bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study of the effects of renal impairment on the pharmacokinetic (PK) and safety of satraplatin in patients (Pts) with refractory non-hematologic cancer
Authors: Hong D. S. , Galsky M. , Chiorean E. , Mulkerian D. , Greene D. , Nathan F. E. , Petrone M. , Camacho L. H. 
Published: March 2020

2044 Background: Satraplatin (S) is a novel oral platinum analog with demonstrated activity in the treatment of pts with platinum-sensitive malignancies. A worldwide, double-blind, placebo-controlled randomized trial evaluating S as 2nd line therapy for hormone refractory prostate cancer (HRPC) has recently completed enrollment. The current study wasis designed to understand the effect of varying degrees of renal impairiment on the safety and PK of satraplatin. Methods: The study includes 4 levels of renal dysfunction, and 8 pts/cohort: Group 1 (G1) = Normal Renal Controls; G2 = Mild renal impairment (CrCl 50–80 mL/min); G3 = Mod. impairment (CrCl 30-<50 ml/min); G4 = Severe impairment (CrCl <30 mL/min). S was administered orally at 80mg/m2/d on d1–5 every 35 days. Results: 21 pts (of a planned total of 32) have been enrolled (13M/8F), median age 63 (range 45–72). Tumor types: Bladder (6), Renal (3), Breast (2), Prostate (2), Colon (2), Other (6). Among 15 evaluable pts, the cohort distribution is G1: 6 pts, G2: 4, G3: 4, and G4: 1. Twenty-six cycles of S have been delivered, and 11 pts have completed at least 2 cycles of therapy. Hematologic toxicities during the first 2 cycles include grade (G) 3/4 neutropenia (0 pts), G 3/4 thrombocytopenia (1), and G 3/4 anemia (1). No significant cardiac, renal, hepatic, or neurologic toxicity has been observed. Nausea, vomiting, and diarrhea were mild to moderate, and controlled with oral therapy. Of 4 pts with evaluable disease, 1 has stable disease, and 3 have progressed. Conclusions: S is well tolerated in pts with varying degrees of renal dysfunction. Updated safety and PK data will be presented at the meeting. [Table: see text]
Novel monoclonal antibodies for measuring 5-fluorouracil concentrations in biological fluids
Authors: Salamone S. J. , Courtney J. B. , Stocker D. , Harney R. L. 
Published: March 2020

2055 Background: Therapeutic drug monitoring of anticancer drugs has potential for improving treatment of individual patients. 5-Fluorouracil (5-FU) has been reported to exhibit high pharmacokinetic variability and in some cases severe toxicity. Pharmacokinetic guided dosing of 5-FU using physical methodologies has demonstrated clinical usefulness in decreasing toxicity while resulting in equivalent or improved outcomes. The current physical methods for measuring 5-FU require specially trained personnel, are expensive, time consuming and therefore not amenable for widespread use. However, an automated immunoassay would provide a rapid, simple and inexpensive method to routinely measure levels of 5-FU in patients. Methods: In order to develop monoclonal antibodies that were selective for 5-FU, immunogens were prepared by attaching the drug to keyhole limpet hemocyanin (KLH) or bovine thyroglobulin (BTG) via a hydrocarbon tether bound through the N-3 nitrogen. Mice were immunized and the resulting antibodies were screened by ELISA. The selection of antibodies was based on sensitivity and cross-reactivity characteristics. Results: These immunogens were successful in eliciting 20 highly selective monoclonal antibodies for 5-FU with immunoassay dose response curves in the clinical range of 10 ng/mL to 5000 ng/mL. The immunoassay was tested with a mixture of the various pyrimidine compounds at their respective endogenous levels and shown to have no impact on the measurement of 5-FU. The Table below lists typical cross-reactivity performance characteristics that are elicited by this type of immunogen. Conclusion: This library of monoclonal antibodies represents the first report of antibodies selective for 5-fluorouracil. These antibodies will be useful for the rapid and cost effective analysis of 5-FU in human samples, providing a tool for optimization of 5-FU levels by pharmacokinetic guided dosing. [Table: see text] [Table: see text]
Effects of rhIL-7 administration in humans on in vivo expansion of naïve, memory and effector subsets of CD4+ & CD8+ T-cells
Authors: Sportes C. , Hakim F. , Krumlauf M. , Babb R. , Fleisher T. , Brown M. , Engel J. , Buffet R. , Mackall C. , Gress R. 
Published: March 2020

