bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic targeting of CD70 and CD27-CD70 interactions with the monoclonal antibody SGN-70 in Waldenstrom’s Macroglobulinemia (WM)
Authors: Ho A. W. , Hatjiharissi E. , Branagan A. , Hunter Z. , McEarchern J. , Law C. , Grewal I. S. , Santos D. , Tai Y. , Treon S. P. 
Published: March 2020

2509 Background: WM represents a lymphoplasmacytic lymphoma characterized by a monoclonal IgM gammopathy and possesses a mast cell component that may contribute to its pathogenesis. The tumor necrosis factor (TNF) receptor family member, CD27, is a transmembrane co-stimulatory molecule that is also secreted in a soluble form (sCD27). Recent evidence has suggested that interactions between CD27 and its TNF-like ligand, CD70, play a critical role in regulating B-cell activation and survival, and therefore, may provide a viable therapeutic target for the treatment of WM. Methods: Patients with the consensus panel diagnosis of WM who provided written consent were evaluated. ELISA assay kits were obtained from Bender MedSystems. Flow cytometric analysis, RT-PCR, and calcein ADCC assays were performed as previously described (Santos et al, in press). Results: By ELISA, WM patients displayed dramatically higher levels of sCD27 in their sera (median 7.45, range 0–19.42 U/ml) versus healthy donors (median 0, range 0–2.78 U/ml; p = 2.5 × 10−7). CD27 was expressed in 7/7 patients using RT-PCR analysis, and on the tumor cell surface of 5/12 patients. CD70, the target for CD27, was widely expressed on tumor cells (6/6) and mast cells (10/11) using flow cytometric analysis. To define the functional role of sCD27 in WM, we cultured BCWM.1 (CD27−CD70+) WM cells, LAD1 (CD27−CD70+) mast cells, and primary tumor and mast cells (CD70+) isolated from WM patients with sCD27 (0.1–50 ug/mL), and observed no effect on their proliferation or induction of apoptosis. However, culture of LAD1 and primary WM mast cells (10/10) with sCD27 resulted in marked upregulation of two TNF family ligands which support the growth and survival of WM cells: CD40L (CD154) and a proliferation induction ligand (APRIL). Importantly, the anti-CD70 mAb SGN-70 (1 ug/ml) inhibited this upregulation by sCD27, establishing the specificity of the CD27-CD70 interaction. In addition, SGN-70 demonstrated significant ADCC against BCWM.1 WM cells at dose levels up to 20 ug/ml. Conclusions: Taken together, these studies suggest a novel functional role for sCD27 in the pathogenesis of WM, and demonstrate the feasibility of targeting CD70 and sCD27-CD70 interactions with the SGN-70 monoclonal antibody. [Table: see text]
A pilot study of a PANVAC-V and PANVAC-F in patients (pts) with metastatic carcinoma
Authors: Gulley J. , Arlen P. M. , Dahut W. L. , Tsang K. , Jones J. , Pazdur M. , Jones E. , Kotz H. L. , Schlom J. 
Published: March 2020

2512 Background: The vast majority of carcinomas express either MUC-1 or CEA. Preclinical and clinical studies have demonstrated that induction of T-cell responses directed against CEA and MUC-1 can lead to anti-tumor activity without toxicity. Two novel vaccines have been developed: (a) PANVAC-V (V) a recombinant vaccinia virus containing CEA and MUC-1 with modified agonist epitopes and 3 costimulatory molecule transgenes, and (b) PANVAC-F (F) a similar recombinant fowlpox virus. Methods: This pilot study enrolled 25 pts with metastatic carcinoma who had progressive disease after chemotherapy. Pts received V priming followed by F boosts every 2 weeks × 3 then monthly with restaging scans every 2 months while on study. All vaccines were given with sargramostim at the vaccine site. The primary endpoint was safety. Class I and class II immune responses to CEA were analyzed. Class I responses were assayed by ELISPOT, intracellular cytokine, and tetramer binding; and class II responses were assayed by ELISA using CEA protein and class II peptides. Results: Treatment was well tolerated with 135 cycles given. Only one grade 3 toxicity (syncope during a flu-like illness) was possibly related to vaccine. Apart from injection site reactions, only 9 cycles (7%) were associated with transient grade 2 toxicity (generally flu-like syndromes). Class I and class II immunologic responses were demonstrated. A pt with metastatic breast cancer and 5 large liver metastasis had a 24% decrease in unidimensional measurement of disease for 6 months. A pt with metastatic gastric cancer had stable disease for 5 months. Furthermore, a pt with metastatic clear cell ovarian cancer s/p chemotherapy had complete disappearance of large volume, symptomatic ascites accompanied by marked improvement in the appearance of mesenteric stranding and a CA-125 reduction from 281 U/mL to continued sustained normal values (< 20 U/mL). Conclusions: This vaccine can be given safely and can generate therapy specific immunologic responses. In addition 1 pt with metastatic ovarian cancer had a dramatic clinical response. Based on this, we have initiated a pilot study specifically for ovarian cancer pts to gain more information on which to base a large clinical endpoint trial. No significant financial relationships to disclose.
Immune evasion by CD200: New approaches to targeted therapies for chronic lymphocytic leukemia (CLL)
Authors: Kretz-Rommel A. , Dakappagari N. , Qin F. , McWhirter J. , Oltean D. , Ravey E. , Wu D. , Springhorn J. , Saven A. , Bowdish K. 
Published: March 2020

