoimmune diseases identified were thyroid disorder (n = 188), psoriasis (n = 70), and vitiligo (n = 44). For the four agents identified, mean duration of dosing was 183, 187, 196, and 145 days. Worsening of underlying autoimmune disease occurred in 16%, 6%, 13% and 6%. There were two grade 4 cases of hyperglycemia in patients with diabetes, three cases each of grade 3 AEs related to the underlying disorder in patients with psoriasis, interstitial lung disease, and hypothyroidism, and one grade 3 AE in a patient related to ankylosing spondylitis.For two of these agents, data were available on the development of grade 1-4 irAEs (per investigator) that required treatment with systemic steroids, which occurred in 8% and 9% of patients. Conclusions: Clinical trial data demonstrates relative safety of the use of PD-1/PD-L1 immunotherapy agents in patients with a history of autoimmune disease compared to their use in patients without such history. No consistent pattern of worsening of baseline autoimmune disease was identified. These results should be interpreted with caution, as diagnostic method and clinical manifestations of reported baseline autoimmune conditions are not known.
Product characteristics associated with in vivo expansion of anti-CD19 CAR T cells in patients treated with axicabtagene ciloleucel (axi-cel).
Authors: Locke Frederick Lundry , Rossi John , Neelapu Sattva Swarup , Xue Allen , Better Marc , Zhang Xiao , Ghobadi Armin , Lekakis Lazaros J. , Miklos David Bernard , Jacobson Caron Alyce , Braunschweig Ira , Oluwole Olalekan O. , Siddiqi Tanya , Lin Yi , Timmerman John , Reagan Patrick Michael , Navale Lynn , Go William Y. , Wiezorek Jeffrey S. , Bot Adrian 
Published: September 2018

3023 Background: Axi-cel (formerly KTE-C19) is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy. ZUMA-1 is a multicenter, registrational trial of axi-cel in patients (pts) with refractory aggressive non-Hodgkin lymphoma. In a prespecified interim analysis, ZUMA-1 met its primary endpoint, with a 76% objective response rate and a 47% complete response rate ( Blood 2016;128:LBA-6). Post-treatment CAR T cell blood levels were associated with objective response. Here, we describe novel associations between product characteristics and CAR T cell levels in pts. Methods: CAR T cell characteristics in axi-cel produced from 62 pts were analyzed by flow cytometry and modeled against CAR T cell levels. In vivo CAR T cell levels were measured by qPCR. T cell expansion during production (fold expansion/total days in culture) was compared with CAR T cell blood levels, using a partition analysis with expansion rates of ≥1 vs < 1. Wilcoxon 2-sample test and linear regression were used. Results: Axi-cel contained CCR7+ T cells (median, 42%; range, 15–73%), with naïve (CD45RA+/CCR7+; median, 12%; range, 1–57%), central memory (CD45RA−/CCR7+; median, 29%; range, 12–49%) phenotypes, and more differentiated CCR7− effector memory and effector T cells. On infusion, CAR T cells expanded rapidly, reaching peak levels within 2 weeks (median, 43 cells/μL; range, 1–1513), and were also measurable in all pts at 1 month (median, 2 cells/μL; range, 0.03–89). The CCR7+/CCR7− T cell ratio in axi-cel associated positively with peak ( P =0.001) and cumulative ( P =0.003) CAR T cell levels through 1 month. Axi-cel lots that expanded more rapidly during production (≥1.0-fold/d; n = 18/62) associated with higher cumulative levels of CAR T cells ( P =0.03). Other product characteristics, eg, CD4/CD8 ratio or number of infused T cells, were not significantly associated with CAR T cell blood levels. Conclusions: An association was observed between CAR T cell expansion in vivo and both the T cell growth rate during production and product cell phenotype pretreatment. A key attribute of axi-cel product was the presence of CCR7+ naïve/central memory T cells, without upfront T cell subset selection. Clinical trial information: NCT02348216.
Characterization of anti-CD19 chimeric antigen receptor (CAR) T cell-mediated tumor microenvironment immune gene profile in a multicenter trial (ZUMA-1) with axicabtagene ciloleucel (axi-cel, KTE-C19).
Authors: Galon Jerome , Rossi John , Turcan Sarah , Danan Corinne , Locke Frederick Lundry , Neelapu Sattva Swarup , Miklos David Bernard , Bartlett Nancy L. , Jacobson Caron Alyce , Braunschweig Ira , Oluwole Olalekan O. , Siddiqi Tanya , Lin Yi , Timmerman John , Reagan Patrick Michael , Lekakis Lazaros J. , Unabia Sherryonne , Go William Y. , Wiezorek Jeffrey S. , Bot Adrian 
Published: September 2018

