bluuebunny/crossref_metadata_2025_split huggingface dataset:
HIV-positive Kaposi sarcoma and immune checkpoint blockade.
Authors: Galanina Natalie , Goodman Aaron , Cohen Philip R , Kurzrock Razelle 
Published: February 2018

63 Title: HIV-Positive Kaposi Sarcoma and Immune Checkpoint Blockade Background: Kaposi sarcoma (KS) is an incurable, virally mediated malignancy arising in HIV-positive patients. We report the first observations on the safety and efficacy of checkpoint blockade in these patients. Methods: We identified eight evaluable patients with HIV-related Kaposi sarcoma who received ≥1 dose of checkpoint blockade. Data on demographics, treatment efficacy, and the effects on immune function (HIV and HHV8 viral load, CD4 count) and toxicity were curated. Results: Median age was 45.5 years (range, 38-63); all men; median, one prior regimen; all were treated with nivolumab 3mg/kg IV days 1 and 14 of each 28-day cycle. PD-L1 expression was assessed retrospectively and was low in 3 out of 4 patients with available data. All patients were receiving anti-retroviral therapy. The majority (75%) had preserved CD4 count and undetectable HIV viral load (Table). The response rate (RR) was 62.5% (5 of 8 patients) with 1 complete remission and 4 partial remissions; the remaining 3 patients have stable disease. Median follow up to date is 3.5 months and no patients has discontinued therapy. No grade >2 toxicities were noted. Most common side effects included fatigue, gastrointestinal discomfort, pruritis, and onycholysis. There was an overall increase in CD4 counts. Conclusions: Preliminary observations suggest that checkpoint blockade with nivolumab has low toxicity and high anti-tumor activity in KS. Additionally, patients experienced improvement in CD4 count. [Table: see text]
Natural killer cell activity: A test for immune reactivity with clinical perspectives.
Authors: Nederby Line , Hansen Torben , Raunkilde Louise , Jensen Lars Henrik , Jakobsen Anders Kristian Moeller 
Published: February 2018

87 Background: Natural Killer (NK) cells are essential in the biological fight against cancer and the activity of these cells has been suggested as a biomarker for immunological reaction in cancer patients. An assay has been introduced to measure NK cell activity (NKA) in a simple and standardized manner. Following stimulation of NK cells in whole blood with a recombinant protein, it utilizes the concentration of interferon-gamma (IFNγ) in plasma as a surrogate marker for NKA. This study aimed to verify that the test was indeed measuring NKA and whether it could predict the response to cytostatic treatment in metastatic colorectal cancer (mCRC). Methods: Blood was collected in dedicated tubes (NK Vue Promoca) and placed at 37°C. After 24 hours the plasma was analyzed for IFNγ by ELISA (NK Vue ELISA). Blood from patients with mCRC (n = 22) were sampled at baseline and prior to each treatment cycle, and IFNγ levels were compared to response data from first evaluation. The protocol is ongoing hence the results are preliminary. In healthy controls (n = 8), IFNγ was measured intracellularly using flow cytometry at baseline and after 5-, 10-, 15-, 20-, 24-, and 28 hours of incubation. Results: When analyzing the distribution of cells among the IFNγ expressing subset, the proportion of NK cells was significantly different than that of monocytes, T-, and NKT cells at all time points of incubation (p < 0.0001), thus suggesting that the readout of the test was indicative of the NK cells´ ability to mount a response. Using the NKA test, plasma levels of IFNγ in healthy controls were all above 200pg/mL after 24 hours of incubation. The mCRC patients were divided into three NKA groups: 1) IFNγ dropped below 200pg/mL or remained below that level throughout treatment (n = 9), 2) IFNγ remained above 200pg/mL throughout treatment (n = 5), and 3) IFNγ changed from being below 200pg/mL to above that level during treatment (n = 8). The response rates were 11%, 40%, and 100%, respectively, and the difference was significant (p < 0.001). The positive and negative predictive values of increasing IFNγ were 100% and 79%. Conclusions: These data suggest that increasing NK cell activity during treatment has predictive potential in mCRC. The NKA test performs reliably in this setting. Clinical trial information: NCT02705300.
Immunological impact of ramucirumab on tumor microenvironment in advanced gastric cancer.
Authors: Togashi Yosuke , Tada Yasuko , Kotani Daisuke , Kawazoe Akihito , Doi Toshihiko , Nishikawa Hiroyoshi , Shitara Kohei 
Published: February 2018

