bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bayesian AI to delineate molecular signatures of patient susceptibility to potential hematologic events in a phase I study of BPM31510 (ubidecarenone) in solid tumors.
Authors: Sarangarajan Rangaprasad , Subbiah Vivek , Hong David S. , Kiebish Michael , Vishnudas Vivek , Grund Eric M , Miller Gregory M , Rodrigues Leonardo O , Dion Hedy , Stevens Janice , Akmaev Viacheslav R , Narain Niven R. 
Published: September 2018

e14042 Background: BPM 31510 is a ubidecarenone containing nanodispersion elicits anticancer effect by switching cancer cells energy generation from glycolysis to mitochondrial OXPHOS; i.e. reverses Warburg effect. This Phase 1 study is evaluating safety of 144-hour infusion of BPM 31510 as a single agent and in combination with 3 standard chemotherapy regimens. The molecular adaptive study design enabled longitudinal multi-omic molecular profiling to delineate personalized cause-and-effect networks relating patient biology to clinical outcomes using unbiased Bayesian statistics based bAIcis Artificial Intelligence (AI) technology Methods: Eligible pts (aged ≥ 18 y) were relapsed/refractory to standard therapy. The monotherapy arm received IV BPM31510 for 144-hour infusion in 28d cycles, and combination arms (gemcitabine, 5-FU or docetaxel) were primed with BPM 31510 for 3 wks followed by weekly dosing in a 6wk cycle. Doses were escalated in a 3+3 schema. Endpoints were safety, PK and multi-omics analysis. Clinical information was processed and integrated with multi-omic molecular data (metabolomics, lipidomics and proteomics), utilized bAIcis to learn relationships and extract actionable information from pt records, molecular features and corresponding clinical response. Results: As of 10 Dec 2016, 97 pts have been enrolled. Hematologically-related DLTs were reported at 171mg/kg in monotherapy and 137mg/kg in the BPM31510+gemcitabine arm (maximum administered dose). The bAIcis-generated set of predictors defining coagulation-related events in the clinical trial population include proteins, lipids, and metabolites, the levels of which can potentially predict undesirable events prior to and 24h after the 1st treatment with BPM 31510. Conclusions: BPM31510 is well tolerated as a monotherapy and in combination with chemotherapeutic agents. Molecular signatures of susceptibility have been identified through use of multi-omic based AI analysis. Molecular signatures predictive of coagulation-related events will be assessed in Phase 2 and 3 trials to guide the development plan for BPM 31510 as anticancer agent. Clinical trial information: NCT01957735.
Tolerability of paclitaxel/carboplatin (PCb) in solid tumor patients (pts) infected with HIV.
Authors: Haigentz Missak , Moore Page C. , Ratner Lee , Henry David H. , Rubinstein Paul G. , Ramos Juan Carlos , Rudek Michelle A. , Eng Yoko , Cooley Timothy Patrick , Deeken John F. , Little Richard F. , Mitsuyasu Ronald T. ,   AIDS Malignancy Consortium
Published: September 2018

e14077 Background: Although cancer has long been a recognized hallmark of the HIV epidemic, the preservation of immunologic health with modern antiretroviral therapy (ART) and aging has resulted in a population increasingly susceptible to cancers not traditionally associated with advancing immunosuppression. Several of these cancers (including lung, anal and head & neck) are seen in excess compared to the background population. Defining tolerability of standard treatments and analyzing potential interactions between ART and chemotherapy provides evidence necessary to mitigate treatment disparities. Methods: We conducted a study to evaluate the tolerability of PCb in HIV+ cancer pts. AMC-078 (NCT01249443), originally designed as a phase I of vorinostat in combination with fixed doses of P (at 175mg/m2) and Cb (AUC 6) every 3 weeks, was amended to study pts treated with PCb alone after phase III testing in the background population was negative for the combination in lung cancer. Eligibility criteria: PS ≤ 2, advanced solid tumor and normal organ function, including CD4 count > 100 cells/mcL on stable ART. Up to 6 cycles of PCb were permitted. Clinically significant adverse events (AE) in prior cycles were managed by dose reductions. Results: 17 pts (10M/7F; median CD4, 389/mcL) were accrued, including lung (9) and anal (3) cancers; 8 pts had ritonavir (potent CYP inhibitor)-containing ART. 65 PCb cycles were administered to 16 evaluable pts, for a mean of 4+ cycles/pt; only 2 pts were treated with vorinostat. AE of special interest included ≥G3 (febrile) neutropenia and ≥ G2 neuropathy, below. 4 pts had partial responses (3 confirmed). Pharmacokinetic analyses (7 pts) are pending. Conclusions: PCb has similar toxicity profile in fit pts with HIV infection. No signal for worse myelosuppression or neuropathy was observed by ART regimen. Routine use of GCSF or empiric dose reduction for presumed risk is unjustified. Results support standard cancer treatment for this underserved population. Clinical trial information: NCT01249443. [Table: see text]
Expression of PD-L1 in colorectal cancer that lack mutations in RAS or TP53 genes.
