bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics (PK) of blinatumomab and its clinical implications.
Authors: Wu Benjamin , Hijazi Youssef , Wolf Andreas , Brandl Christian , Sun Yu-Nien , Zhu Min 
Published: March 2020

3048 Background: Blinatumomab is an investigational, bispecific, single-chain T cell engaging (BiTE) antibody of 55 kD that targets CD19 on B cells and CD3 on T cells. Blinatumomab induces polyclonal T cell activation and proliferation, resulting in redirected lysis of CD19+target cells. Comprehensive analysis of its PK and the clinical implications is presented. Methods: PK data from 131 patients enrolled in 3 phase 1 or 2 studies of non-Hodgkin lymphoma (NHL; N=76), relapsed/refractory acute lymphoblastic leukemia (r/r ALL; N=36), and ALL with minimal residual disease (MRD; N=19) were analyzed. Blinatumomab was given by constant IV (cIV) infusion at 0.5, 1.5, 3, 5, 10, 15, 30, 60 and 90 μg/m2/d over 4 weeks/cycle. Serum blinatumomab concentrations were assessed using a validated bioassay. PK parameters, including volume of distribution (V), half-life (t1/2) and clearance (CL), were analyzed with noncompartmental methods. CL was derived by dividing infusion rate by blinatumomab concentration at steady state (Css). Mean CL from each patient was used to determine disease heterogeneity and for covariate analyses. Effective dose was assessed with PK, in vitroand clinical B cell data. Results: At the doses tested, blinatumomab had linear PK that was stable over time. V (~5 L) approximated that of monoclonal antibodies. Blinatumomab had a t1/2 of ~2 h, with systemic CL of ~2 L/h. Minute blinatumomab concentrations were detected in the urine of 3 (of 13) NHL patients at a dose of 60 μg/m2/d. There was no trend of NHL, r/r ALL or ALL with MRD; CrCL, age, gender, weight, or body surface area (BSA) influencing CL. Preliminary analysis showed comparable mean CL values in patients with CrCL ≥30 mL/min, ranging from 1.9 to 2.6 L/h. To achieve Css above the in vitro EC90 value for leukemia cell lines (470 pg/mL) and complete B cell suppression in patients, 15 μg/m2/d of blinatumomab given as cIV over 4 weeks/cycle is desired for ALL treatment. Conclusions: Blinatumomab PK was linear, stable, and independent of NHL, r/r ALL or ALL with MRD. Kidney involvement in its excretion was limited at the investigated doses. cIV administration is required due to the short t1/2. Flat or BSA-based dosing can be used in adults. A cIV dose of ≥15 μg/m2/d provides adequate exposure for ALL treatment. Clinical trial information: NCT00274742, NCT01209826, NCT00560794.
An engineered immunotherapy (NKTR-214) with altered selectivity toward the IL2 receptor: Efficacy and tolerability in a murine tumor model.
Authors: Charych Deborah H. , Addepalli Murali , Lee Steve , Chang Thomas , Liu Xiaofeng , Pena Rhoneil , Sweeney Terry , Hoch Ute , Doberstein Stephen K. , Kantak Seema S. 
