bluuebunny/crossref_metadata_2025_split huggingface dataset:
Healthcare provider awareness and integration of immunotherapy for stage III NSCLC.
Authors: Andrie Rachael , Quill Timothy A. , Vinther Angelique , Stacy Tina B. , Obholz Kevin 
Published: July 2019

123 Background: In February 2018, immunotherapy was approved for patients with unresectable stage III NSCLC without progression after concurrent chemoradiotherapy (cCRT). The anti–PD-L1 inhibitor durvalumab is now considered by most experts to be the standard of care (SoC) in this setting based on improved survival outcomes. Methods: We conducted a series of 5 CME-certified symposia to provide healthcare providers (HCPs) with education that included expert and guideline recommendations on the optimal use of durvalumab therapy for patients with unresectable stage III NSCLC. These symposia were conducted at 3 major oncology conferences (NCCN Annual, AACR, ASCO Annual) and 2 managed care pharmacy (MCP) conferences (AMCP Annual, AMCP Nexus) over an 8-month period after durvalumab was approved (Table). Polling questions designed to assess key aspects of HCP knowledge and practice patterns were repeated at each symposium and responses were collected through an audience response system. Results: Across the 5 symposia, on average fewer than 45% of responding HCPs recommended durvalumab consolidation therapy for an ideal patient candidate with stage III NSCLC after cCRT (Table). Among responding HCPs across 4 symposia, on average fewer than 30% identified the optimal recommended duration of 1 year of durvalumab therapy based on current clinical evidence. Physicians did identify the optimal management of immune-related pulmonary toxicity associated with durvalumab treatment more often than other HCPs (Table). Conclusions: These pre-education data suggest that a large percentage of HCPs are not fully aware of the available clinical evidence and are delayed in the implementation of immunotherapy for unresectable stage III NSCLC. [Table: see text]
Phase I study of CpG ODN(K3), a novel toll-like receptor 9 agonist, for advanced lung cancer: Interim analyses of safety and immunity in subcutaneous injection cohort.
Authors: Otsuka Tomoyuki , Nishida Sumiyuki , Hamaguchi Masanari , Shibahara Takayuki , Shiroyama Takayuki , Kimura Keiko , Hirata Haruhiko , Kida Hiroshi , Ishii Ken J. , Kumanogoh Atsushi 
Published: July 2019

126 Background: CpG oligodeoxynucleotide (CpG ODN) (K3), a toll-like receptor 9 agonist, is a novel synthetic single-strand DNA immune adjuvant for cancer immunotherapy. CpG ODN(K3) induces the production of type 1 IFNs and pro-inflammatory cytokines in innate immune cells, leading to a potential Th1-type adaptive immune response against cancer cells, leading to an immunogenic tumor microenvironment. To determine the recommended dose (RD) of CpG ODN(K3) via subcutaneous injection (sc) or intravenous administration (iv) and to investigate the immune response induced by CpG ODN(K3) in advanced lung cancer patients, we designed an open-labeled, dose-escalation phase I study. Methods: Pts with advanced lung cancer who had achieved CR, PR or SD after the prior Pt-based chemotherapy were enrolled. The primary endpoint was the proportion of DLTs at each dose level. Secondary endpoints included safety profile, immune response including dynamic changes of immune cell and cytokine production, and PFS. In a 3+3 dose-escalation design, the dosage levels for CpG ODN (K3) were 5 or 10 mg/body sc and 0.2 or 0.6 mg/kg iv on day1, 8, 15 and 29. Pts without PD or unacceptable toxicity were allowed to receive CpG ODN(K3) up to a maximum of 6 months. Results: 6 pts were treated in sc part. 5 had NSCLC (3 had adenocarcinoma, 1 squamous cell carcinoma, and 1 mucoepidermoid carcinoma) and 1 had SCLC. There were no DLTs at any dose levels. Treatment-related toxicities were limited to G1 and G2 including local skin reactions. No pts experienced serious AEs including immune-related AEs. Some pts exhibited the dynamic change of immune-related cells and the immediate production of inflammatory cytokines and chemokines, such as IL1-beta, CCL2, and CXCL10, and Th1 cytokines including IFN-gamma, in response to CpG ODN(K3), suggesting that CpG ODN(K3) elicited innate immunity followed by Th1 adaptive immune response. Conclusions: This was the first clinical application of CpG ODN(K3) for cancer pts. CpG ODN(K3) sc was well-tolerated and was expected to activate innate immunity followed by Th1 adaptive immune response. Clinical trial information: UMIN000023276.
The role of high-dimensional profiling of the systemic immune response on optimal sequencing of radiotherapy (RT) and immune checkpoint blockade (ICB).
Authors: Chua Kevin Lee Min , Fehlings Michael , Chu Pek Lim , Lin Xiao-Tian , Yeo Eugenia , Low Kar Perng , Poon Dennis , Ong Enya , Woo Wai Yee , Wee Joseph , Nardin Alessandra , Iyer N Gopalakrishna , Tan Daniel Shao-Weng , Soo Khee Chee , Newell Evan , Chua Melvin Lee Kiang 
Published: July 2019