3025 Background: Axi-cel is an autologous anti-CD19 CAR T cell therapy. ZUMA-1 is a multicenter, registrational trial of axi-cel in patients (pts) with refractory/aggressive B-cell non-Hodgkin lymphoma (NHL). In a pre-specified interim analysis, ZUMA-1 met its primary endpoint with 76% objective response rate and 47% complete response (Blood 2016;128:LBA-6). We describe, for the first time, a tumor microenvironment immune gene signature associated with CAR T cell treatment (tx) of NHL pts. Methods: Paired biopsies, pre- and within 3 weeks post-axi-cel tx, were analyzed by digital gene expression followed by a pre-specified bioinformatics algorithm applied to IGES15 and IGES21 genes involved in immune-mediated tumor regression (Immunosign; Galon Immunity 2013). Immunosign profiles expression of a pre-defined set of effector T cell, Th1, chemokine, and cytokine genes. Expression analysis and hierarchical clustering were used to define an axi-cel-related tumor immune gene signature. Wilcoxon signed rank test with multiple test correction by FDR (Benjamini-Yekutieli) was used. Results: Gene expression profile comparisons of pre- and post-axi-cel tx biopsies from 14 pts showed profound changes in gene expression within the tumor environment after infusion. The most upregulated genes post-axi-cel tx were CCL5 (RANTES), CTLA4, and GZMA (log2 fold change > 2, P< 0.05, FDR < 0.050). Immune checkpoints PD-L1 and LAG3 were also upregulated post-axi-cel (log2 fold change > 1.6, P< 0.05, FDR < 0.055). Other genes associated with T cell proliferation, homing, and effector function were also upregulated: IL-15, GZMK, CXC3CL1 (Fractalkine), CD8A, and STAT4 (log2 fold change > 1.6; P< 0.05, FDR < 0.074). Additional baseline tumor characteristics and associative analysis will be presented. Conclusions: We define a mechanistic tumor immune gene signature in NHL pts associated with axi-cel tx. This signature comprises upregulation of T cell activation, effector, chemokine, and immune checkpoint genes. These data will potentially lead to rational optimization of T cell interventions in cancer Clinical trial information: NCT02348216.
Non-invasive clinical visualization of tumor infiltrating lymphocytes in patients with metastatic melanoma undergoing immune checkpoint inhibitor therapy: A pilot study.
Authors: Markovic Svetomir , Galli Filippo , Suman Vera J. , Nevala Wendy Kay , Paulsen Andrew M , Hung Joseph C , Gansen Denise N , Erickson Lori A , Marchetti Paolo , Wiseman Gregory A. , Signore Alberto 
Published: September 2018

3034 Background: Unique to modern immune therapy for cancer is that early in the course of treatment, patients frequently exhibit transient tumor enlargement (pseudo-progression, pPROG) due to tumor infiltration by lymphocytes (TIL). Currently, pPROG cannot be reliably distinguished from true tumor progression (PROG). There is a need for biomarker techniques to discriminate pPROG (effect of therapy) and PROG (therapy failure). Nuclear medicine offers radiopharmaceuticals capable of imaging immune cells; images can be fused to evaluate functional and anatomic characteristics of tumors, and potentially discriminate pPROG from PROG. Methods: In our study of metastatic melanoma patients, SPECT/CT imaging with 99mTc-interleukin-2 (99mTc-IL2) was performed to visualize TIL. Images were collected before/after 12 weeks of ipilimumab (IPI) or pembrolizomab (PEMBRO) therapy. The 99mTc-IL2 tracer was synthesized by conjugating succinimidyl-6-hydrazinopyridine-3-carboxylate (HYNIC-NHS) with commercial interleukin-2 (Aldesleukin). HYNIC-IL2 was incubated with tricine, 99mTcO4- (370-740 MBq) and SnCl2. After labelling 99mTc-IL2 was purified by reverse-phase chromatography and diluted in 5% glucose with 0.1% human albumin before injection. Five patients were enrolled in this study. Two patients failed to complete the 12 week 99mTc-IL2 scan due to discontinuation of IPI after: 1) grade 3 colitis and 2) patient refusal for adverse events attributed to IPI. No adverse events attributable to the tracer infusion were reported. Results: Metastatic lesions could be visualized by the tracer. Some lesions decreased in size, while others increased. A positive correlation was found between size and 99mTc-IL2 uptake, before and after therapy, suggesting the potential discrimination of tumor PROG (no 99mTc-IL2 uptake) from pPROG (high 99mTc-IL2 uptake). Immunohistochemical staining for TIL of 99mTc-IL2 positive and negative lesions are illustrated. Conclusions: The results demonstrate feasibility of 99mTc-IL2 imaging as a clinically useful tool capable of discriminating tumor PROG from pPROG. A clinical validation study is in progress. Clinical trial information: NCT01789827.