98 Background: Ramucirumab (RAM), a monoclonal antibody against VEGFR2, was recently approved for the treatment of advanced gastric cancer (GC). However, little is known about the immunological effects in advanced GC patients. Methods: Patients with advanced GC who had been planned to receive chemotherapy containing RAM were prospectively enrolled for this study from January 2016 to September 2016. Paired samples were obtained from peripheral blood mononuclear cells (PBMCs) and tumor infiltrating lymphocytes (TILs) in primary tumors pre- and post-RAM therapy to investigate immune profiles. Results: A total of 59 PBMCs and TILs from 18 patients were collected. Higher frequencies of FOXP3highCD45RA-CD4+ T cells (effector regulatory T cells: eTregs) were detected in TILs compared with PBMCs (19.05±10.48% vs 1.89±1.0%, P < 0.0001), and the presence of high eTreg in TILs was not reflected in PBMCs. eTregs of TILs, but not of PBMC were significantly decreased after RAM-containing therapies (22.67±11.19% vs. 16.33±8.44%, P = 0.034). Expressions of immune checkpoint (IC) molecules (PD-1, CTLA-4, LAG-3, and ICOS) were much higher in TILs than those in PBMCs, and all these molecules exhibited higher expressions on eTregs than on CD8+ T cells. Among them, ICOS was specifically expressed by eTregs in TILs. PD-1+CD8+ T cells in TILs were significantly decreased after RAM-containing therapies (54.99±19.06% vs. 39.23±17.15%, P = 0.0005), but not in PBMC. Patients with partial responses had significantly higher frequency of eTreg in pre-treatment TIL than those with progression disease (32.56±12.11% vs. 14.83±3.18%, P = 0.036). Furthermore, patients with high eTreg frequency had significantly longer progression-free survival than those with low frequency (161 days vs. 76 days, P = 0.024). Conclusions: There was significant difference in immune profile between PBMC and TIL in GC patients. eTregs and PD-1 expression on CD8+T cells in TILs, not in PBMCs were decreased after RAM-containing therapies. This observation suggests the importance of TIL analyses and might be a rationale to use RAM as an immunomodulator in combination with IC inhibitors.
Phase I/II study of low-dose cyclophosphamide, tumor-associated peptide antigen-pulsed dendritic cell and low dose GM-CSF for solid and hematological tumors.
Authors: Mirandola Leonardo , Figueroa Jose A. , Nguyen Diane Duyen Thuy , Dahlbeck Scott , Chiriva-Internati Maurizio 
Published: February 2018

TPS216 Background: Despite advances in understanding the biology of hematologic malignancies (HM) and solid malignancies (SM), and the availability of new treatment options, many patients with HM and SM remain incurable. Since the majority of cancer patients display a defective immune response to tumor antigens, the ex-vivo activation of dendritic cells (DC), through their exposure to tumor associated antigens, is an attractive and active area of investigation. We and others have explored the potential immunotherapeutic targets included our DC vaccine, i.e., SP17, Ropporin, AKAP4, PTTG1, SpanxB, NY-ESO-1, MAGE-1, HM1.24, Her2/Neu. Notably, SP17-pulsed DC have been reported to induce a safe and clinically significant response in patients with multiple myeloma and ovarian cancer. Methods: We hypothesize that treatment of patients with HM or metastatic SM using autologous DC will result in antigen-specific CD4+ T-cell and/or CD8+ CTL responses without significant toxicities. We also hypothesize that the responses generated against specific antigens may translate into clinical anti-tumor activity. Primary Objective: Phase I (6 subjects). To determine safety of intradermal/subcutaneous DC vaccine therapy, low-dose cyclophosphamide and GM-CSF, in patients with metastatic SM or HM who demonstrate a response, or whose disease remains stable, after conventional first-line systemic therapy, or who have failed conventional systemic therapy. Secondary Objective: Phase II (up to 17 subjects). To determine immune responses associated with intradermal/subcutaneous DC vaccine therapy, low-dose cyclophosphamide and GM-CSF, in patients with metastatic SM or HM who demonstrate a response, or whose disease remains stable, after conventional first-line systemic therapy, or who have failed conventional systemic therapy. The study population is currently drawn from patients at various clinical institutions following contractual agreements. Clinical trial information: NCT02709993; NCT02705703; NCT02224599; NCT02223312.
A phase II study of talimogene laherparepvec followed by talimogene laherparepvec + nivolumab in refractory T cell and NK cell lymphomas, cutaneous squamous cell carcinoma, Merkel cell carcinoma, and other rare skin tumors (NCI #10057).
Authors: Silk Ann W. , LeBoeuf Nicole R. , Rabinowits Guilherme , Puzanov Igor , Burgess Melissa Amber , Devata Sumana , Moore Dirk , Goydos James Steven , Chen Helen X. , Kaufman Howard , Zloza Andrew , Mehnert Janice M. 
Published: February 2018