Published: March 2020

3060 Background: Cytokine-based immunotherapy has been successful for the treatment of cancer, with potential for durable responses in multiple indications. One approach towards stimulating the immune system is to target the heterotrimeric interleukin2 receptor, IL2R. NKTR-214 uses polymer technology to alter receptor subunit selectivity to favor expansion of CD8+ memory effector T cells (CD8T) in the tumor over CD4+ regulatory T cells (Treg). In addition, polymer conjugation is designed to improve exposure and enhance tumor localization, significantly improving efficacy, modulating vascular leak syndrome (VLS) and allowing flexible dosing regimens. Methods: C57BL/6 mice bearing established subcutaneous B16F10 melanoma were treated with NKTR-214 at a variety of doses (0.25-4.0 mg/kg) and schedules (q5dx3 to q14dx2). Mice treated with clinically validated IL2 were administered 3mg/kg, bidx5 for 2 cycles. Efficacy was measured by monitoring tumor volumes. Tolerability was evaluated by survival. VLS was measured by injection of Evans Blue dye followed by colorimetry in lungs. Tumor immunotyping, by flow cytometry. Results: Tumors from mice receiving NKTR-214 had a CD8/Treg ratio of over 1,000 versus 14 for IL2. NKTR-214 administered at 2 mg/kg, q9dx3 was identified as the optimal regimen and showed tumor growth delay of 26 days compared to 9 days for optimally dosed IL2. 90% of NKTR-214 treated mice tolerated treatment compared to 67% for IL2. VLS was completely resolved prior to administration of the next dose of NKTR-214, unlike IL2. NKTR-214 was well tolerated in rats at two schedules, at MTD. Conclusions: NKTR-214 is a highly differentiated cytokine with a new mechanism of action that may provide options for cancer immunotherapy. Polymer conjugation of a clinically validated cytokine alters the IL2R selectivity to favor expansion of tumor killing immune cells (CD8T) over regulatory immune cells (Treg) in the tumor. The conjugate is also designed to improve exposure and enhance tumor localization, offering more options of dose and schedule. The optimal dose and schedule is cytokine-sparing, provides substantial tumor growth delay, and reduces toxicity.
Phase I clinical trial of a genetically modified and oncolytic vaccinia virus GL-ONC1 with green fluorescent protein imaging (NCT009794131).
Authors: Khan Khurum Hayat , Young Anna-Mary , Mateo Joaquin , Tunariu Nina , Yap Timothy Anthony , Tan David Shao Peng , Mansfield David , Wong Mabel , Riisnaes Ruth , Harrington Kevin J. , De Bono Johann Sebastian 
Published: March 2020

3062 Background: GL-ONC is a genetically engineered virus attenuated by insertion of the ruc-gfp (Renilla luciferase and Aequorea green fluorescent protein fusion gene), beta-galactosidase (lacZ) and beta-glucuronidase (gusA) reporter genes into the FL14.5L, J2R (thymidine kinase) and A56R (hemagglutinin) loci, respectively. A phase I trial of intravenous (i.v) GL-ONC1 was pursued to evaluate safety, tolerability, tumour delivery, neutralising antibody development and antitumor activity. Methods: GL-ONC1 was administered at escalating doses (1x105, 1x106, 1x107, 1x108, 1x109, 3x109 plaque forming units (pfu) on day 1; 1.667x107 and 1.667x108, 1.667x109pfu on days 1-3) utilizing a 28-day cycle and a 3+3 dose escalation design. Paired biopsies before treatment and on day 8 for pharmacodynamic and viral delivery evaluation were obtained. Green flourescent protein (GFP) imaging was performed on skin rash and mucosal tumour lesions at baseline and after each cycle. Results: To date, 33 patients (pts) across 8 cohorts have been treated with 1 dose limiting toxicty reported of grade 3 transaminitis after a single infusion at 1x109pfu. Other reported adverse events (n) included pyrexia (26), musculoskeletal pain (10), fatigue (8), nausea and vomiting (4). 2 pts had transient transaminitis; both had liver metastases, which may have contributed to this. 2 pts developed minimally symptomatic poxvirus skin pustules, which appeared green by GFP and were positive to viral plaque assay (VPA). Overall, stable disease (SD) by RECIST was seen at >24 weeks (n=6) and 8-12 weeks (n=5). 2 out of 4 pts in cohort 8 (one with cholangiocarcinoma and another with non-small cell lung caner) achieved SD for median 5.5 months, with a drop in tumour markers at the time of infusions. Conclusions: GL-ONC1 is well tolerated; more frequent delivery of the virus (2 weekly, at the same dose) is planned in an attempt to increase agent exposure. Clinical trial information: NCT009794131.
Immunotherapy with CpG-ODN in neoplastic meningitis: A phase I trial.