13 Background: Combinatorial RT-ICB potentiates anti-tumour reactivity by modulating the immune response. We therefore performed in-depth phenotypic profiling of the systemic T cell compartment following treatment with RT-ICB. Methods: We recruited 20 patients with biopsy-proven metastatic renal cell and non-small cell lung carcinoma, who were treated with a sandwich regime of ICB-RT-ICB under a prospective observational study protocol, and compared against a RT alone-treated cohort (N = 10). All patients received ablative RT (8-50 Gy/1-5 fr) for oligoprogression and/or local palliation. Blood samples were longitudinally collected at pre-RT, 14 d post-RT and cycle 2 ICB post-RT. Deep T cell profiling was performed by mass cytometry using a customised 41 parameter panel, together with high dimensional analysis tools. Results: Median follow-up of the overall cohort was 18 mo; median duration of ICB received in the ICB-RT-ICB arm was 15 mo. We observed significant diversity of the systemic T cell repertoire between patients at baseline, and this corresponded to significant interpatient heterogeneity in T cell responses specific to the central/effector memory, EMRA and Treg subsets post-RT. Dramatic local response (complete response at 1 mo post-RT) was significantly higher in the ICB-RT-ICB cohort compared to the RT alone cohort (12/20 vs 1/10, P <0.01). This clinical phenomenon corresponded to an increased % Ki67highCD8 and CD4 T cells post-RT exclusively in the combinatorial treated cohort, which was further enhanced upon resumption of ICB (mean = 10% vs 3% [CD8]; 13% vs 2% [CD4]; P <0.01). Deeper immunophenotyping of the Ki67high subsets revealed associated high expression of GranzymeB and Eomes. Conclusions: Here, we observed changes in the T cell phenotypes that varied remarkably across all patients following RT. We further highlight a RT-dependent T cell proliferation amongst all RT-ICB-treated patients that was further enhanced by ICB in prior responders. This immune phenomenon may account for the dramatic responses to combinatorial treatment, and informs on optimal sequencing strategies for combining RT and ICB.
Response rate and safety of standard-dose nivolumab with reduced-dose ipilimumab in metastatic melanoma.
Authors: Mehmi Inderjit , Hill Jordan 
Published: July 2019

140 Background: Reduced-dose nivolumab in combination with standard-dose ipilimumab was shown to improve overall response rate (58%), progression free survival (11.5 months), and overall survival compared to ipilimumab alone in Checkmate 067. Improved outcomes were accompanied by an increased risk of toxicities with a 59% rate of grade 3-4 toxicities for the combination. Keynote 029 evaluated standard-dose pembrolizumab with reduced-dose ipilimumab with a slightly lower risk of grade 3-4 toxicities at 45%. Here we report outcomes for standard-dose nivolumab combined with reduced-dose ipilimumab in metastatic melanoma. Methods: We conducted a retrospective review of metastatic melanoma patients that received standard-dose nivolumab with reduced-dose ipilimumab at West Virginia University Cancer Institute. Response to therapy and incidence of immune-related adverse events were assessed. Results: From February 2017 to October 2018, 11 patients received the alternative dosing regimen. Only 1 (9%) patient experienced a grade 3-4 toxicity, and 3 (27%) additional patients experienced a grade 1-2 toxicity. The overall response rate was 54%. Conclusions: Standard-dose nivolumab in combination with reduced-dose ipilimumab is better tolerated than reduced-dose nivolumab with standard-dose ipilimumab without a loss in overall response rate.
Autoimmune toxicities with anti-PD-1 treatment of metastatic melanoma in predominantly older patients: A single institutional experience.
Authors: Parmar Harsh V , Kerr Phil , Stevenson Christina Elizabeth , Masternak Sophie , Hegde Upendra P. 
Published: July 2019