TPS219 Background: Talimogene laherparepvec, a modified herpes virus agent, induces a response in 65% of injected melanoma tumors. The combination of talimogene laherparepvec with ipilimumab or pembrolizumab appears promising in clinical trials of advanced melanoma. Talimogene laherparepvec-based therapy may be effective in other cancers of the skin and lymph nodes that are anatomically accessible for intratumoral injection. Methods: This phase II study will evaluate intratumoral talimogene laherparepvec monotherapy in 4 parallel disease cohorts: 1) Refractory T cell and NK cell lymphomas including cutaneous T cell lymphoma, 2) Merkel cell carcinoma 3) Cutaneous squamous cell carcinoma and 4) Other advanced/refractory non-melanoma skin cancers. Lymphoma patients must be refractory to or intolerant of all standard life-prolonging therapies. Skin cancer patients must be advanced/unresectable or refractory to one or more treatments including surgery, radiation therapy, or medical therapy. Prior PD-1-directed therapy is allowed. If an objective response is not achieved by Week 12, the PD-1 blocking antibody nivolumab will be added. The primary endpoint is the response rate with talimogene laherparepvec and secondary endpoints include response rate with the combination and overall survival. Using a two-stage design, if 1 or more response is observed in the first 9 patients in each parallel cohort, 8 additional patients will be accrued for a total sample size of 36 to 68 patients across the 4 disease cohorts. Tumor biopsies of injected lesions are mandatory at baseline and Week 6, and optional at Week 16 and the time of progression. Optional biopsies of non-injected lesions (when applicable) at Week 6 and 16 will be analyzed to identify biomarkers of systemic immunity. Tumor tissue and/or blood will be assayed for PD-L1 expression, RNA profiling, immune cell profiling, HVEM, NECTIN 1/2, IDO, tryptophan and L-kynurenine, mutational load, TIL TCR clonality, and prior exposure to herpes simplex type 1 virus and Merkel cell polyomavirus. Clinical trial information: NCT02978625.
Phase 1b trial of cabozantinib in combination with atezolizumab in patients with locally advanced or metastatic urothelial carcinoma (UC) or renal cell carcinoma (RCC).
Authors: Maia Manuel C. , Agarwal Neeraj , McGregor Bradley Alexander , Vaishampayan Ulka N. , Choueiri Toni K. , Green Marjorie C. , Hessel Colin , Scheffold Christian , Schwab Gisela , Powles Thomas , Pal Sumanta K. ,   XL184-021 study group
Published: February 2018

TPS42 Background: Cabozantinib (CABO) is an oral receptor tyrosine kinase inhibitor of MET, VEGFR, and TAM family receptors (TYRO3, AXL, and MER). It is approved for patients (pts) with RCC after prior therapy with antiangiogenic therapy, and has demonstrated clinical activity in UC. In clinical studies, CABO exposure increased circulating CD8+ T cells and reduced immune-suppressive monocytes and Tregs. In preclinical tumor models, CABO increased MHC class 1 expression on tumor cells and reduced myeloid-derived suppressor cells. CABO may facilitate an immune-permissive tumor environment and may enhance response to immune checkpoint inhibitors. Atezolizumab (ATEZO), an anti-PD-L1 mAb, is approved for: locally advanced/metastatic UC in pts who are cisplatin-ineligible or have disease progression during/following platinum-containing chemo; pts with metastatic NSCLC and disease progression during/following platinum-containing chemo. We present the study design of an ongoing phase 1b study combining CABO with ATEZO in pts with locally advanced/metastatic UC or RCC. Methods: This multicenter, phase 1b, open-label study aims to assess safety, tolerability, preliminary efficacy, and pharmacokinetics of CABO in combination with ATEZO (NCT03170960). The study will enroll pts with advanced UC (bladder, renal pelvis, ureter, urethra) or RCC. It consists of two stages: dose escalation and expansion. In the dose-escalation stage (3+3 design), a recommended CABO dose for the combination will be established. In the expansion stage, four tumor-specific cohorts will be enrolled: 1) pts with UC who have progressed on/after platinum-containing chemo; 2) chemo-naïve pts with UC who are cisplatin ineligible; 3) chemo-naïve pts with UC who are cisplatin eligible; and 4) untreated pts with RCC with clear cell histology; the primary objective is to determine the objective response rate in each cohort. Exploratory objectives include correlation of tumor and plasma biomarkers, and changes in immune cell profiles with clinical outcome. The study has been initiated and enrollment target is 120 pts across the 4 expansion cohorts. Clinical trial information: NCT03170960.
Combination of bemcentinib (BGB324): A first-in-class selective oral AXL inhibitor, with pembrolizumab in patients with triple negative breast cancer and adenocarcinoma of the lung.
Authors: Yule Murray , Davidsen Kjersti , Bloe Magnus , Hodneland Linn , Engelsen Agnete , Lie Maria , Bougnaud Sebastien , D'Mello Stacey , Aguilera Kristina , Ahmed Lavina , Rybika Agata , Milde Naeval Eline , Boniecka Anna , Thiery Jean Paul , Chouaib Salem , Brekken Rolf A. , Gausdal Gro , Lorens James 
Published: February 2018

