bluuebunny/crossref_metadata_2025_split huggingface dataset:
EGF-based cancer vaccine: Optimizing predictive and surrogate biomarkers.
Authors: Crombet Ramos Tania , Neninger Elia , Gonzalez Jorge , Rodriguez Pedro Camilo , Garcia Beatriz , Popa Xitlally , Mazorra Zaima , Viada Carmen , Luaces Patricia Lorenzo , Gonzalez Gisela , Lage Agustin 
Published: March 2020

3013 Background: EGFR is overexpressed in many epithelial tumors. EGF is one of the most important growth factors that stimulates EGFR, in a paracrine way. CIMAvax-EGF is a therapeutic cancer vaccine intended to induce antibodies against EGF. It is composed by recombinant EGF conjugated to P64 from N.Meningitides as a carrier and Montanide, as adjuvant. Methods: Two controlled trials were done in advanced NSCLC and castration-resistant prostate cancer patients (CRPC). A multicentric, randomized Phase III trial was designed to assess the efficacy, immunogenicity, and safety of CIMAVAx-EGF in advanced NSCLC patients. Patients with histology- or cytology-proven NSCLC at stage IIIB/ IV were enrolled. All subjects received 4 platinum-based cycles before entering the study. On the other hand, a multicentric, randomized Phase II trial was designed to assess the immunogenicity and safety of the vaccine in CRPC patients. The EGF cancer vaccine was administered in combination with mitoxantrone and prednisone. Results: 405 patients bearing NSCLC and 200 men with CRPC were enrolled in the 2 trials. In both studies the vaccine was immunogenic. Antibody titers against EGF increased with vaccination and EGF concentration in sera showed a fast reduction after immunization. The anti-EGF antibody response was directly correlated with overall survival. CIMAVax-EGF was safe and most prevalent adverse events were grade 1-2 injection site pain, fever, headache, nausea, vomiting, and chills. The vaccine significantly increased the survival of the NSCLC patients while it did not augment significantly the overall survival of the CRPC patients. In both studies, EGF concentration was measured at baseline and it was found to be much higher than in normal subjects. High EGF concentration predicted greater benefit after vaccination. On the contrary, NSCLC and prostate control patients with high levels of EGF had a poorer outcome. Conclusions: Antibody response against EGF is a surrogate marker of survival. High EGF concentration might be a predictive marker of vaccine efficacy and a poor prognostic biomarker for non-vaccinated NSCLC and CRPC patients. The predictive and prognostic value of the EGF concentration will be validated prospectively. Clinical trial information: IIC EC 081.
Association of tumor PD-L1 expression and immune biomarkers with clinical activity in patients (pts) with advanced solid tumors treated with nivolumab (anti-PD-1; BMS-936558; ONO-4538).
Authors: Grosso Joseph , Horak Christine E. , Inzunza David , Cardona Diana M. , Simon Jason S. , Gupta Ashok Kumar , Sankar Vindira , Park Jong-Soon , Kollia Georgia , Taube Janis M. , Anders Robert , Jure-Kunkel Maria , Novotny Jim , Taylor Clive R. , Zhang Xiaoling , Phillips Therese , Simmons Pauline , Cogswell John 
Published: March 2020

3016 Background: The immune checkpoint receptor programmed death-1 (PD-1) negatively regulates T-cell activation. In a phase I study, nivolumab, a PD-1 receptor blocking antibody, demonstrated durable clinical activity. Evaluation of the expression of the PD-1 ligand, PD-L1, by IHC with the 5H1 Ab suggested a correlation between pretreatment tumor PD-L1 expression and clinical response (Topalian et al, NEJM 2012). Methods: 304 pts with non-small cell lung cancer (NSCLC, n=127), melanoma (MEL, n=107), renal cell (RCC, n=34), colorectal (n=19) or prostate cancer (n=17) received nivolumab between 2008-2012 (0.1−10 mg/kg