144 Background: Anti-PD-1 therapy has become an effective method of treating patients including elderly subjects diagnosed with un-resectable or metastatic melanoma. While effective, toxicity reports in elderly are conflicting. Some reports indicate no added autoimmunity with older melanoma patients, while we had previously reported our concerns of heightened autoimmune toxicity with anti-PD-1 treatment of melanoma in elderly subjects. This report includes updated results in 36 patients receiving anti-PD-1 treatment for melanoma with an increased proportion of older subjects from a single institute. Methods: Between 2014-2018, we performed retrospective review of charts of patients treated with anti-PD-1 agents for stage III and IV melanoma following IRB approval. Data for treatment outcomes and grade III and IV immune related adverse events were collected. Results: 36 patients were treated with either Pembrolizumab or Nivolumab that included stage IV melanoma (28 pts), un-resectable stage III (5 pts) and stage III melanoma in adjuvant setting (3 pts). 30 out of 36 patients were over 60 years of age (median age 77, range 62-90) and 6 patients were younger than 60 years (median age 48, range 24-56). 16 out of 30 patients over age of 60 years (53%) experienced grade III or IV toxicities following anti-PD-1 therapy compared to none (0%) in age below 60 years. Overall, 19 patients are alive either with disease or on treatment with stable, partial or complete responses. 17 patients have died, out of which 12 died of progressive disease, 2 elderly patients died suddenly and 3 elderly patients died of autoimmune toxicity (myasthenia gravis like syndrome, acute inflammatory demyelinating polyneuropathy, pneumonitis). Some unusual autoimmune toxicity seen in elderly subjects included diabetes mellitus, Behcet disease, acute inflammatory demyelinating polyneuropathy, retinitis, Bell's palsy and bullous pemphigoid). Conclusions: Our data continue to indicate that increased risk of severe autoimmune toxicity following anti-PD-1 treatment involved older patients over 60 years of age. This finding may highlight the increased susceptibility of autoimmunity with aging.
MHC-1 genotype as a predictor of response to immunotherapy.
Authors: Goodman Aaron , Pyke Rachel , Kato Shumei , Okamura Ryosuke , Sokol Ethan , Frampton Garrett Michael , Miller Vincent A. , Carter Hannah , Kurzrock Razelle 
Published: July 2019

149 Background: MHC-1 molecules present intracellular peptides on the surface of tumor cells for recognition by CD8+ cytotoxic T-cells. Cancers with a high tumor mutational burden (TMB) are more likely to respond to immune checkpoint blockade (ICB) due to the increased chance of having a mutated peptide presented by MHC-1. However, the interaction between TMB and patient-specific MHC-1 and ICB response is unknown. Methods: We analyzed 83 patients with diverse solid tumors treated with ICB for TMB and MHC-1 (tissue next generation sequencing (NGS) (Foundation Medicine)). TMB low vs high were defined as <20 vs ≥20 mut/mb, respectively. Patient Harmonic-mean Best Rank (PHBR) (Marty et al. 2018) scores the ability of the MHC-I of an individual to bind and present a specific missense mutation. Patients were assigned the PHBR of their best presented missense driver mutation. PHBR low (strong presentation) vs high (weak presentation) were defined as <1.01 vs ≥1.01 respectively (cutoff per a receiver operator curve). Overall response rate (ORR) (includes stable disease for ≥6 months) was determined (RECIST criteria). Results: The ORR, PFS, and OS for patients treated with ICB with PHBR low vs. high tumors was 72% vs 28% (P = 0.01), 6.3 vs 4.1 months (P = 0.03), and 37.1 vs 13.9 months (P = 0.25), respectively. The ORR, PFS, and OS for TMB low vs high was 36% vs 67% (P = 0.02), 4.3 vs 14.1 months (P = 0.01), and 12.0 months vs not reached (P = 0.03), respectively. The ORR, PFS, and OS for TMB high/PHBR high vs TMB high/PHBR low was 38% vs 85% (P < 0.01), 3.9 vs 26.8 months (P <0.01), and 17.1 vs not reached (P = 0.02), respectively Conclusions: MHC-1 genotype and the ability to present driver neo-antigens predicts which patients with TMB high will respond to ICB.[Table: see text]
Analysis of real-world PD-L1 IHC testing for clinical use in patients across multiple tumor types.
Authors: Krigsfeld Gabriel S , Prince Emily , Zerba Kim , Chizhevsky Vladislav , Ragheb Josette William , White James William 
Published: July 2019