Authors: Ursu Renata , Taillibert Sophie , Psimaras Dimitri , Banissi Claire , Bailon Olivier , Le Rhun Emilie , Guillamo Jean Sebastien , Marantidou Athina , Hoang-Xuan Khê , Belin Catherine , Carpentier Antoine F 
Published: March 2020

3065^ Background: TLR9 agonists, such as phosphorothioate oligodeoxynucleotides containing CpG motifs (CpG-ODNs), are immunostimulating agents with antitumor effects in animal models. Neoplastic meningitis is a devastating disease, with no efficient therapeutic available. A phase I trial was conducted in patients with neoplastic meningitis to define the safety profile of subcutaneous injections, combined or not with intra-CSF administration of a CpG ODN. Methods: The diagnostic of neoplastic meningitis was based on a positive CSF cytology or on the association of clinical symptoms with meningeal enhancement on MRI. Cohorts of 3-6 patients were treated for 5 weeks with escalating doses of CpG-28 (level 1 and 2: 0.1and 0.3 mg/kg/week subcutaneously (sc); level 3 to 6: 0.3mg/kg sc associated with 3/7/12/18 mg intrathecally every other week). Concomittant treaments with radiotherapy or chemotherapy were allowed. The primary endpoint was tolerance. Secondary endpoints were time until neurological progression and survival. Results: Twenty-nine (29) patients were included. Primary cancer was malignant glioma (n=15), lung carcinoma (n=7), breast cancer (n=3), melanoma or melanocytoma (n=2), ependymoma (n=1), and colorectal cancer (n=1). At diagnosis median age was 56 years and median KPS was 70%. The treatment was well tolerated. Adverse effects possibly or probably related to the studied drug consisted in grade 2 lymphopenia, anemia and neutropenia (n=19), local erythema at injection sites (n=14), fever (n=10) and seizure (n=11). Two serious adverse events were considered as possibly or probably related to the protocol: one local infection and one intra-cerebral haemorrhage. Interestingly, median survival was higher in patients (n=8) who were concomitantly treated with bevacizumab a time of protocol (19 weeks vs 15 weeks, p=0.11). Conclusions: CpG-28 was well tolerated at doses up to 0.3mg/kg subcutaneously and 18 mg intrathecally. Main side effects were limited to local erythema, lymphopenia and fever. Combination with bevacizumab warrants further clinical investigations. Clinical trial information: P060301.
AFM11, a CD19/CD3 bispecific tandab, to facilitate T-cell-mediated killing of CD19+ cells.
Authors: Zhukovsky Eugene , Reusch Uwe , Burkhardt Carmen , Knackmuss Stefan , Fucek Ivica , Eser Markus , McAleese Fionnuala , Ellwanger Kristina , Little Melvyn 
Published: March 2020

3068 Background: CD19, due to broader expression on B cell subtypes, is an attractive alternative to CD20 as a target for treatment of B cell malignancies. T cells are potent tumor-killing effectors that cannot be recruited by full length antibodies, however TandAb technology harnesses their cytotoxic nature for oncology indications. The CD3 RECRUIT TandAb AFM11 enables T cells to potently and specifically kill CD19+ tumors and possesses advantageous PK properties enabling intravenous dosing. Methods: We constructed AFM11, a human bispecific tetravalent antibody with two binding sites for both CD3 and CD19. In vitro efficacy and safety were evaluated on CD19+ cell lines and primary tumors. In vivo efficacy was evaluated in a murine NOD/scid xenograft model reconstituted with human PBMC. Results: In vitro assays demonstrate higher potency and efficacy of target cell lysis by AFM11 relative to a bispecific tandem scFv. CD8+ T cells dominate early cytotoxicity (4 hrs) while after 24 hrs both CD4+ and CD8+ T cells equally contribute to tumor lysis with EC50 of 0.5 – 5 pM; cytotoxicity is independent of cell CD19 density. AFM11 exhibits similar cytotoxicity at Effector:Target ratios from 5:1 to 1:5 and facilitates T cell serial killing of its targets. AFM11 activates T cells only in the presence of CD19+ cells. In PBMC cultures AFM11 induces CD69 and CD25 expression, T cell proliferation, and production of IFN-γ, TNF-α, IL-2, IL-6, and IL-10. Depletion of CD19+ cells from PBMC abrogates these effects, and indicates strict CD19+ target-dependent T cell activation. Thus, AFM11 should not elicit the devastating cytokine release observed when full length antibodies bind CD3. Cell lysis by AFM11 is restricted to CD19+ targets asCD19- bystanders are not lysed in co-culture assays. Up to one week co-incubation with AFM11 does not inhibit T cell cytotoxicity and thus it does not induce anergy. In vivo AFM11 exhibits a dose-dependent growth inhibition of Raji tumors; a single dose of AFM11 exhibits similar efficacy as 5 daily injections. Conclusions: AFM11 is a highly efficacious novel drug candidate for the treatment of CD19+ malignancies with an advantageous safety profile and anticipated dosing regimen.