2519 Background: Although the human immune system is capable of raising an immune response against many cancer types, that response is insufficient to eradicate the cancer in most patients, possibly due to immune evasion through negative regulation of the immune system by the tumor. We identified the immune-suppressive molecule CD200 to be upregulated 1.5–5.4-fold on CLL cells in all 80 patients examined. Interaction of CD200 with its receptor alters cytokine profiles from Th1 to Th2 in mixed lymphocyte reactions, and results in the induction of regulatory T cells, which are thought to hamper tumor-specific effector T cell immunity. We addressed whether CD200 expression on tumor cells plays a role in immune evasion, thereby preventing elimination of tumor cells by the immune system in a xenograft hu/SCID mouse model, and whether treatment with an antagonistic anti-CD200 antibody affects tumor growth. Methods: The human non-Hodgkins lymphoma cell lines RAJI and Namalwa were transduced with human CD200 and injected subcutaneously together with human peripheral blood lymphocytes (PBL) into NOD/SCID mice. Tumor growth over time was compared among mice that either received CD200-expressing tumor cells or received tumor cells lacking CD200 expression. In subsequent experiments, mice were treated with chimeric or humanized anti-CD200 antibodies (doses ranged from 1 to 20 mg/kg) by intravenous injection. Treatment was either started immediately or 7 days after tumor cell injection. Results: As expected, PBLs reduced CD200-negative RAJI or Namalwa tumor growth by up to 75%. In contrast, growth of RAJI or Namalwa tumors expressing CD200 at levels comparable to that of CLL was not reduced by PBLs. Administration of anti-CD200 antibodies at 5 mg/kg resulted in nearly complete tumor growth inhibition (1/10 mice developed a small tumor) over the course of the study even when treatment was started 7 days after tumor cell injection. Conclusions: CD200 expression on tumor cells inhibits the ability of human lymphocytes to eradicate tumor cells. Treatment of CD200-expressing tumors with antagonistic anti-CD200 antibodies inhibits tumor growth, indicating the potential for anti-CD200 therapy as a promising approach for CLL. No significant financial relationships to disclose.
Effect of interleukin-2 (IL-2) and 13-cis retinoic acid (RA) on vascular endothelial growth factor (VEGF) and durable response in patients with advanced solid tumors showing a partial response (PR) or stable disease (SD) to chemotherapy
Authors: Recchia F. , Saggio G. , Di Blasio A. , Amiconi G. , Cesta A. , Candeloro G. , Alesse E. , Rea S. 
Published: March 2020