TPS43 Background: Activation of the receptor tyrosine kinase AXL has a profound suppressive effect on the innate immune system. AXL is overexpressed on multiple cell types in the tumour immune microenvironment including dendritic cells, NK cells and tumour-associated macrophages. AXL signalling in immune cells supports tumour immune escape by downregulating dendritic cell activity, modulating efferocytosis as well as favouring an immunosuppressive chemokine profile and M-MDSC expansion. AXL is prevalent in tumours resistant to anti-PD-1 therapy (Hugo, 2016). Axl expression in tumour cells confers resistance to effector T cell cytotoxicity. Bemcentinib (BGB324) is a first-in-class, highly selective and orally bioavailable small molecule AXL inhibitor in phase II clinical development. In pre-clinical models of pancreas, breast and lung cancer, inhibition of AXL signalling with bemcentinib reversed multiple tumour immune suppressive mechanisms as evidenced by increased infiltration of cytotoxic T lymphocytes, NK and NKT cells and decreased infiltration of M-MDSCs (Wnuk-Lipinska, 2017). Bemcentinib enhanced the effect of immune checkpoint blockade via PD-1 or CTLA-4 in lung and mammary adenocarcinoma mouse models and achieved sustained tumour immunity. Methods: BGBC007 (NCT03184558) and BGBC008 (NCT03184571) are open-label, phase II studies designed to assess the anti-tumour activity of bemcentinib in combination with pembrolizumab in patients with previously treated TNBC and adenocarcinoma of the lung respectively. All patients will be treated with bemcentinib in combination with pembrolizumab continuously for up to two years. The primary endpoint is objective response rate, secondary endpoints include duration of response, progression free survival according to RECIST 1.1, pharmacokinetics, safety and tolerability. Pretreatment tumour specimens are scheduled to assess AXL expression/signalling and PD-L1 expression; the levels of circulating immune-related cytokines and soluble AXL receptor will also be measured in longitudinal patient plasma samples. Both studies are open to recruitment. Clinical trial information: NCT03184558.
AIDS malignancy consortium (AMC) 095: A phase I study of ipilimumab (IPI) and nivolumab (NIVO) in advanced HIV-associated solid tumors (ST) with expansion cohorts in HIV-associated solid tumors and classical Hodgkin lymphoma (cHL).
Authors: Rajdev Lakshmi , Chiao Elizabeth , Lensing Shelly , Streicher Howard , Little Richard F. , Dittmer Dirk , Einstein Mark , Haigentz Missak , Sparano Joseph A. , Mitsuyasu Ronald T. 
Published: February 2018

TPS44 Background: Immune checkpoint blockade (ICB) using agents that target the priming phase (i.e. CTLA-4) and effector phase (e.g. PD-1) of host immunity, used individually or in combination, has emerged as a therapeutic strategy for cancers. However, little is known about the safety, tolerability and efficacy of ICB in patients (pts) with HIV infection and cancer. Methods: AMC 095 (NCT02408861) is a multicenter, international phase I study of the PD-1 inhibitor, nivo alone or in combination with a CTLA-4 inhibitor, ipi, in 2 cohorts stratified by CD4 counts (Stratum 1: CD4 counts≥200/uL and Stratum 2: CD4 count 100-200/uL) with additional expansion cohorts at the recommended phase II dose in pts with ST and cHL. The primary study objective is to determine the safety and feasibility of nivo alone and the nivo+ipi combination. Secondary objectives are to evaluate the effects of single agent nivo, and ipi+ nivo, on HIV replication and immune function (HIV viral load in plasma using conventional assay, CD4+, and CD8+ cells), and to obtain preliminary information regarding response. The trial was initiated in 8/15, as of 9/30/17, the study is ongoing, and 14 pts have been enrolled. Updated information on the safety and responses will be presented. Clinical trial information: NCT02408861. Funded by the NCI Grant #UM1CA121947.[Table: see text]
Practice-based evidence for factors associated with urinary incontinence following prostate cancer care.
Authors: Li Kevin , Magnani Christopher J. , Bozkurt Selen , Seto Tina , Blayney Douglas W. , Brooks James D. , Hernandez-Boussard Tina 
Published: February 2018