Authors: Albitar Maher , Sudarsanam Sucha , Ma Wanlong , Jiang Shiping , Chen Wayne , Funari Vincent Anthony , Agersborg Sally 
Published: September 2018

e14500 Background: PD-L1 expression as detected by immunohistochemistry (IHC) is significantly lower in colorectal cancers (CRC) when compared with lung cancer or other types of cancer. We explored if mutations in the RAS/RAF gene family, TP53 or PIK3CA can define a subgroup of CRC that express PD-L1. Methods: Tissue samples collected from 107 patients with CRC were studied for the expression of PD-L1 using clone SP142. The same samples were also tested for mutations in NRAS, KRAS, HRAS, BRAF, TP53, and PIK3CA using Next Generation Sequencing (NGS). Results: Of the 107 CRC samples only 15 (14%) showed PD-L1 positive tumor cells (≥1%) and 8 of the 15 (7.5% of total) had PD-L1 in ≤5% of tumor cells. Detected mutations in these samples were as follows: TP53 65%, KRAS 49.5%, PI3KCA 22.5%, NRAS 5%, HRAS 1%, and BRAF 17%. There was no correlation between PD-L1 expression and mutation status in any of the RAS/RAF genes. There was also no correlation between TP53 mutation and PD-L1 expression. This was true irrespective if PD-L1 expression is considered as a continuous variable or when cut-off points of 5%, 20%, or 50% were used. However, patients without any mutation in RAS or TP53 had significantly (P = 0.005) more expression of PD-L1 when cut-off point of 5% is used. This remained true if PD-L1 expression is considered as a continuous variable (P = 0.04). There was no correlation between PIK3CA and PD-L1 expression. Conclusions: PD-L1 expression is significantly more common in CRC that lack mutations in RAS or TP53. PD-L1 expression is detected in 31% of patients with wild-type RAS/TP53 as compared with 12% in patients with RAS/TP53 mutations (P = 0.04). If a cut-off point of 5% is used, 31% of RAS/TP53-wild-type CRC were positive for PD-L1, while only 6% of RAS/TP53- mutant CRC were positive for PD-L1 (P = 0.005). This suggests that in CRC without RAS/TP53 mutation, the PD-L1 may play a more important role in oncogenesis. Exploring immunotherapy in this group of CRC patients might be justified.
The expression level and prognostic value of PD-L1 and PD-1 in cervical carcinoma patients.