2521 Background: A large proportion of patients with advanced solid tumors (AST), showing response to chemotherapy, experiences relapse from resistant stem cells that form minimal residual disease (MRD). High serum levels of VEGF have been shown to be associated with MRD and with a short relapse-free survival (RFS). We have shown, that low-dose IL-2 and RA, decreased VEGF and enhanced the immune function of patients with AST responding to chemotherapy (Clin Cancer Res 2001, Anticancer Res 2005). Primary endpoint of this study was to evaluate if IL-2/RA decreased VEGF and restored the immune function in patients with AST that had a PR or SD to chemotherapy. Secondary endpoint was the evaluation of the efficacy of IL2/RA in RFS and overall survival (OS). Methods: 100 consecutive AST patients (66% PR, 34% SD), with a mean VEGF of 520 pg/mm3, were entered into the study from 01/97 to 05/04. Median age was 66 years with 57% males. Diagnosis: Lung 28, head & neck 15, kidney 13, gastric 11, ovary 10, breast 10, miscellanea 13. Therapy consisted of self-administered subcutaneous IL-2, 1.8 X 106 IU and oral RA, 0.5 mg/Kg for 5 days/week for 2 cycles of 3 weeks, with a 1-week rest, for 1 year. Therapy was continued, with intermittent schedules until progression. Immune function and tumor markers were assessed every 2 months, response every 4 months. Results: After a median follow-up time of 42 months (16–106) and 900 courses of therapy, a statistically significant decrease of VEGF (148 pg/mm3, p<0.002) and improvement of lymphocytes, NK and CD4+/CD8+ ratio, with respect to baseline values, was observed. 5-year RFS and OS were 30% and 38%, respectively. 28% of patients were converted to a complete response: Their 5-year RFS and OS were 73% and 94%, respectively. No WHO grade 3 or 4 toxicity was observed, while grade 2 cutaneous toxicity and fever occurred in 20% and 13% of patients, respectively. Conclusions: The administration of IL-2/RA determines, with a low toxicity profile, a statistically significant decrease of VEGF, an improvement of all immunological parameters known to be prognostically relevant and a durable clinical response in 28% of patients. No significant financial relationships to disclose.
A phase I/II, open label trial of Lewis Y specific monoclonal antibody IGN311 to evaluate safety and efficacy in patients with malignant effusion
Authors: Bauernhofer T. , Samonigg H. , Regitnik P. , Lileg B. , Weizer W. , Waxenecker G. , Kainer M. , Wiederkum S. , Loibner H. , Kircheis R. 
Published: March 2020

2547 Background: Treatment of CRC patients (pts) with the humanized mAb IGN311 targeting the carbohydrate Lewis Y eliminated circulating tumor cells in blood and thereby confirmed the clinical profile of the parent murine antibody ABL364, which showed elimination of Lewis Y and cytokeratin positive cells in bone marrow of pts with breast cancer. Methods: An open-label, single treatment arm, uncontrolled study with IGN311 (100mg per dose, intravenously on day 1 and 7) in pts with malignant effusion (ascites or pleural effusion) is being conducted with the primary objective to examine safety and tolerability. Secondary objectives are volumetric measurement of the malignant effusion and to obtain data for several immunological parameters. Results: 4 pts (2 pts with gastric cancer and malignant ascites, 2 pts with breast cancer and malignant pleural effusion / ascites) have completed the study until December 2005. IGN311 was well tolerated with only one patient showing up to grade 2 nausea, vomiting and skin rashes as side effect after 1st application which was easily managed. In all pts significant levels of IGN311 were measured followed by an increase in CD45 positive cells in the effusion. The patient with the highest level of Lewis Y expressing tumor cells showed a reduction of effusion volume during treatment. Conclusions: IGN311 was well tolerated, permeated into malignant effusion and attracted immune cells leading to decreased tumor cell counts in the effusion. In the case of strong Lewis Y expression of malignant cells in the effusion a reduction of the effusion volume could be demonstrated. [Table: see text]
Vaccination of hormone-refractory prostate cancer patients with peptide cocktail-loaded dendritic cells: Results of a phase I clinical trial
Authors: Meye A. , Fuessel S. , Schmitz M. , Zastrow S. , Linne C. , Richter K. , Lobel B. , Hakenberg O. W. , Hoelig K. , Rieber P. E. , Wirth M. P. 
Published: March 2020

2551 Background: For patients with hormone-refractory prostate cancer (HRPC) treatment options are limited. Immunotherapies based on dendritic cells (DCs) might represent promising alternatives. In a Phase I clinical trial, we evaluated the safety and feasibility of a vaccination with monocyte-derived DCs loaded with a cocktail consisting of HLA-A*0201-restricted peptides derived from prostate cancer-associated antigens (PSA, PSMA, survivin, prostein, trp-p8). Methods: Eight HRPC patients were enrolled in this study (Table). Each patient underwent two leukaphereses, for the isolation of monocytes and subsequent generation of mature DCs. Patients received a total of four vaccinations each with peptide cocktail-loaded DCs at a dose of 1 x 107 cells both intradermally and intravenously every other week. Clinical response was monitored by the determination of the PSA level. The induction of a peptide-specific T-cell response was assessed by ELISPOT analysis. Results: Apart from local erythema and edema at the site of intradermal administration no side effects were noted. Four of eight patients showed a temporary PSA decline. One patient displayed a partial response with a PSA decrease > 50% for seven weeks and further stabilization for five weeks. Stable PSA values or decelerated PSA increases were observed in the three remaining patients. In ELISPOT analyses, three of four PSA responders also showed antigen-specific CD8+ T-cell activation against prostein, survivin and PSMA. Conclusions: The described protocol represents a safe and feasible concept for the induction of clinical and immunological responses. The application of a peptide cocktail derived from different antigens as a novel treatment modality is supposed to allow for the genetic and biologic heterogeneity of PCa. [Table: see text] [Table: see text]
Immunopharmacology of cancer vaccines: Restoration of NKG2D levels and functions in metastatic melanoma treated with exosomes
Authors: Chaput N. , Andre F. , Menard C. , Escudier B. , Robert C. , Lhomme C. , Zitvogel L. , Tursz T. 
Published: March 2020