The effect of copper nanoparticles on the progression of tumor in vivo.
Authors: Kachesova Polina Sergeevna , Goroshinskaya Irina Aleksandrovna , Borodulin Vladimir Borisovich 
Published: March 2020

3084 Background: The study of the anticancer activity of copper nanoparticles (CuNP) measuring 70-75 nm in rats transplantable tumors. Methods: Experiments were carried out on white outbreed male rats with transplanted sarcoma 45 (9.10-dimethyl-1.2-benzanthracene-induced fusiform cell fibrosarcoma, S-45) and Pliss’s lymphosarcoma (Pliss). 0.5 ml of tumor tissue suspension (1x106 cells) in saline was inoculated subcutaneously in rat dorsal region for induction of sarcoma 45 or Pliss's lymphosarcoma. 7-8 days after tumors transplantation the animals were divided into three groups. Group 1: control (rats received 0.3 ml of saline only). Group 2: CuNP in 0.9% w/v of NaCl were injected intratumorally (1.25 mg/kg bodyweight). Group 3: The same amount of CuNP was injected intraperitonially. Animals received nanoparticles four times a week for one week, then after a week's break, the procedure was repeated. The associated nanoparticles are spherical in shape and have an oxide film on its surface. CuNP effect on tumor growth was determined by the mass (M) and size (V) of tumors. Results: The analysis of the received data showed that administration of CuNP to rats with S-45 caused reduced growth rates or cases with complete regression (8 of 17 cases) in 67.0% of experimental animals independently of injection way (V=0.81±0.3 cm3, M=0.91±0.3 g). The other 33% of rats with S-45 showed tumor growth (V=7.58±1.3 cm3, M=9.2±1.6 g). Overall, for the entire group of animals with S-45, nanoparticles inhibited tumor growth of 45%. In the control group there was an increase of tumor growth (V=9.0±1.8 cm3, M=10.4±2.5 g). CuNP introduction to animals with Pliss caused a delay in tumor growth and partial or complete regression (12 of 28 eight cases) in 40.0-48.0% of the rats in the route of Cu injection (V=1.4±0.8 cm3, M=10.4±2.5g). Observation of the remaining animals revealed tumor growth (V=60.6±5.93 cm3, M=67.13±8.7 g). In the whole group tumor growth inhibition was 50.0%. In the control group we observed increase of tumor growth (V=62.1±5.21 cm3, M=75.9±8.2 g). Conclusions: Thus the study showed that the copper nanoparticles possess antiproliferative activity, can inhibit the growth of transplanted tumors in rats and may be potentially used in anticancer medical therapy.
Preclinical testing using novel CT20p petide-nanoparticle combination in breast cancer.