IV Q2W) during dose escalation and/or cohort expansion. Formalin-fixed paraffin-embedded tumor tissue and peripheral blood mononuclear cells (PBMC) were analyzed to explore potential pharmacodynamic/ predictive biomarkers associated with nivolumab therapy. Tumor surface PD-L1 expression was evaluated by IHC using an automated assay based on a sensitive and specific PD-L1 mAb (28-8) distinct from 5H1. PD-L1 positivity (PD-L1+) was defined as ≥5% cell membrane staining of any intensity. Lymphocyte subsets in PBMC were measured using flow cytometry. Results: Tumor membrane PD-L1 was measured in 101 MEL and NSCLC pts. 17/38 (45%) of MEL and 31/63 (49%) of NSCLC biopsies were PD-L1+. A numerically higher objective response rate (ORR), longer progression-free survival (PFS), and overall survival (OS) was seen with PD-L1+ in MEL pts (Table).Analysis of the association of PD-L1 expression with ORR, PFS and OS in NSCLC is ongoing. A correlative analysis of pt response with pre-/post-dose levels of lymphocytes will be presented. Conclusions: These data, using a novel, automated PD-L1 IHC assay and mAb, support the hypothesis of tumor PDL1+ predicting activity of nivolumab in advanced cancer, which is being prospectively assessed in phase III trials. Clinical trial information: NCT00730639. [Table: see text]
Deletion and mutation of IL10RA gene on chromosome 11q23 to avert CpG-B oligodeoxynucleotides-induced apoptosis of human chronic lymphocytic leukemia B cells.
Authors: Liang Xueqing , Bachanova Veronika , Chen Wei 
Published: March 2020

3023 Background: Targeting TLR9 expressed on human CLL cells with CpG-B oligodeoxynucleotides leads to IL-10-induced tyrosine phosphorylation of STATs and apoptosis of B-CLL cells. However, B-CLL cells from a small subset of patients were resistant to CpG-B ODN treatment. Here, we investigated the molecular mechanism by which B-CLL cells are sensitive or resistant to CpG-B ODN treatment. Methods: Purified CD19+CD23+CD5+primary B-CLL cells were cultured for 5 days with/without CpG-B ODN (CpG 2006, CpG 685) or rh-IL-10. B-CLL cell apoptosis were determined by viable cell counts, Annexin V/PI and TMRE staining, Western blot and intracellular staining of the activation/cleavage of caspases, PARP, Bax translocation and cytochrome c release, IL-10R1 expression and IL-10 binding by flow cytometry, IL10RA gene deletion by FISH, IL10R1 S138G mutation by Bi-PASA, The tyrosine or serine phosphorylation of STATs by Western blot. Results: Fifteen CpG-sensitive and 11 CpG-resistant primary CLL samples were comparatively studied. B-CLL cells from 15/15 CpG-sensitive samples were induced into apoptosis by either CpG-B ODNs or IL-10 in a treatment time and dose-dependent manner. Both CpG-B ODNs and IL-10 significantly increased pTyr701-STAT1/pTyr705-STAT3 expression and induced apoptosis via the mitochondrial apoptotic pathway in 15 primary B-CLL cells. No IL-10RA gene deletions were detected, 13/15 patients were IL10R1 S138G AA wildtypes and 2/15 patients were AG heterozygotes. In contrast, CpG-B ODNs or IL-10 failed to induce apoptosis in 11/11 CpG-resistant B-CLL cells. Interesting, 2/11 CLL samples had IL10RA genes deletion and 7/11 had IL10R1 S138G GG homozygote mutation. IL10RA gene deletion significantly decreased the IL10R1 expression; both IL10RA gene deletion and mutation significantly decreased the IL-10 binding, abolished or reduced CpG-B ODNs or IL10-induced pTyr701-STAT1/pTyr705-STAT3 expression in B-CLL cells. Conclusion: Deletion and mutation of IL10RA gene on chromosome 11q23 averts CpG-B ODN-induced apoptosis of human B-CLL cells, which may serve as biomarker to predict sensitivity or resistance of CLL to CpG-B ODN treatment.
Investigating genes and micro-RNAs that may predict clinical benefits of anti-CTLA-4 therapy.