Authors: Zhang Songan , Bao Yong Xing , Huerxidan Niyazi , Liu Pan , Zhao Huarong , Gulixian Tuluwengjiang , Zhang Yang , Xiao Lei , Su Weipeng , Dilidaer Sidike , Ye Jianwei ,   Cancer Center of 1st Affliated Hospital XinJiang Medical University
Published: September 2018

e14501 Background: By testing the expression of PD-L1 in tissues and expression of PD-1 in matched blood samples in the cohort of cervical cancers patients and cervical benign disease patients, investigate the correlation between the expression level and their prognostic value. Methods: 70 tissue samples of cervical squamous cell carcinoma and 70 tissue samples of cervical benign lesion were collected respectively, and 24 cases of the cervical squamous cell carcinoma had matched peripheral blood samples, compared to 30 cases with matched peripheral blood samples in benign lesions. Immunohistochemistry was used to detect the expression of PD-L1 in the tissues. Flow cytometry was used to detect the proportion of CD4+PD-1+ and CD8+PD-1+ subsets in peripheral blood. Log-rank and COX regression were employed to analyze the survival time, clinical features and the information above. Results: There was no difference among age, marriage age, times of pregnancy, age of menarche, menopause, ethnic cultural level and occupation, except for family history of cancer. The portion of CD4+PD-1+ T cells and CD8+PD-1+ T cells in peripheral blood positively correlated with the expression of PD-L1 in tissue samples of cervical squamous cell carcinoma patients (R2 = 0.734, P = 0.000; R2 = 0.66, P = 0.000), while there were less correlation in cervical benign patients (R2 = 0.138, P = 0.043; R2 = 0.174, P = 0.022). There were significantly differences in the portion of CD8+PD-1+T cells and PD-L1+ cancer cells between cervical cancer group and cervical benign disease group (P = 0.000, P = 0.002). The portion of CD8+PD-1+ T cells correlated with the status of menopause (chi square = 7.152, P = 0.012). There was no relationship among the tumor size, differentiation, depth of invasion and PD-1 expression in peripheral blood cervical cancer group or cervical benign disease group. Conclusions: The cervical squamous cancer patients had more CD4+PD-1+ T cells in peripheral blood and PD-L1+ cells in tissues, which correlated to the grading and prognosis of the tumor.
Non-invasive, blood-based DNA and RNA profiling for cancer immunotherapy and PARP inhibitor clinical trials.
Authors: Yu Jianjun , Zhao Zhixin , Wang Amy , Cheung Tak , Du Pan , Jia Shidong 
Published: September 2018

e14527 Background: The response to cancer immunotherapy (CI) and other target therapies varies widely across patients, making it difficult for physicians to select right treatment for a given patient. Studies report that patients with high PD-L1 gene expression are likely to respond to checkpoint blocking drugs, but there are still many patients whose tumor test for the PD-L1 protein are negative respond to the drugs. Recent publications show that tumor mutation burden and microsatellite instable (MSI) are good indicators of the cancer immunotherapy responses. However, as tissue biopsy remains a practical challenge in clinic due to its insufficient quantity or lack of access, non-invasive molecular test has provided a new alternative option to detect or monitor genomic alternations of tumors in clinical drug development. Methods: Based on Predicine’s Gene RADAR (RNA and DNA Single Molecule Digital Reading) technology platform, here we introduce PrediSeq-CI and PrediSeq-HRD (homologous recombination deficiency) blood tests, a non-invasive, next-generation sequencing (NGS)-based multiplex assay that enables real-time monitoring of temporal change of tumor heterogeneity and sensitive detection of genomic alterations related to cancer immunotherapy and DNA-repair homologous recombination pathways at both RNA and DNA levels. Results: Technical validation was performed to evaluate assay sensitivity, specificity and accuracy using reference samples with known genetic profiling. The panels have been further tested using tissue biopsy and plasma samples from cancer patients. Conclusions: The successful development of PrediSeq-CI and PrediSeq-HRD liquid biopsy tests offer an efficient solution to stratify and monitor cancer patients who may benefit from cancer immunotherapy as well as HRD-targeted therapeutics.
Active specific immunotherapy for lethal canine hemangiosarcoma: A model system for the treatment of angiosarcoma with curative intent.