151 Background: A number of programmed death ligand 1 (PD-L1) IHC diagnostic tests have been approved by the FDA to guide treatment with programmed death-1/PD-L1 inhibitors. We evaluated PD-L1 assay utilization and concordance across all tumor types, including melanoma (MEL) and squamous cell carcinoma of the head and neck (SCCHN), using real-world cancer samples tested at a single reference laboratory in the United States. Methods: 55,652 samples with clinical characteristics were provided by Symphony Health Solutions. NeoGenomics Laboratories, Inc assessed PD-L1 expression using the Dako PD-L1 IHC 28-8 or 22C3 pharmDx, or Ventana PD-L1 SP142 assay tests between October 2015 and April 2018, according to the manufacturers’ protocols at the time of the study. Clinical characteristics were matched to PD-L1 test results using unique identifiers. Data were analyzed by BioStat Solutions, Inc. Results: 61,568 tests from 55,652 patients were included. Across all 61,568 tests, 88.8% were carried out with 22C3, 9.8% with 28-8, and 1.4% with SP142. The 28-8 and 22C3 pharmDx assays showed high analytical concordance in all 3113 matched samples with PD-L1 expression data for both assays (OPA = 96.2%, Spearman’s r = 0.96; Table). The failure rate across all tests was 3.5%, and 96.6% of patients had a quantifiable test result. Average test turnaround time was 3.1 days, with a 9.1-fold increase in total number of tests performed between Q4 2015 and Q1 2018 (from 1163 to 10,544). Subgroup analyses for 678 patients (1.2%) with MEL and 270 patients (0.5%) with SCCHN will be presented. Conclusions: Despite an increased demand for PD-L1 testing in the US, most patients received a result in 2–4 days. These real-world analytical data support the potential interchangeability of the Dako PD-L1 IHC 28-8 and 22C3 pharmDx assays in clinical practice for assessing tumor cell membrane PD-L1 expression across tumor types, and provide context on the evolution and adoption of PD-L1 testing for patients with cancer. [Table: see text]
Isolation and characterization of exosomes from IDH mutant gliomas.
Authors: Ludwig Nils , Rao Aparna , Yerneni Saigopalakrishna Saileelaprasad , Amankulor Nduka , Whiteside Theresa 
Published: July 2019

152 Background: Mutations in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) are found in > 70% of intermediate grade gliomas. Gain-of-function mutations in IDH1 promote diffuse glioma formation through epigenetic reprogramming of a number of genes, including immune-related genes. Tumor-derived exosomes (TEX) accumulate in the tumor microenvironment (TME) and in body fluids of patients. TEX serve as a communication system between tumor and normal cells. Circulating TEX carry a complex molecular and genetic cargo and interfere with functions of immune cells. This study characterizes TEX produced by IDH mutant glioma spheres and TEX from plasma of patients with IDH mutant gliomas. Methods: TEX produced by patient-derived IDH1(mut) or IDH1(wt) glioma spheres or TEX in patient’s plasma were isolated by mini size exclusion chromatography (mini-SEC). TEX morphology, size, numbers and molecular profile were characterized and the crossing of the blood-brain barrier (BBB) and biodistribution was investigated by in vivo imaging of TEX. Interactions of TEX with endothelial cells, astrocytes and immune cells were demonstrated by confocal microscopy. Results: TEX isolated from supernatants of IDH1(mut) or IDH1(wt) glioma spheres by mini-SEC carried TSG101 and showed the typical size and vesicular morphology of exosomes. BCA protein assays and qNano analysis revealed an elevated exosome production by IDH mutant cells ( p< 0.01). TEX carried immunosuppressive proteins (FasL, CTLA-4 and TRAIL) and IDH mutant exosomes carried higher levels of these proteins and of adenosine pathway components CD39 and CD73. Labeled TEX injected in the white matter of mice crossed the BBB and were detectable in distant organs 24h after injection. TEX were rapidly internalized by endothelial cells and astrocytes, but not by T cells, which interacted with TEX by surface signaling. These results were confirmed by investigating TEX isolated from glioma patient’s plasma. Conclusions: The data suggest that TEX play an important role in IDH mutant gliomas and drive tumor progression in part by inducing suppression of immune cells. Future efforts will focus on characterizing immunosuppressive effects of TEX derived from IDH mutant cells vs gliomas without IDH mutations.
Phase I study to evaluate the safety and efficacy of rivoceranib (apatinib) and nivolumab in patients with unresectable or metastatic cancer.
Authors: Chawla Sant P. , Chua Victoria S. , Gordon Erlinda Maria , Moradkhani Ania , Kim Katherine , Quon Doris , Wong Steven , Sumner Robert , Mac Virginia , Huang Raymond , Wang Kelly , Kim Jiyeun , Kim Bumjin , McGinn Arlo N. , Park Cheol Hee , Houston Scott , Sankar Neil 
Published: July 2019