Authors: Gao Jianjun , Chen Hong , Ng Tang Derek , Sharma Padmanee 
Published: March 2020

3043 Background: Blockade of T cell co-inhibitory receptor CTLA-4 with a monoclonal antibody, ipilimumab, has led to augmented anti-tumor immune responses, clinical benefit, and FDA approval of ipilimumab for the treatment of metastatic melanoma. Only a subset of patients benefit from anti-CTLA-4 therapy. In order to identify genes, microRNAs, and signaling pathways that are modulated by anti-CTLA-4, which may be used for potential correlation with clinical outcomes or provide additional targets for therapy, we purified and analyzed CD4+T cells from patients treated with anti-CTLA-4 for changes in gene and microRNA expression profiles. Methods: On an IRB-approved phase Ia presurgical clinical trial, 6 patients with localized bladder cancer were treated with two doses of ipilimumab at 10 mg/kg at weeks 1 and 4. Pre-therapy and post-therapy blood samples were collected for CD4+ T cell enrichment by using the T cell isolation kit from Miltenyi Biotec (Auburn, CA). RNA and microRNA were isolated from purified CD4+T cells using Qiagen RNA isolation kits for Affymetrix microarray and micoRNA array analyses. Microarray data were then analyzed using Ingenuity iReport (Redwood City, CA). RT-PCR and Western blot were used to confirm significant changes in genes or pathways identified in microarray analyses. Results: Anti-CTLA-4 treatment resulted in modulation of differentially expressed genes (DEGs). After two doses of treatment, anti-CTLA-4 significantly changed expression of a total of 289 DEGs. Further pathway analyses indicated that anti-CTLA-4 induced a variety of pathways involved in cell proliferation and immune modulation, including PI3K/AKT, MAP/ERK, and IFN/JAK-STAT pathways. We have also identified 9 microRNAs that potentially regulate the expression of genes changed by anti-CTLA-4 therapy. Conclusions: Anti-CTLA-4 treatment results in modulation of multiple genes, microRNAs, and pathways, which likely play important roles in anti-tumor immune responses. We are currently testing a number of these identified genes and microRNAs as potential predictive biomarkers for anti-CTLA-4 therapy in a small cohort of patients who had complete response vs. progression of disease after anti-CTLA-4 therapy.
Therapeutic superiority of a TCR-like antibody to an intracellular WT1 oncogene peptide compared with the tyrosine kinase inhibitor imatinib in a mouse model of Philadelphia chromosome positive (Ph+) ALL.
Authors: Dubrovsky Leonid , Brea Elliott Joseph , Veomett Nicholas J , Dao Tao , Yan Su , Liu Cheng , Scheinberg David A. 
Published: March 2020

3047 Background: Acute and chronic leukemias demonstrate significantly increased expression of the Wilms tumor gene 1 (WT1) product, including CD34+ CML stem cells, making WT1 an attractive therapeutic target. However, WT1 protein is intracellular and currently un-druggable. ESKM is a fully human IgG1 antibody that targets a 9 amino acid sequence (RMF) of the protein WT1 in the context of HLA-A0201. Methods: BV173 is an HLA-A0201 positive Ph+ ALL cell line. It over-expresses WT1 and binds strongly to ESKM. We evaluated the in vitro and in vivo efficacy of ESKM in combination with TKIs. Antibody-dependent cell-mediated cytotoxicity (ADCC) was evaluated in vitro by chromium release assay, utilizing human PBMC effectors. In vivo tumor growth was assessed in NSG mice bearing disseminated luciferase tagged BV173 with bioluminescence imaging and flow cytometry of the bone marrow after sacrifice. Imatinib was used at maximum tolerated doses for these mice as determined in pilot studies. Results: The addition of imatinib in vitro did not affect the ability of ESKM to perform ADCC. The BV173 engrafted NSG mice treated with ESKM with and without TKIs showed tumor regression one week after beginning therapy, clearing leukemia from the liver and spleen. Mice relapsed primarily in the bone marrow, with increasing luciferase signal after two weeks of therapy. Compared to untreated control animals, after 5 weeks of therapy, imatinib alone only reduced tumor growth by 45%; ESKM alone reduced growth by 81%, and the combination of ESKM and imatinib reduced growth by more than 95%. Flow cytometry of cells remaining after treatment showed binding of ESKM, suggesting escape was not due to down regulation of the epitope. Conclusions: In this mouse model of Ph+ ALL, ESKM antibody therapy is superior to imatinib and the combination of both modalities is additive. This antibody is efficacious in vitro and in vivo against WT1 overexpressing leukemias, in context of HLA-A0201. This combination holds promise as a therapy for leukemias in patients who are HLA-A0201 positive, with the potential of improved cytoreduction in patients with Ph+ leukemias.