Authors: Decker William Karl , Douglass Laurel , Halpert Matthew M , Konduri Vanaja , Chen Yunyu , Liang Dan , Levitt Jonathan M , Neal Brittany , Hudson Caleb , Hottinger Heidi , Piscoya Sindy , Wilson Nicola , DiBernardi Lisa , Stallings Shonda , Omarbekov Zharkyn , Seelhoff Lori , Ramirez Oscar , Yao Qizhi Cathy , Bhardwaj Ratan D , Ravi Vinod 
Published: September 2018

e14539 Background: Angiosarcoma is a deadly malignant neoplasm of the vascular endothelium. Metastases are often present at diagnosis, and 5-year survival is only 10-30%. Though it comprises only 1% all soft tissue sarcoma diagnoses, it is a major killer among companion canines, responsible for an estimated 120,000 deaths per year in the US. The canine disease (termed HSA) closely mimics the human disease in both pathology and genetics. It frequently presents in the dog as acute hemoabdomen secondary to splenic rupture. Even if life-saving splenectomy is performed, median OS is only 48 days, and 1 year OS hovers at 0%. Given the accelerated timeline of the canine disease, the outbred dog is an ideal system in which to translate novel therapeutic approaches. Here we report an analysis of a phase I multi-site, open-label veterinary trial of chemo-immunotherapy performed on consecutively-presenting splenectomized companion canines with histopathologically-verified HSA. Methods: Subjects were administered two cycles of 20 mg/m2 (low-dose) doxorubicinand an autologous cell-therapy reported to generate durable CD8+ memory similar to that of physiologic viral infection. Vaccine was generated from mobilized peripheral blood and cryopreserved tumor antigen and was administered with type I interferon. Disease burden was monitored monthly by abdominal ultrasound, chest x-ray, and echocardiogram. Results: At the time of submission, median OS had not been reached in the per protocol population, with 75% of animals alive and healthy (NED or ongoing PR) at up to 1 year post-splenectomy (p < 0.0002). Ultrasound documented resolution of local mesenteric disease in one animal, sternal lymphadenopathy in another, and hepatic metastases in a third. In the intent-to-treat population, median OS was 109 days with 43% of animals alive and healthy at up to 1 year post-splenectomy. Conclusions: Administration of autologous cell therapy with low-dose doxorubicin is feasible, safe, and highly efficacious in the companion canines. If subjects survived long enough to begin treatment, prognosis became favorable. The results suggest that additional clinical studies in both canines and humans are warranted.
Antitumor effect of a whole tumor cell vaccine expressing human fibroblast activation protein in murine tumor models.
Authors: Chen Meihua , Lang Jin Yi , Li Tao , Wang Qifeng , Xu Guangchao , Lu Shun 
Published: September 2018

e14542 Background: Immunosuppressive factors in the tumor microenvironment reduce the therapeutic efficacy of cancer vaccines; therefore, dampening the tumor immunosuppressive environment while activating antitumor immunity should be a useful approach for cancer therapy. Cancer-associated fibroblasts (CAFs) are among the most important cellular components of the tumor microenvironment and play an important role in the development and progression of tumors. Fibroblast activation protein α (FAPα) is a type II transmembrane protein specifically expressed by CAFs in most epithelial cancers. Gene sequence homology between human and murine FAPα is 90%. Heterogeneity of genes in the evolution of the formation of such nuances can be utilized to break immune tolerance, enhance immunogenicity, induce tumour cell autoimmune responses and thus inhibit tumor growth. Methods: Tumor cells were transfected with human FAPα plasmids employing the cationic lipid DOTAP. Its antitumor effects were investigated in three established tumor models. The potential immune mechanisms were investigated through adoptive immunotherapy and 51Cr release assay. The distributions of the immune cells in the tumor microenvironment were detected by immunohistochemical staining and flow cytometry. Results: Our results shown that whole tumor cell vaccine expressing human FAPα significantly inhibit tumor growth and prolong the survival of tumor bearing mice. This antitumor immune response was involved both of cellular and humoral immune responses. FAPα specific neutralizing antibodies were found in the serum of vaccinated mice and CAFs were significantly reduced within the tumors. Furthermore, this vaccine enhanced the infiltration of CD4+ T cells and CD8+ T cells, and suppressed the accumulation of immunosuppressive cells in the tumor microenvironment. Conclusions: These findings suggest that whole tumor cell vaccine expressing human FAPα inhibit tumor growth by producing FAPα specific neutralizing antibodies and CTLs, and targeting tumor cells and CAFs. These observations provide a new strategy for the clinical use of genetically modified tumor cells as cancer vaccines.