2504 Background: IL-7 has a critical and non-redundant role in T-cell lymphopoiesis and peripheral T-cell homeostasis. IL-7 administration may prove clinically valuable in conditions of disease induced (HIV) or iatrogenic T-cell depletion and for modulation of vaccine immune responses. In the first phase I study in humans, recombinant human interleukin-7 (“CYT 99–007”, Cytheris Inc., Rockville, MD) was administered subcutaneously every other day for two weeks in adults with refractory malignancies at 3, 10, 30 and 60 μg/kg/dose. Biologic activity, defined as a 50% increase over baseline of peripheral blood CD3+ T-cells, was seen at and above the 10μg/kg/dose in all patients. The kinetics of proliferation and expansion of peripheral blood T-cell subsets were analyzed. Methods: Multicolor flow cytometry was performed at baseline, 1, 2 and 3 weeks. Among CD4+ cells, the most naïve were defined as CD45RA+ /CD31+. Among CD4+ & CD8+ cells, the main naïve, memory and effector populations were defined respectively as CD45RA+/CD27+, CD45RA-/CD27+ and CD45RA-/CD27-. Within each subset, the number of cells in cycle was defined by Ki67 staining. Results: Following IL-7 therapy, there was marked proliferation of all T-cells subsets, peaking at week 1, most striking for the naive subsets with 30–70% of circulating cells induced to cycle. Proliferation rates were halved by week 2 despite continuation of treatment, coincident with the observed down-regulation of the IL-7 receptor. Cycling returned to baseline by week 3. Significant proliferation was also induced in effector and memory CD4+ and CD8+ T-cells but to a lesser magnitude, resulting in a greater net expansion of the naïve subsets, still ongoing one week after the end of treatment. Conclusions: IL-7 administration induces marked expansion of naïve, memory and effector CD4+ & CD8+ T-cells in humans. Consistent with the known down-regulation of the IL-7 receptor upon IL-7 exposure, proliferation rates decrease during the second week of treatment. rhIL-7 induced T-cell expansion may prove clinically valuable in adoptive immunotherapy as an adjunct to tumor vaccination and / or immunorestorative agent. [Table: see text]
A phase I trial of combination immunotherapy with CTLA-4 blockade and GM-CSF in hormone-refractory prostate cancer
Authors: Fong L. , Kavanagh B. , Rini B. I. , Shaw V. , Weinberg V. , Small E. J. 
Published: March 2020

2508 Background: CTLA-4 is an costimulatory molecule expressed on activated T cells that delivers an inhibitory signal to these T cells. CTLA-4 blockade with antibody treatment augments T cell responses and anti-tumor immunity in animal models. Clinical trials with anti-CTLA-4 antibody treatment have demonstrated clinical responses in different malignancies including melanoma and hormone-refractory prostate cancer (HRPC). We have also shown that administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) can also induce PSA declines in HRPC patients, presumably through enhancing presentation of endogenous antigens. The current study examines whether combining systemic GM-CSF to CTLA-4 blockade can augment immune and/or clinical responses in HRPC patients. Methods: In a phase I trial of patients with metastatic HRPC, sequential cohorts of 3–6 patients received GM-CSF (sargramostim, Berlex) 250 mg/m2/d SC on days 1–14 of a 28-day cycle with escalating doses (0.5, 1.5 or 3 mg/kg) of ipilimumab (MDX-010), a fully human anti-CTLA antibody (Medarex/BMS), given IV on day 1 of each cycle x 4 cycles. Patients were monitored for toxicity as well as for T cell activation. PSA and radiographic tests were performed at baseline and through therapy to evaluate for clinical response. Results: 18 patients were accrued. Ipilimumab-related dose-limiting toxicity was limited to one patient with grade 3 rash at the 3 mg/kg priming dose level. Seven patients had <50% declines in their serum PSA levels. A dose response relationship was seen between ipilimumab dose and activation of both CD4 and CD8 T cells in the blood. These effects were increased compared to effects seen with ipilimumab treatment alone in prior studies. Interferon-gamma production and lytic activity were also enhanced in circulating antigen-specific CD8+ T cells by the combination. Conclusions: GM-CSF may enhance T cell activation induced by CTLA-4 blockade. With increasing doses of anti-CTLA-4, both CD4 and CD8 T cell activation can be detected in the blood, consistent with a dose-response relationship. Supported by the UCSF Prostate SPORE NIH P50 CA89520. No significant financial relationships to disclose.
Phase I, multicenter trial of CNTO 328, an anti-interleukin(IL)-6 monoclonal antibody (mAb) in subjects with selected hematologic malignancies
Authors: Kurzrock R. , Voorhees P. , Fayad L. , Orlowski R. , Van Rhee F. , Furman R. , Borghaei H. , Zaki M. H. , Prabhakar U. , Garay C. 
Published: March 2020