Phase II study of dendritic cell vaccination combined with recombinant adenovirus-p53 in treatment for patients with advanced pancreatic carcinoma.
Authors: Chai K , Ai Yq , Jiang Lw 
Published: March 2020

3049 Background: There are few choices of treatments for advanced pancreatic carcinoma (PC) due to the resistances to chemo- or radio-therapy. Immunotherapy based on dendritic cell (DC) vaccines and p53-based gene therapy are two promising therapeutic modalities. They also demonstrated favorable safety profiles. In this study, we compared the immunological and clinical response between DC vaccine therapy and DC vaccine combined with recombinant adenovirus-p53 (rAd-p53) gene therapy. Methods: Thirty-six patients with a stage IV pancreatic cancer, 21 men and 15 women with an average age of 56.2 years old, were included in this study and randomly assigned to two groups: 16 patients in DC group (DCG) and 20 in DC plus rAd-p53 group (DPG). The DCG patients received autologous antigen-loaded DC (antigen from isolated pancreatic cancer cells) and the DPG patients received both DC and rAd-p53. DC vaccines were injected intra-dermally once every week for 4 injections and rAd-p53 were given by intravenous injections once per 3 days for 5 times at a dose of 3 x 1012viral particles. The response, safety and peripheral blood lymphocyte subsets were investigated. Results: The post-treatment CD3+, CD3+CD4+, CD4+/CD8+ ratio of patients’ peripheral blood in both groups were increased. But the percent of CD4+CD25+ regulatory T cells were significantly decreases. In DPG, 5 patients had a partial response (PR) and 4 patients had stable disease (SD) according to the RECIST standard. The 3 and 3 DCG patients achieved a PR and SD, respectively. The disease control rates (PR+SD) were 45.0% and 37.5% for DPG and DCG, respectively. The 6-month overall survival rates were 50.0% and 43.8% for DPG and DCG, respectively. The median survival times were 6.8 and 5.5 months for DPG and DCG, respectively. Mild to medium grade fever was observed in most of the patients in the two groups. No serious adverse events were found. Conclusions: DC-based immunotherapy and p53 gene therapy are safe and appropriate treatments for patients with advanced pancreatic carcinoma. The combined treatments showed more beneficial results than the DC immunotherapy alone.
A phase II study of Recchia's immunomodulatory schedule (RIS) as a maintenance therapy in high-risk tumors after a response.
