bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I study of 1-methyl-D-tryptophan in patients with advanced malignancies.
Authors: Soliman Hatem Hussein , Neuger Anthony , Noyes David , Vahanian Nicholas N. , Link Charles J. , Munn David , Streicher Howard , Sullivan Daniel , Antonia Scott 
Published: March 2020

2501 Background: The indoleamine 2, 3 dioxygenase pathway (IDO) can create immune suppression and unresponsiveness to tumor antigens in tumor-bearing hosts. 1-methyl-D-tryptophan (1-MT) is an oral inhibitor of the IDO pathway, currently in development as an immune adjuvant for anti-tumor vaccines and chemotherapy. The primary goal of this trial is to determine the MTD and toxicity for oral 1-MT. Secondary endpoints include response rates, PK, serum tryptophan catabolites, circulating T-reg cells, and C reactive protein (CRP) levels. Methods: This phase I study utilizes a 3+3 design comprised of ten dose levels (200, 300,400,600,800,mg QD, 600, 800,1200,1600,2000mg BID). Inclusion criteria: patients with measurable metastatic solid malignancy, age ≥18, life expectancy >4 months, and adequate organ/marrow function. Exclusion criteria: chemotherapy in the past 3 weeks, untreated brain metastases, active autoimmune disease, or malabsorptive GI disease. Continuous toxicity monitoring early stopping rules were used. Results: At submission, 48 out of the planned 50 patients were accrued. MTD was not reached at 2000mg BID. At 200mg QD dose, 3 patients previously treated with active immunotherapy (ipilimumab, n=2, CD40-mAb, n=1) developed an autoimmune hypophysitis. Since IDO is closely linked to both CTLA-4 and CD40/CD40L pathways this was considered on-target effect. Subsequently, patients with prior immunotherapy were excluded and no additional treatment related G3-5 adverse events were observed. Five patients showed SD>6 months (2 melanoma, 2 sarcoma 1 colon) as well as some mixed responses were seen in some patients including regression of a liver visceral metastases. 1-MT plasma PK AUC and Cmax were proportional with dose. Cmax (~40 μM at 2000mg BID) is at 2.9 hours and the t1/2 is at 10 hours. Elevations in CRP levels and declines in T-reg cell counts were seen across multiple dose levels. Additional correlative data analysis is ongoing. Conclusions: The treatment was well tolerated and orally bioavailable. Biologic activity in terms of prolonged disease stabilization, induction of hypophysitis, and changes in T-reg levels and CRP were observed. Trials combining 1-MT with docetaxel and a dendritic cell vaccine are ongoing.
Isolation of human anti-MICA antibody from cancer patients responding to immunotherapies.
Authors: May Kenneth F. , Franz Bettina , Harvey Christopher , Hodi F. Stephen , Dranoff Glenn , Wucherpfennig Kai 
Published: March 2020

2502 Background: Immunotherapy is a promising modality for the treatment of cancer, and elucidating the mechanism of action is crucial to guiding patient selection and developing future immunotherapeutic strategies. Engagement of the immune molecule NKG2D by the cancer antigen MICA is important for immune surveillance of many cancers. Tumors can evade immune surveillance by shedding cell surface MICA, which leads to dampening of anti-tumor immunity. Investigations by our laboratory revealed that patients responding to immunotherapy can mount antibody responses targeting MICA, which permits re-engagement of immunity. Methods: Patients with advanced cancer treated at our institution with immunotherapies (tumor cell vaccination, ipilimumab) were identified, including several with long-term clinical remissions. Plasma was analyzed for MICA reactivity to three distinct MICA alleles, and rare memory B cells reactive to MICA were isolated using tetramerized MICA protein. Immunoglobulin heavy and light chain variable domains were sequenced with single cell RT-PCR to generate recombinant monoclonal antibody. Results: Plasma from patients treated with immunotherapy revealed considerable inter-patient variation in reactivity to MICA. Patients with marked plasma reactivity (including several with sustained clinical remissions) were selected for isolation of rare memory B cells reactive to MICA. From these cells, we have generated a recombinant fully-human MICA-reactive monoclonal antibody that exhibits binding to a variety of MICA alleles. Conclusions: We have developed novel methods to analyze anti-MICA antibody responses and isolate rare memory B cells from cancer patients who gained significant clinical benefit from immunotherapy. This has facilitated the generation of fully human recombinant anti-MICA monoclonal antibody. To our knowledge, this is the first example of a specific antibody reactive to a cancer antigen isolated from a cancer patient responding to immunotherapy. As these antibody responses likely played a role in tumor destruction, these results inform the development of new antibody-based immunotherapies targeting the NKG2D-MICA pathway.
Myeloid-derived suppressor cell quantity prior to treatment with ipilimumab at 10mg/kg to predict for overall survival in patients with metastatic melanoma.
Authors: Kitano Shigehisa , Postow Michael Andrew , Cortez Czrina , Rasalan Teresa , Gallardo Humilidad F. , Panageas Katherine , Yuan Jianda , Wolchok Jedd D. , Lesokhin Alexander M. 
Published: March 2020