Authors: Vishnubhotla Priya , Boohaker Rebecca J , Lee Michael W , Nemec Kathleen N , Khaled Amr , Santra Santimukul , Perez G.Micheal , Perez J.Manuel , Khaled Annette R 
Published: March 2020

3085 Background: Patients with metastatic breast cancer may be initially responsive to treatment, but a significant number develop refractory disease. There is a critical unmet need to develop effective therapeutic approaches given the unique metabolism of tumor cells. Methods: We examined the cytotoxic properties of a novel peptide, CT20p, derived from the C-terminus of Bax. For delivery to cells, the amphipathic nature of CT20p allowed it to be encapsulated in polymeric nanoparticles (NPs). NPs were made using aliphatic hyperbranched polyester (HBPE) that incorporated surface carboxylic groups and interior hydrophobic cavities for encapsulation of CT20p. To examine the cytotoxic potential and targeting capacity of CT20p-NP-HBPE, we treated MDA-MB-231 and MCF-10A breast cancer cell lines with the combination and measured changes in mitochondrial function, cell metabolism and induction of cell death. The ability of CT20p-NP-HBPE to cause tumor regression was examined by subcutaneously implanting MDA-MB-231 cells in nude mice. Results: Initial results showed that CT20p caused the release of calcein from mitochondrial-like lipid vesicles, without disrupting vesicle integrity, and, when expressed as a fusion protein in cells, localized to mitochondria. While the peptide alone had little effect upon intact cells, when encapsulated and delivered by nanoparticles, CT20p-HBPE-NPs proved an effective killer of breast cancer cells. CT20p-NP-HBPE initiated non-apoptotic cell death within 3 hours of treatment by targeting mitochondria and deregulating cellular metabolism. Nanoparticles alone or nanoparticles encapsulating a control peptide had minimal effects. The cytotoxicity of CT20p-NP-HPBE was most pronounced in breast cancer cells, sparing normal, epithelial cells. In implanted breast tumors, CT20p-NP-HBPE accumulated in tumors within 24 hours and reduced tumor burden by 50-80%. Conclusions: These results reveal the innovative features of CT20p that allow nanoparticle-mediated delivery to tumors and the potential application in combination therapies that target the unique metabolism of cancer cells.
Role of mesenchymal stem cells in delivering Newcastle disease virus to glioma cells and glioma stem cells and enhancing the oncolytic effect of the virus by secreting TRAIL.
Authors: Slavin Shimon , Kazimirsky Gila , Ziv-Av Amotz , Brodie Chaya 
Published: March 2020

3100 Background: Newcastle disease virus (NDV), an avian paramyxovirus, is tumor selective and oncolytic by induction of apoptosis. Preclinical and clinical studies in patients with glioblastoma (GBM) using NDV demonstrated occasional clinical benefits with no major side effects. Limitations to the use of NDV as virotherapy of GBM is the inefficient delivery into cancer cells in the brain. Methods: Mesenchymal stromal cells (MSCs) can migrate towards cancer cells. We examined potential delivery of oncolytic effect of NDV (MTH-68/H) against glioma cell lines and glioma stem cells (GSCs) and the ability of MSCs to deliver NDV to glioma cells and GSCs in culture. Results: NDV induced a dose-dependent cell death in the glioma cells U87, A172 and U251 with maximal effects at 10 MOI. In contrast, we found only small level of apoptosis or changes in self-renewal in three GSCs infected with NDV. We found that MSCs derived from bone marrow, adipose tissue and cord were successfully infected by NDV and were able to deliver the virus to co-cultured glioma cells and GSCs. In addition, treatment of glioma cells and GSCs with culture supernatant of infected MSCs increase apoptosis of glioma cells as compared to the effect of direct infection of glioma cells. Moreover, the culture supernatants of the infected MSCs induced cell death in GSCs that were resistant to the oncolytic effect of NDV, suggesting that factor(s) secreted by the infected MSCs sensitized the glioma cells and GSCs to the cytotoxic effects of NDV. Using antibody array and ELISA we identified TRAIL as the factor secreted from infected MSCs. Indeed, treatment of infected glioma cells with TRAIL increased the cytotoxic effect of NDV and sensitized GSCs to the oncolytic effects of NDV. Conclusions: MSCs can be employed to deliver NDV to GBM. In addition, MSCs can also sensitize glioma cells and GSCs to oncolysis by NDV. Considering the resistance of GSCs to chemotherapy and radiation therapy, treatment of GBM with MSC-mediated targeted oncolytic NDV may provide a new clinical tool for treatment of GBM and eradication of GSCs.
Do ascorbic acid and viscum album improve PFS in NSCLC?
Authors: Raza Fatima Zehra , Ranjan Smita , Kloecker Goetz H. 