2513 Background: IL-6 is implicated in the pathophysiology of several malignant diseases, including multiple myeloma (MM) and other hematological malignancies. CNTO 328 is a chimeric monoclonal antibody (mAb) that specifically binds and neutralizes human IL-6 with high affinity. A phase I trial is being conducted to assess safety and pharmacokinetics (PK) of CNTO 328 in subjects with B-cell non-Hodgkin’s lymphoma (NHL), MM, or Castleman’s Disease (CD). Methods: This trial will enroll at least 6 patients (pts) onto each of 5 cohorts, with 3 pts having a baseline C-reactive protein (CRP) of <10 mg/L, and 3 with ≥10 mg/L. Dose limiting toxicity (DLT) is defined as a ≥ Grade 3 event (excluding hematologic toxicity), or ≥Grade 2 allergic reaction/hypersensitivity attributed to CNTO 328 after the first administration. Results: Results from the first 13 subjects (3 CD, 3 MM and 7 NHL) enrolled in Cohorts 1 and 2 are currently available. Pts have received a median number of 4 (range 2 to 12) intravenous doses. CNTO 328 alone was well tolerated without pre-medication, and no DLTs have been observed. Some grade 3 or 4 adverse events (AEs) such as nausea, vomiting, elevated triglycerides, and decreased neutrophils were observed. Two subjects experienced serious AEs (SAEs) that were deemed unrelated to CNTO 328. Each of 3 pts with CD showed a clinical response, including improvement of hemoglobin, reduction of fever, resolution of rash, or decrease in lymphadenopathy. In one case of mantle cell NHL there was a reduction in lymphadenopathy. Two of 4 pts with previously progressive MM showed stabilization of M-protein levels and in % plasma cells in the bone marrow after one cycle of therapy. PK data is being analyzed. Conclusions: Treatment with CNTO 328 has been well tolerated at doses up to 6 mg/kg q 2 weeks. No clinical immune reaction to this chimeric mAb has been observed, and early evidence of tumor response and disease control has been observed. [Table: see text]
Endothelin receptor B predicts poor prognosis in epithelial ovarian cancer (EOC) and can be inhibited to increase intratumoral T cells and enhance tumor vaccine therapy
Authors: Buckanovich R. J. , Kim S. , Benencia F. , Sasaroli D. , Gimotty P. , Coukos G. 
Published: March 2020

2524 Background: An inability of T cells to penetrate into tumor islets leads to a poor clinical outcome. We sought to identify tumor endothelial regulators of T cell trafficking. Methods: We used immunohistochemistry-guided laser capture microdissection to isolate and profile of vascular cells from EOC with or without (12 each) intratumoral T cells (ITC). Quantitative PCR (qPCR) and western blot of 60 EOC tumors was used to confirm array results and quantitate expression. Kaplan-Meier curves were generated to estimate survival according to high and low expression of ETRB (as determined by ROC analysis). Cox proportional hazard model was used to estimate the hazard ratio (HR). ETRB peptide antagonist BQ-788 was given QOD for 2 weeks to anti-tumor vaccinated mice with established ovarian tumors. After 8 weeks we used FACS and IHC to assess the presence of tumor-infiltrating T cells. Results: We identified ETRB as upregulated by the tumor vascular cells from tumors lacking ITCs. qPCR showed ETRB mRNA was 5.4 fold increased in ITC(-) vs. ITC(+) tumors. Univariate analyses demonstrated that ETRB expression was an independent prognosticator for both OS and DFS in EOC; the five-year overall survival rate was 70% for low ETRB expression versus <5%for high ETRB expression (p < 0.05, HR 0.35 (95% CI 0.17–0.71)). Bivariate analysis indicated that high ETRB expression predicted suboptimal cytoreduction (p < 0.05). High expression of ETRB strongly correlated with ITC (-). ETRB blockade in a murine tumor vaccine model with peptide BQ-788 restricted tumor growth, reduced ascites, and increased survival compared to control animals. Analysis of BQ-788 treated tumors revealed a 5–15× increase in CD4+ and CD8+ intratumoral T cells. Conclusion: ETRB is an important new biomarker, for EOC patients, that correlates with ITC status and predicts both suboptimal cytoreduction and poor clinical outcome. Antagonism of ETRB in mice can restore an otherwise ineffective anti-tumor immune response. This suggests that ETRB inhibition may be a powerful adjuvant for tumor immunotherapy. No significant financial relationships to disclose.
A new method of constructing CD20/CD22 bispecfic antibody fusion proteins with improved direct lymphoma cytotoxicity compared to rituximab
Authors: Chang C. , Losman M. , Loo M. , Qu Z. , Rossi E. A. , Goldenberg D. M. 
Published: March 2020