Evaluating the reversible control of an engineered CAR T cell ON-switch.
Authors: Gilbert Amy , Santoro Stephen , Tse Tiffany , Candelario-Chopra Tara , Gomes Tina , Campos Jose , Spelman Michael , Seacrest Stephaine , Coyle Scott , Rupp Levi , Emtage Peter 
Published: September 2018

e14550 Background: CAR T cell therapy holds enormous promise for many cancer types but its application may be limited by serious toxicities. To lower this hurdle, our aim is to engineer tunable cell therapies. One of our approaches includes a “ON-switch” chimeric antigen receptor (Wu et al., Science 2015) that requires the administration of a small molecule acting as a dimerizing agent between one polypeptide chain containing the antigen recognition domain and half of an inducible heterodimerization system and another polypeptide chain containing the second half of the inducible heterodimerization motif, the CD3ζ chain and a costimulatory motif. Using an FDA approved small molecule drug, we evaluate the reversibility of ON-switch CAR T cells in preclinical models. Methods: First, we evaluated the proliferation, cytotoxicity and cytokine production of several ON-switch constructs in human primary T cells. Next, to address the reversibility of the ON-switch (ON→OFF→ON), we performed a series of co-culture experiments where the small molecule drug was added to tumor cells and ON-switch CAR T cells, then washed out, and then re-introduced back into the co-cultures. We compared CAR T cell mediated killing and cytokine production from the On-switch CAR T cells relative to a canonical CAR T control. Results: Our On-switch CAR T cells were shown to proliferate, secrete cytokines as well as mediate dose dependent cytotoxicity in the presence of the small molecule drug. Importantly, in the presence of antigen but in absence of the small molecule drug we did not measure any significant functional activity in our ON-switch CARs. Additonally, following the removal of the small molecule drug over a period several days we did not observe any significant CAR mediated cytotoxicity. Following the subsequent re-addition of the small molecule, we observed further CAR T cell mediated cytotoxicity against tumor cells. Conclusions: These results show that the small molecule inducible On-switch CARs maintain functional activity as well as reversibility allowing for the tunable control of a CAR T cell.
Phase I study of anti-PD1 in combination with low-dose decitabine in patients with advanced and untreated malignancies.