Authors: Sureda Manuel , Rebollo Joseba , Vazquez Begona , Bretcha Pere , Cañon Rosa , Duarte Maritza , Munoz Vicente , Brugarolas Antonio 
Published: March 2020

3074 Background: F. Recchia et al. (Interleukin-2 and 13-cis retinoic acid in the treatment of minimal residual disease: A phase II study. Int J Oncol. 20: 1275-1282, 2002) previously defined the possibility of achieving a chronic immune stimulation through a prolonged low dose sc interleukin 2 (IL2)-based schedule, leading to a prolongation of PFS in advanced cancer patients (pts). A confirmatory phase II study was started. Methods: Pts diagnosed of high risk solid tumors in response to chemotherapy were included. RIS consisted in low dose IL2 (1.8 MU sc per day, 5 days per week, 3 weeks per month) plus oral isotreonin (CRA, 0.5 mg/kg) the same days of IL2 and/or sc PEG-interferon (50 µg per week of treatment). No Chx was allowed with RIS, but concurrent maintenance with TKI or Hx was permitted. Results: Since 08/2007 to 01/2013, 69 pts (39 M/30 F, median age 60 y, range 31-78) were included. 51 pts were treated with stage IV disease. 36 pts entered in complete response (CR), 29 in partial response (PR), 1 with progressive disease, 3 adjuvant. 4/69 grade 3/4 toxicity, (6%): 1 fatal poliserositis resistant to cortisone after 20 months of RIS, 1 stopped RIS for reaction requiring steroids, 1 for multiinfarction dementia, 1 for grade 3 liver toxicity. 3 pts presented other alterations managed along the course of the RIS (1 PVT, 1 ITP, 1 angina resolved after stent placement). Grade 1-2 fever, fatigue and joint pain were commonly observed but usually controlled with NSAIDs. Among the 68 pts evaluable for response, one pt progressed, 26 presented stable disease (median TTP 3 mo, range 2-28), 3 presented PR (1 melanoma, 1 prostatic ca, 1 ovarian ca; 9, 11 and 28 mo respectively), and 38 maintained or presented CR (median TTP 19 mo, range 2-62+). Three pts in PR were converted to a CR during RIS (1 pancreatic ca, 1 ovarian ca, 1 larynx ca). Conclusions: In this study we confirm the previous results reported by F. Recchia et al. RIS represents a good alternative for high risk pts with solid tumors after systemic chemotherapy induced response with acceptable tolerability and offers in selected pts a possibility of obtaining a CR after a PR. Further validation and randomized studies are warranted.
Physicochemical, functional, and pharmacologic comparability between the proposed biosimilar rituximab GP2013 and originator rituximab as the foundation for biosimilarity.
Authors: da Silva Antonio , Kronthaler Ulrich , Meyer Ines , Fritsch Cornelius , Schneiderer Timo , Stangler Thomas , Visser Jan Marinus 
Published: March 2020

3075 Background: Development of a biosimilar involves extensive characterization of the originator product and a target-directed iterative development process ensuring comparability to the originator with similar clinical efficacy, safety and quality. Here we report the physicochemical, functional and pre-clinical pharmacological characterization of a proposed rituximab biosimilar (GP2013). Methods: A variety of physicochemical methods were used to analyze primary and higher order structure, post-translational modifications and size heterogeneity. Functional characterization included a series of bioassays (in vitro target binding, ADCC, CDC and apoptosis) and SPR-based Fc receptor binding assays. Comparative PK and PD were assessed in cynomolgus monkeys, the pharmacologically most relevant species. Results: GP2013 has the same primary amino acid sequence and higher order structure as the originator rituximab and both were comparable with regard to charge variants, specific amino acid modifications, glycan pattern and size heterogeneity (low- and high-molecular weight variants & particles). Functionally GP2013 could not be distinguished from originator rituximab preclinically. In primates, PK analysis confirmed bioequivalence between GP2013 and originator rituximab with nearly identical AUC values and 90% CIs entirely within the standard acceptance range of 0.8-1.25. Bioequivalence of PD response was also shown, with 95% CIs of areas under the effect-time curves (AUEC) ratios for relative change from baseline in B-cell populations within the 0.8-1.25 acceptance range. Conclusions: Using a broad panel of analytical methods it was shown that GP2013 is highly similar to originator rituximab at the physicochemical level. In addition, the preclinical comparability exercise confirmed that GP2013 and originator rituximab are pharmacologically similar with regard to FcR and CD20 binding, ADCC, CDC and apoptosis potency, PK exposure and B-cell depletion. As such, we anticipate that the ongoing clinical trials will help provide confirmatory evidence of similar efficacy and safety to the originator product.
Superparamagnetic nanoparticles targeting cancer cells invading the extracellular matrix.