2536 Background: Anti-CD20 and anti-CD22 monoclonal antibodies (MAbs) have been shown to have antitumor activity in non-Hodgkin’s lymphoma (NHL) patients. Since preclinical and clinical trials also suggested that combining CD20 and CD22 MAbs, which have different mechanisms of action, could improve antitumor activity without a commensurate increase in toxicity, we hypothesized that a therapeutic advantage may be achieved with bispecific MAbs that bind simultaneously to both CD20 and CD22. Methods: A new platform technology, termed the Dock and Lock method (DNL), was successfully applied to produce a trivalent bispecific antibody, named TF3, which comprises two recombinant Fab fragments of hA20 (humanized anti-CD20 MAb; IMMU-106) stably tethered to one recombinant Fab fragment of epratuzumab (humanized anti-CD22 MAb; IMMU-103) via the specific interaction between a dimerization-and-docking domain and an anchoring domain appended to hA20 and epratuzumab, respectively. The cytotoxicity of TF3 was evaluated by cell-based assays using NHL cell lines. Results: TF3 is stable in both human and mouse sera andexhibitsthe samebinding affinity as hA20 IgG or epratuzumab Fab by competitive ELISA. With a 3-day MTT assay, TF3 at 10 nM inhibited 50% and 60% growth of Daudi and Ramos cells, respectively. Further, the observed anti-proliferative activity increased synergistically to >90% in the presence of anti-IgM (0.1 μg/mL). Results from a cell counting assay also demonstrated the ability of TF3 at 1 μM to completely inhibit the growth of Daudi and the potency of TF3 at 1 nM was comparable to that of rituximab at 1 μM under the same experimental conditions, reflecting a 1000-fold enhancement. Conclusions: These findings, to be extended by ongoing in vivo studies, suggest that the new DNL platform technology for making bispecific antibody fusion proteins provided a CD20/CD22 binding protein that is significantly more potent than rituximab in an in vitro NHL direct cytotoxicity assay. [Table: see text]
A novel rationally designed agonist antibody fragment that functionally mimics thrombopoietin
Authors: Renshaw M. , Frederickson S. , Lin B. , Su X. , Wang Y. , Bowdish K. 
Published: March 2020

2541 Background: Thrombocytopenia, or low platelet count, is a significant clinical problem associated with ITP, cancer chemotherapy, or other clinical settings. To avoid transfusions, agents that stimulate platelet production are in development. Clinical trials with recombinant versions of thrombopoietin (TPO), which stimulates platelet production in a lineage specific manner by binding to cMpl receptor (cMpl-R) on megakaryocytic progenitors, were demonstrated to increase platelet counts in humans. However, the possible generation of an anti-TPO immune response that cross-reacts with and impairs the function of the endogenous cytokine is a significant disadvantage of this treatment approach. Alternate thrombopoietic agents that lack native TPO primary sequences have been developed to address this concern. Methods: Using rational design, antibody fragments (Fabs) that mimic TPO were created. A peptide with cMpl-R binding capability was grafted into different CDRs of a fully human Fab scaffold. Functional presentation of the peptide was optimized using phage display and cell-based panning. Select antibodies and fragments containing two grafted peptides were assayed for their ability to stimulate cMpl-R in vitro. In vivo stimulation of platelet production was tested in normal mice injected daily for five days with either rhTPO (90 μg/kg) or Fab59 (0.2 mg/kg, 2 mg/kg or 5 mg/kg) or negative control Fab (5mg/kg). Results: Several candidates demonstrated agonist activity in an in vitro cMpl-R signaling reporter assay, including Fab59 which was estimated to be equipotent to TPO. In vivo, a rise in peripheral platelet counts comparable to rhTPO was seen with Fab59 at 2 mg/kg and 5 mg/kg. Serum antibodies generated in response to dosing with Fab59 did not cross-react with murine or human TPO. Conclusion: These rationally-designed mimetic Fabs may provide a therapeutic intervention for thrombocytopenia while avoiding the potential generation of neutralizing antibodies to endogenous TPO. [Table: see text]
Immune evasion by melanoma and ovarian tumor cells through upregulation of the immunosuppressive molecule CD200
Authors: Siva A. , Xin H. , Qin F. , Mickel A. , Faas S. , Kretz-Rommel A. , Bowdish K. S. 
Published: March 2020