Authors: Wang Chunmeng , Liu Yang , Zhang Wenying , Chen Meixia , Shi Lu , Dong Liang , Li Xiang , Yang Qingming , Nie Jing , Han WeiDong 
Published: September 2018

e14555 Background: Anti-PD1 have produced significant antitumor activity in multiply malignancies, however, resistance to anti-PD1 is becoming increasingly apparent in recent years. Low-dose decitabine, a classical DNA hypomethylating agent, was shown to boost effector T cell function and trigger a T cell-mediated response. This phase I study was designed to assess the safety, immunological effects and antitumor activity of this novel combination in patients with advancedanduntreated lymphomas and solid tumors. Methods: Patients were treated with decitabine (10mg/d on day 1-5) and anti-PD1 (2-3mg/kg, day 8) per 3 weeks. Modified salvage regimens (lymphoma: COP; solid tumors: platinum-based chemotherapy) were allowed to be intermittently inserted for patients with aggressive progression. Treatment continued unless disease progression or severe toxicity. Safety was assessed by CTCAEv4.0, and response by standard international criteria. The phenotype and activity of T cells were periodically measured in peripheral blood by flow cytometry. Results: Todate, 11 patients with heavily treated history and refractory bulky lesions have been enrolled, including 8 with lymphomas (7 NHL, 1 HL resistant to anti-PD1) and 3 with metastatic solid tumors (2 gastric cancers, 1 esophageal cancer) failure to anti-PD1. 5 patients (45%) experienced Grade ≥ 3 toxicities, with 1 taken off due to toxicity, and 1 died of asystole during the term of severe cytokine release syndrome (CRS). The common events of leukocytopenia and CRS were prominent features of anti-PD1 plus decitabine. 9 patients were evaluable for response, 1 HL obtained complete response, 3 NHL and 3 solid tumors achieved partial response, and 2 NHL had stable disease with nearly 20% shrinkage. The frequency of interferon-γ-producing CD8+ T cells in the total CD3+ population was largely increased after anti-PD1 plus decitabine infusion. Conclusions: Decitabine augmented the pro-inflammatory effects of anti-PD1 characterized by systemic inflammation response, and further improved antitumor activity of anti-PD1. Clinical trial information: NCT02961101. Clinical trial information: NCT02961101.
Analysis of response rate with anti-PD1/PDL1 antibodies in advanced solid tumors: A meta-analysis of randomized clinical trials (RCT).
Authors: Carretero-González Alberto , Lora David , Ghanem Ismael , Zugazagoitia Jon , Castellano Daniel , Sepúlveda Juan Manuel , Lopez-Martin Jose A. , de Velasco Guillermo , Paz-Ares Luis G. 
Published: September 2018

e14576 Background: Anti-PD1/PDL1 antibodies (mAbs) have been shown to increase overall survival (OS) compared to standard of care (SOC) in solid tumors (mainly melanoma and lung cancer). Despite the efficacy in OS, a significant proportion of patients (pts) will have progressive disease (PD) as best response. Therefore, we have conducted a meta-analysis to study the rates of response comparing these novel antibodies with SOC (chemotherapy or targeted therapy). Methods: We conducted a search of the published RCT in MEDLINE and EMBASE analyzing anti-PD1/PDL1mAbs monotherapy compared to SOC. All studies used RECIST v1.1. Relative risk (RR) with 95% confidence interval (CI) of response rates between groups was estimated. Clinical heterogeneity was explored via subgroup analyses for location of primary tumor, number of previous treatment lines and selected population by PDL1 expression. Results: Eleven studies accounting for 6,396 pts were included (anti-PD1/PDL1 mAbs: 3,333 pts; SOC: 3,063 pts[2,637 pts: chemotherapy, 426 pts: targeted therapy]). Adjusted response rates were (N ,%): Complete Response (CR)(50/3035, 1.65%), Partial Response (PR)(558/3035, 18.39%), Stable Disease (SD)(585/2345, 24.95%) and PD (896/2345, 38.21%); and CR (7/2769, 0.25%), PR (241/2769, 8.70%), SD (744/2083, 35.72%) and PD (744/2083, 35.72%) with anti-PD1/PDL1 mAbs and SOC, respectively. Anti-PD1/PDL1 mAbs improved CR rate (RR 4.70) and PR rate (RR 2.38). There were no differences in the PD rate between groups (RR 1.09; table 1). Subgroup analyses showed a significant improvement in clinical benefit with anti-PD1/PDL1 mAbs for melanoma (RR 1.5; 1.42-1.91 95% CI) and pts treated in the first line setting (RR 1.57; 1.27-1.95 95%CI). Conclusions: Anti-PD1/PDL1 mAbs increase overall response rate compared to SOC without an increase in PD rate. Melanoma and pts treated in first line setting seem to have greater benefit with anti-PD1/PDL1 mAbs. [Table: see text]