2554 Background: The C-type lectin-like stimulatory immune receptor Natural Killer group 2 receptor (NKG2D) is expressed by NK and CD8+ T cells. NKG2D engagement is a natural mediator of immunosurveillance which can be compromised by locally sustained ligand expression. In cancer patients with NKG2D ligand- expressing tumors, NK and CD8+ T cells often express low levels of NKG2D and are functionally compromised. Dentritic cell-derived-exosomes (Dex) are nanomeric vesicles harboring functional MHC/peptide complexes capable of promoting T cell immune responses and tumor rejection in mice. Two Dex Phase I trials highlighted the and the safety of exosome administration. The observation of clinical regressions in the absence of detectable T cell responses prompted the search for alternate effector mechanisms. We study NKG2D expression and NK cells function in peripheral lymphocytes before and after Dex therapy. Methods: Exosomes were purified from day 7 autologous monocyte derived-DC cultures. Fifteen patients were enrolled and received exosome vaccinations. NK cells functions prior or following exosome vaccines were tested in standard Na251CrO4 chromium release assays. NKG2D and NKG2D ligand expression were studied using flow cytometry and/or western blot experiments. Results: In sharp contrast with DC, Dex bear functional NKG2D ligands leading to a selective downregulation of NKG2D activating receptors on autologous NK cells in vitro. Long term administration of Dex could enhance NKG2D expression levels on NK and CD8+ T cells in 50% of patients, restoring killing of NKG2D ligand expressing K562 and autologous tumour. In contrast to NKG2D ligands shed by tumors mediating immunosuppressive activity, exosomal NKG2D ligands promote NKG2D-dependent effector functions in vivo, that might account for the non MHC restricted-antitumor effects observed in the trial. Conclusions: NK cell activation represent a new pharmacodynamic for Dex leading to tumor recognition and regression in vivo. The Phase II trial using Dex shall include the monitoring of NKG2D ligands on Dex preparation and follow up NKG2D levels, functions and polymorphism in patients. No significant financial relationships to disclose.
Intrapericardial cellular immunotherapy for malignant pericardial effusion using autologous IL-2-activated TILs
Authors: Toh U. , Fujii T. , Seki N. , Ogo E. , Shirouzu K. , Yamana H. 
Published: March 2020

2555 Background: Pericardial effusion (PE) and cardiac tamponade caused by malignant pericarditis are critical conditions in cancer patients, which still lack a recommended protocol for their long-term management. The aims of this study were to investigate the presence of cytotoxic T lymphocytes (CTLs) in malignant PE and to determine the clinical response to administering autologous tumor-infiltrating lymphocytes (TILs) into the pericardial cavity. Methods: Initially, we identified human lymphocyte antigen class-I-restricted and tumor-specific CTLs within the interleukin-2 (IL-2)-activated TILs in PEs from four patients, on the basis of interferon-g production and lactate dehydrogenase-release assays. Clinically we observed favorable responses to the pericardial transfer of IL-2-activated autologous TILs in four patients: one male with advanced esophageal cancer, one female with recurrent lung cancer and two female with recurrent breast cancer, respectively. Autologous TILs from PEs were expanded in vitro with IL-2, characterized for CD3, CD4 and CD8 markers, checked for contamination and then infused into the patient’s pericardial space through a catheter. This was repeated biweekly. Results: After treatment, there were no signs of recurrence of PE in either case, as determined by radiography, echocardiography and computed tomography. The only adverse effects seen were grade 1 fevers. Conclusions: These results suggested that intrapericardial cellular immunotherapy with autologous TILs could be a safe and effective treatment for controlling malignant pericarditis with associated cardiac tamponade, and that tumor-specific CTLs present in malignant PE might be important for tumor rejection. No significant financial relationships to disclose.
Hematologic malignancies developing in previously healthy individuals who received hematopoietic growth factors: Implications for use of colony stimulating factors in healthy volunteers participating in early phase clinical studies and in healthy blood product donors
Authors: Lyons A. E. , Balasubramanian L. , Andritsos L. A. , Evens A. , Kuzel T. , Vose J. M. , Bierman P. J. , Kuter D. J. , Devine S. M. , Bennett C. L. 
Published: March 2020