106 Background: Urinary incontinence (UI) is a common complication following treatment for localized prostate cancer. Past studies evaluating UI risk factors use surveys or chart abstraction, which may be costly and lack generalizability. Electronic health records (EHR) allow us to examine UI at a population level. We applied data mining methods to EHR data to: (1) evaluate rates of UI following prostate cancer treatment; and (2) evaluate potential risk factors for posttreatment UI. Methods: We conducted a retrospective analysis of patients undergoing prostatectomy or radiation therapy for localized prostate cancer between 2009-2016, and who received follow-up care at our medical center. Our cohort was constructed from the institutional EHR and the California Cancer Registry. The primary outcome was the presence of UI, measured in three-month intervals from the start of first-line treatment. The secondary outcome was UI 12-24 months following treatment (“late UI”). UI was assessed using natural language processing of EHR clinician notes. UI was also assessed with the EPIC-26 quality of life survey, which a subset of patients had prospectively completed. Results: Our cohort consisted of 2783 men, of whom 1907 (69%) underwent surgery and the remainder received radiation; of this cohort, 609 (22%) had data on late UI status. UI prevalence was higher among surgery than radiation patients across all posttreatment time points, and 278 of 434 (64%) surgery patients had late UI compared to 78 of 175 (45%) radiation patients (p < 0.001). Univariable analyses showed an association between pretreatment and late UI among surgery patients as measured in the EHR (OR 2.5, 95% CI 1.0-6.5, p = 0.05) and by EPIC-26 (OR 8.1, 95% CI 1.8-36.5, p = 0.01). Only surgery (compared to radiation) was a significant predictor of late UI (OR 5.8, 95% CI 1.1-32.3, p = 0.05) in multivariable regression with EHR data. Conclusions: Using EHR data, we found that treatment modality was a significant predictor of late UI among prostate cancer patients who underwent prostatectomy or radiation therapy. These results suggest the utility of EHRs in patient-centered outcomes research in prostate cancer care, and should be validated at other sites.
Performance of a clinically validated urine exosome gene expression test to predict high grade prostate cancer in men with a prior negative biopsy.
Authors: Donovan Michael Joseph , Torkler Phillipp , Noerholm Mikkel , Skog Johan , McKiernan James M 
Published: February 2018

119 Background: The over-diagnosis of low grade, indolent prostate cancer (PCa) initiates significant patient anxiety regarding treatment options and health risk. To address this clinical need, we developed and subsequently validated a noninvasive, easy to administer, supportive diagnostic test (ExoDx Prostate(IntelliScore), EPI) to guide the initial prostate biopsy decision process for men with PSA 2-10ng/mL. The EPI test is a urine exosome gene expression assay to discriminate high-grade (GS 7 PCa) from low-grade (GS 6) and benign disease, thereby potentially reducing the number of unnecessary biopsies. As many men have had prior negative/ benign biopsies, we sought to understand the performance of EPI in this selected population. Methods: Utilizing men with prior negative biopsies from two clinical trials we evaluated performance of the EPI test with respect to subsequent biopsy outcomes. We used the previously validated and alternative EPI cut-points of 15.6 and 20, respectively, to assess performance with AUC, sensitivity, and NPV. Results: A total of N = 286 patients with a prior negative biopsy; mean age 65 years, mean PSA 6.2 ng/mL, 22% positive family history, 15% African American; 32% positive biopsy rate: 20% GS6 (ISUP1) and 12% > / = GS7 PCa (ISUP≥2). AUC 0.68 vs. AUC 0.59 for standard of care (i.e. PSA, age, race, family history) and AUC 0.51 for PSA alone. By comparison the EPI initial biopsy AUC was 0.71. Using the previously validated EPI cut-points of 15.6 (or alternative 20) yielded NPVs of 92% and 95%, and number of avoided biopsies of 23% and 32%, respectively, and sensitivity of 85.7% for both cut-points. Notably, EPI in the initial biopsy setting had a sensitivity of 92 vs. 87% and an NPV of 91 vs. 90%, for the 15.6 and 20 cut-points, respectively. Conclusions: The EPI test is a noninvasive, first-catch, non-DRE gene expression array that accurately discriminates low-grade and benign biopsy outcomes from high-grade prostate cancer. The test performs well in both the initial and prior negative biopsy patients and has the potential to reduce the overall number of unnecessary biopsies in both settings.