2545 Background: Immune escape by tumors can occur by multiple mechanisms, each a significant barrier to immunotherapy. Upregulation of the immunosuppressive molecule CD200 on chronic lymphocytic leukemia cells inhibits Th1 cytokine production required for an effective cytotoxic T cell response. CD200 expression on human tumor cells in animal models prevents human lymphocytes from rejecting the tumor; treatment with an antagonistic anti-CD200 antibody restored lymphocyte-mediated tumor growth inhibition. This study evaluated CD200 expression on other cancers, and its effect on immune response. Methods: CD200 levels in ovarian adenocarcinoma and metastatic melanoma samples were evaluated by RT-QPCR and immunohistochemistry. Cell-surface CD200 on melanoma and ovarian cancer cell lines was assessed by flow cytometry. The effect of CD200 on cytokine production in mixed lymphocyte reactions (MLR) was assessed by adding the cells to cultures containing human monocyte-derived dendritic cells and allogeneic T cells. Th1 and Th2 cytokines in culture supernatants were detected by ELISA. Results: RT-QPCR showed CD200 expression levels upregulated in serous ovarian adenocarcinoma compared to normal samples. In malignant melanoma, CD200 expression in jejunum metastases was significantly higher than in normal samples, and 2 of 6 lung metastases showed CD200 upregulation. IHC showed strong, membrane-associated CD200 staining on malignant cells of two melanoma patients. Three ovarian cancer patients showed varying levels of CD200 tumor staining; all showed strong stromal staining. CD200 was highly expressed on the cell surface of SK-MEL-24 and SK-MEL-28 melanoma and OV-CAR-3 ovarian cancer cell lines and moderately expressed on the melanoma cell line SK-MEL-5. Addition of these cell lines to MLRs downregulated the production of Th1 cytokines; addition of CD200-negative cell lines did not. Inclusion of an antagonistic anti-CD200 antibody during the culture restored Th1 cytokine responses. Conclusion: Melanoma and ovarian tumor cells can upregulate CD200, thereby potentially suppressing anti-tumor immune responses. Therapy with an antagonistic anti-CD200 antibody may permit an effective cytotoxic immune response against the tumor cells. [Table: see text]
Ex vivo activation and expansion of γδ T cells for immunotherapy of glioblastoma
Authors: Suarez-Cuervo C. , Bryant N. L. , Lopez R. D. , Gillespie G. Y. , Lamb L. S. 
Published: March 2020

2553 Background: Activated γδ T cells will efficiently kill established glioblastoma (GBM) cell lines in vitro. However, their potential for cell therapy has been limited by their relatively small numbers in the peripheral blood and their sensitivity to activation induced cell death (AICD) during ex vivo expansion. Our laboratory developed a method whereby γδ T cells, when stimulated by IFN-γ, IL- 12, and anti-CD2, acquire resistance to AICD and can be expanded in culture with anti-CD3 and IL-2. The γδ T cells expanded by this method are highly cytotoxic to GBM. We have now sought to adapt the laboratory method for human use. Methods: The laboratory method and selection procedure were modified to employ pharmaceutical-grade reagents. Peripheral blood mononuclear cells (1.0 × 106/ml) were stimulated overnight with media containing cGMP grade human serum, IFN-γ, IL-12, and anti-CD2. Media containing human serum, IL-2 and anti-CD3 was then added (1 v/v) and refreshed 1 v/v 3× weekly. The cultures were harvested after two weeks followed by depletion of CD4+ and CD8+ T cells, thereby enriching γδ T cells. Cytotoxicity of expanded of γδ T cells was evaluated against GBM primary tumor cultures, established GBM cell lines, and cultured astrocytes using a commercial flow cytometric method. Results: After two weeks in culture, γδ T cells expanded up to 1000 fold (usually 200–400 fold), consistent with results from our previous research-scale method. Positive selection yielded a γδ T cell product with >80% purity and >70% recovery. The cell products exhibited incremental cytotoxicity against several primary GBM cultures and established GBM cell lines. Astrocytoma cells were not killed. Conclusions: Apoptosis-resistant γδ T cells can be expanded and selected using clinically approvable reagents and in numbers sufficient for immunotherapy of malignant brain tumors. Initial data show that expanded γδ T cells retain cytotoxicity against the GBM primary cultures and spare normal astrocytes. No significant financial relationships to disclose.