18 Background: Due to their immuno-modulatory effects, anti-angiogenic drugs have been clinically investigated in combination with anti-PD-1 therapies. The addition of rivoceranib (apatinib), a highly-selective VEGFR-2 tyrosine kinase inhibitor, is being evaluated in an ongoing 2-part Phase I trial in subjects with locally advanced unresectable/metastatic solid tumors who have received at least 3 doses of nivolumab. A classic 3+3 dose escalation has been completed (Part 1) and the study is currently ongoing with an extension period (Part 2). Herein, we present the safety and preliminary efficacy. Methods: To date, 10 subjects were enrolled in Part 1 while 3 subjects have been enrolled in Part 2. Median number of prior lines of therapy were 3 and 1, respectively, for the two study segments. The major inclusion criteria specified that patients must have received at least 3 doses of nivolumab and are continuing nivolumab therapy. Escalating doses of rivoceranib at 400, 600, and 700 mg po qd was proposed in combination with nivolumab at 240 mg iv q2w to determine the MTD. Best tumor response and time of progression was assessed using RECIST v1.1 and iRECIST. Results: 300 mg rivoceranib was determined as RP2D for Part 2. 5/13 patients had G2/3 hypertension. Common treatment-related AEs were hypertension, hand and foot syndrome, and nausea and immune-related AEs were hypothyroidism and diarrhea. Notably, in 10 evaluable patients, 3 patients had PD and 4 patients showed tumor shrinkage (5-29%). A patient with Malignant Spindled/Epitheloid Sarcoma, who had PD during previous nivolumab treatment has shown tumor reduction, so far, of 9%. A patient with Gastric Cancer, who had stable disease (a 4% increase) after 2 months of nivolumab showed a reduction of 29%, 2 months after introduction of rivoceranib. 2 patients have had stable disease for more than 8 months as of Oct 26, 2018. Conclusions: Preliminary results indicate the potential clinical benefit of a 300 mg starting dose in combination with 240 mg of nivolumab in unresectable/metastatic solid tumors with a tolerable safety profile. Efficacy of ongoing and future patients in Part 2 will be further evaluated. Clinical trial information: NCT03396211.
Managing combination immunotherapy trials from a contract research organization's (CRO's) perspective.
Authors: Balkissoon Jai , Nguyen Binh , Combest Austin J. , Stoitchkov Konstantin Yordanov , Stoyanov Nikolay , Hsu Judy , Reitsma Dirk J. 
Published: July 2019

19 Background: With the increased clinical activity that we are seeing with combination IO therapies, more sponsors are searching for contract research organizations (CROs) that have experience managing combination IO clinical trials which are often large, complex, multi-national, resource-intensive, competitive and highly specialized. Pharmaceutical Product Development (PPD), a contract research organization (CRO) has worked with sponsors in managing combination IO clinical trials. This includes early and late phase trials with many different classes of agents in multiple tumor types. We sought to review PPDs experience in combination immunotherapy trials and highlight key challenges, efficiencies, innovative modern trial designs, endpoints and enrollment strategies in a competitive market. Methods: We reviewed IO trials managed by PPD over the past 5 years, information from PPDs Immuno-Oncology Center of Excellence (IOCOE) and Immuno-Oncology Working Group (IOWG) and the current pace of development of IO therapies. Results: PPD has collaborated with multiple sponsors to manage innovative, complex IO trials that push the boundaries of clinical development. Comprehensive planning and risk management strategies steeped in a deep understanding of the trial environment are essential for successful IO protocols. Protocol and trial optimization have been useful to make trials more efficient and less expensive. Conclusions: IO approvals are increasing at a rapid pace and both sponsors and CROs will need to work together to continue to develop innovative trial designs, biomarkers and endpoints that will determine efficacy and tolerability of combination IO therapies. PPDs innovative tools, technology and resources have been useful to help sponsors with enrollment strategies to prevent increasing study timelines and delays in study results. The IO space is pushing the limitations of scientific, technological and operational advances, and we are happy to continue to share our learnings in this ever-evolving landscape.