2559 Background: Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHu-MGDF aka MGDF) and recombinant granulocyte colony stimulating factor (G-CSF) promote the maturation of hematopoietic progenitor cells. Healthy volunteers/donors have received MGDF in phase I/II clinical trials and G-CSF in allogeneic peripheral blood stem cell transplantation procedures. Herein, we review clinical findings for five previously healthy volunteers/donors who developed hematologic malignancies after the use of MGDF or G-CSF. Methods: Clinical information related to hematologic malignancies were reviewed for three volunteers who had participated in a phase I/II clinical trial with MGDF and two donors who underwent G-CSF mobilized peripheral blood stem cell harvesting procedures for sibling allogeneic stem cell transplantation for acute leukemia. Results: Mantle cell, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia were diagnosed three to five years after exposure among three volunteers who received MGDF. For one of these patients, autoimmune thrombocytopenia and antibodies to MGDF that cross-reacted with endogenous thrombopoietin had developed shortly after MGDF administration and persisted until lymphoma chemotherapy was administered. Following chemotherapy, all three achieved complete remission, although one patient subsequently relapsed. Acute myelogenous leukemia was diagnosed four to five years after exposure in two donors who underwent G-CSF primed stem cell harvests prior to their siblings’ allogeneic stem cell transplantation. Following intensive chemotherapy, one of these patients died from acute leukemia and the second is now in complete remission. Conclusion: Controversy exists over the appropriateness of administering hematopoietic growth factors to healthy individuals. While a causal relationship with hematologic malignancies is uncertain, long-term follow-up among healthy individuals who receive hematopoietic growth factors is needed. No significant financial relationships to disclose.
Phase I clinical trial of hybrid cell vaccination in patients with gastrointestinal cancer
Authors: Iinuma H. , Okinaga K. , Iwasaki K. , Koide T. , Inaba T. , Fukushima R. 
Published: March 2020

2579 Background: Vaccination with hybrid cells of dendritic cells (DCs) and tumor cells can induce specific ant-tumor immunity against multiple tumor antigens including those that are unknown. We report the results of phase I study of hybrid cell vaccines comprised of autologous DC and autologous tumor cells in patients with Stage IV or recurrent gastrointestinal cancer. Method: Thirteen patients with Stage IV or recurrent gastrointestinal cancer were enrolled in this study after informed consent was obtained. Tumor cells were cryopreserved following acquisition from the primary or a metastatic site. DCs were induced from mononuclear cells of patients by culture with cytokines (6 days culture with GM-CSF and IL-4, and a further 1 day culture with TNF-α, IL-1 β, IL-6 and PGE2). Fusion of irradiated tumor cells and DC was created with a combination of PEG and electrofusion (two-step fusion method). At 2 week interval, patients received 4 freshly prepared fusion vaccines, with a constant dose range of 1 × 107 to 4 × 107 cells. The endpoints of this study were assessments of safety, anti-tumor immune response and clinical response. Results: Serious adverse events were not observed in any of the enrolled patients and all Common Toxicity Criteria were grade I. Clinical responses are 1 with partial response (PR), 5 with stable disease (SD) and 7 with progressive disease (PD). Delayed skin tests changed to positive in 5 patients. In patients with PR and SD, a shift to Th1 in Th1/Th2 balance of lymphocytes (IFN γ/IL10, IFN γ/IL4) was demonstrated by ELISPOT and cytokine flow cytometry analysis. After vaccination, decrease of immunosuppressive factors (IAP, TGF-β) in serum were shown in patients with PR and SD. There was no significant differences of CD4+CD25+ cells by vaccination. Conclusion: These results suggests that a strategy of hybrid cell vaccine employing auto-DCs and auto-tumor cells is feasible in patients with gastrointestinal cancer and may show evidence of anti-tumor immune response. No significant financial relationships to disclose.