Authors: Elachy Samar , Ramadan Wegdan , Kalsa Remon , Abou El Azm Nihad , Refaat Tamer , Omar Walaa , Eissa Yasmine , Radi Sanaa H , Abd-El-Moneim Salah-Eldin , Paunesku Tatjana , Woloschak Gayle 
Published: March 2020

3083 Background: Metastatic cancer cells secrete matrix metalloproteinases (MMP), which allow cancer cells to burrow their way to the nearby vasculature. Therefore, MMPs are potential targets for anticancer treatment. Nanoparticles (NPs) can be crafted to adhere to the ECM and subsequently be released in response to advance of invasive cells. The objective of the study is to elucidate the interaction of cancer cells in a three-dimensional culture, with functionalized SPIONS targeted to the extracellular matrix around them. Methods: SPIONS, 15-20 nm in size were functionalized using different coatings: ficoll 400, sucrose, lysine-arginine, dextran50,000. Cellular uptake studies using cervical adenocarcinoma HeLa cell lines were performed to determine the optimum formulation taken up by the cells, using electron microscopy and Prussian blue staining for optical microscopy. Two types of extracellular matrices were used: Rat-tail Collagen type I and ECM gel from Engelbreth-Holm-Swarm murine sarcoma with NPs embedded in them. To assess the capability of cells to invade the matrix, cells were grown on the surface of the matrices for 1 week To evaluate the ability to grow, expand and migrate inside the matrix, cells were embedded within the matrix and left for 14 days. Comparison was made in the presence or absence of SPIONS. Results: Sucrose-coated SPIONS were taken up the best by HeLa cell lines as evaluated by MRI. MMP-1 Secretion allowed HeLa cell invasion of collagen type-1 matrix unidirectionally. Cells could adhere, proliferate, differentiate and migrate in the absence of SPIONS. Cells positive for MMP-9 invaded ECM gel from Engelbreth-Hol-Swarm murine sarcoma matrix also only in the absence of SPIONS. Cells that were found engulfing SPIONS showed morphological features of apoptosis as nuclear pyknosis and karryorhexis. Conclusions: Targeting NPs to the ECM surrounding cancer cells that have developed a metastatic potential represents an attractive platform for cancer therapeutics. The findings show a great promise for development of new theranostic agents, that can be directed to the tumor environment using external magnetic fields, with subsequent suppression of invasion and even destroying malignant cells.
Effect of an adjuvant breast cancer vaccine on disease-specific survival of breast cancer patients with depressed lymphocyte immunity.
Authors: Elliott Robert Lange , Head Jonathan F. 
Published: March 2020

3087 Background: Breast cancer patients were vaccinated in the adjuvant setting with an autologous, allogeneic whole cell vaccine to evaluate the effect on host lymphocyte immunity and disease-specific survival. Methods: We began preparing whole cell preparations for a vaccine study in 1995. Stage I and II breast cancer patients had host lymphocyte immunity against tumors associated antigens evaluated before and after vaccination. Those patients with depressed immunity, determined by a lymphocyte blastogenesis assay (LBA), were offered the whole cell vaccine. Patients were given six intradermal injections (three weekly followed by three monthly). Ten weeks after the last injection the LBA was repeated. Thirty-seven patients were vaccinated in the adjuvant setting with the whole cell autologous, allogeneic vaccine. Results: The vaccine was well tolerated with no severe toxicities. Some patients experienced slight pain and swelling at the injection site and slight chills and fever. The vaccinated patients had a mean follow-up of 12.7 years with mean follow-up of 8.9 and 9.2 years for the patients with normal and depressed immunity, respectively, in the historic control. The 10-year survival was 95% (20 of 21 patients) in the normal immunity historic control, 59% (33 of 56 patients) in the depressed immunity historic control and 89% (33 of 37 patients) in the patients with depressed immunity that were vaccinated in the present clinical trial. Conclusions: The disease-specific survival of the vaccinated patients with depressed immunity in this trial is significantly greater than that of the historic controls of unvaccinated patients with depressed immunity to their tumor associated antigens. This study confirms the importance of maintaining good host lymphocyte immunity after completion of standard therapy and validates the value of cancer immunotherapy in the adjuvant setting.