Published: March 2020

3102 Background: Intravenous vitamin C achieves 70 times higher plasma concentrations of ascorbate as a similar oral dose. Such pharmacologic concentrations(0.3-20mM) kill cancer cells but not normal cells, through extracellular H2O2 generation. Ascorbate treatment depleted ATP and induced autophagy in prostate cancer cells; gemcitabine with ascorbate resulted in 50% inhibition of growth in pancreatic tumor xenografts in mice models. A phase I/II study for pancreatic cancer patients is underway. Viscum album (mistletoe) is widely used in Europe as complementary therapy. Its cytotoxic and immunomodulatory effects are poorly understood. Additional treatment with subcutaneous mistletoe injections improved quality of life in gastric cancer patients in a study. Methods: We report the case of a 54 year old male smoker with adenocarcinoma of the lung (pT4N2M1a), EGFR/RAS/ALK negative. After 5 cycles of chemotherapy (carboplatin/taxol x 3, then carboplatin/pemetrexed x 2) scans showed continued progression. The patient made an informed decision to stop further chemotherapy and initiated complementary medical means, receiving high dose IV vitamin C (75 g, 2 x week) and subcutaneous mistletoe injections every other day, for the last seven months. Results: Six months into the non-standard therapy, a PET/CT shows a PR by RECIST and decreased FDG activity of the biopsy proven primary and metastatic site. The patient feels well, a year now after being diagnosed with advanced NSCLC. Conclusions: Whether the PR and the surprisingly long PFS is due to IV ascorbic acid and/or mistletoe is unknown. A review of the literature reveals reports of similar astonishing clinical results after treatment with either agent. A registry and biorepository of cases treated with alternative modalities may discover markers and biological mechanisms to explain these surprising reports.
Systematic analysis of potential targets for immunotherapy in acute myeloid leukemia.
Authors: Hourigan Christopher Simon , Goswami Meghali , Alkharouf Nawal , Bhagwat Medha , Sardon Heidi May , Williams Ann L , McCoy J. Phillip , Ito Sawa , Strickland Stephen Anthony , Savani Bipin N. , Fraser James W , Sadrzadeh Hossein , Fathi Amir Tahmasb , Qin Lu , Hess Allan , Smith B Douglas , Karp Judith E. , Barrett A. John 
Published: March 2020

3104 Background: The ability to target myeloid malignancies using immunotherapy, without allogeneic transplantation, depends on the capability to target leukemic clones while sparing normal tissues. A variety of putative leukemia associated antigens (LAA) have been identified but an evidence-based list of targets for acute myeloid leukemia (AML) has not yet been established. Methods: De-identified, clinically annotated, samples of peripheral blood and/or bone marrow aspirate from untreated AML patients were collected under IRB-approved protocols from three NCCN cancer centers. Samples were analyzed for commonly observed somatic mutations in ASXL1, DNMT3A, FLT3, IDH1/2, KIT, NPM1, NRAS, RUNX1, TET2, and WT1. Gene expression of 75 consensus LAAs were determined using a custom-designed RT-PCR array. 12 samples underwent extended LAA analysis by flow sorting into “bulk leukemia” and “stem cell enriched” populations. LAA expression was normalized using the geometric mean of three control genes. Results: Samples from 48 AML patients (30 blood, 22 marrow) were suitable for analysis. Average age of patients was 53 (24-86), 50% were female. Cytogenetics were favorable (17%), intermediate (65%) or adverse (19%); 29% presented with a white blood cell count >50,000. Over 10,000 individual data-points were collected. Five distinct patterns of LAA expression were observed in blood from AML patients compared to healthy donors. Conclusions: Understanding the heterogeneity and patterns of AML LAA expression between individuals allows the rational prioritization of potential targets for immunotherapy. Based on our data we predict that targeting any single LAA will likely often be ineffective but that it may be possible to create an inclusive panel of multiple targets with coverage of most AMLs, eliminating the need for individualized personalization of therapy. Such AML antigen signatures may also have utility for minimal residual disease monitoring. [Table: see text]