2518 Background: Ipilimumab, an antibody that blocks the function of the immune inhibitory molecule cytotoxic T lymphocyte antigen 4 (CTLA-4), significantly prolongs survival in patients with metastatic melanoma. Approximately 30% of patients derive clinical benefit from therapy. Defining biomarkers of response to ipilimumab therapy would enable selection of patients more likely to respond and is relevant for both practicing clinicians and for clinical trial design. We performed a pilot correlative study evaluating myeloid derived suppressor cells (MDSC), a population of immune suppressive monocytic cells, as a biomarker of clinical outcome. Methods: Peripheral blood from 26 patients with stage IV melanoma treated with ipilimumab 10mg/kg every 3 weeks for 4 doses at our center, as part of an expanded access program (BMS CA184-045) was assessed for MDSC quantity (%CD14+,HLA-DRlow/- cells) pre-treatment, at week 7, week 12, and week 24 by flow cytometry. MDSC ability to inhibit T cell proliferation was tested using an in vitro suppression assay. Results: We found that lower MDSC quantity pre-treatment predicted for improved overall survival (Hazard ratio 1.07 (1.03, 1.11) p=0.002) and trended toward associating with clinical benefit measured at week 24 imaging (p=0.09). This effect was independent of pre-treatment or week 7 absolute lymphocyte counts (ALC) and pre-treatment LDH when evaluated in a multivariate model with ALC and MDSC quantity HR 1.10; 95% CI 1.04, 1.17 p=0.0006 and LDH and MDSC quantity HR 1.06; 95% CI 1.01, 1.11 p = 0.013. Furthermore, a general trend of increasing MDSC number by week 24 from the pre-treatment baseline was associated with patients that did not achieve clinical benefit. MDSC suppressed peripheral blood T cell proliferation as measured by CFSE dilution in response to anti-CD3 antibody stimulation. Conclusions: Pre-treatment MDSC quantity may predict clinical response following ipilimumab therapy. Further studies evaluating MDSC as a biomarker of ipilimumab therapy are warranted both retrospectively and prospectively in a broader group of patients.
Cyclin-A1 expression in acute myeloid leukemia stem cells and its representation as an immunogenic antigen that can be targeted by cytotoxic T cells.
Authors: Ochsenreither Sebastian , Majeti Ravindra , Loeb Keith , Stirewalt Derek L. , Keilholz Ulrich , Weissman Irving L , Greenberg Philip D 
Published: March 2020

2523 Background: Targeted T-cell therapy represents a more specific and less toxic alternative to allogeneic stem cell transplantation for providing a cytotoxic anti-leukemic response to eliminate the leukemic stem cell (LSC) compartment in acute myeloid leukemia (AML). The aim of this study was to identify a leukemia-associated antigen that is both immunogenic and exhibits selective high expression in AML LSCs. Methods: Expression microarrays of leukemic and normal cells were used to identify suitable candidate genes. Cyclin-A1 appeared to be differentially expressed, and was further analyzed by quantitative RT-PCR, intracellular FACS staining, and immunofluorescence microscopy. T-cell clones specific for cyclin-A1 were generated by stimulation in vitro with an overlapping peptide library, followed by cloning of responding cells. Specificity of the clones was documented by intracellular IFNg and tetramer staining. Cytotoxicity was determined by chromium release and caspase-3 cleavage assays. Results: To identify target candidates with a suitable expression pattern, microarray data from LSCs, hematopoietic cells and healthy tissues were compared. Cyclin-A1 was found to be selectively expressed in LSCs of >50% of AML patients, but minimally expressed in normal tissues with exception of testis. Using dendritic cells and monocytes pulsed with a cyclin-A1 peptide library, T-cells were generated against eight cyclin-A1 oligopeptides. Two HLA A2-restricted epitopes were further characterized, and specific T-cell clones recognized both peptide-pulsed target cells and the HLA A2-positive AML line THP-1. Furthermore, cyclin-A1-specific CD8 T-cells lysed primary AML cells. Conclusions: Cyclin-A1, known to be important in meiosis, is expressed in AML LSCs and testis and can be targeted by T-cells. Thus, cyclin-A1 is the first prototypic LSC-associated leukemia-testis-antigen. Cyclin-A1 already has been shown to be leukemogenic in mice and to promote proliferation and survival in AML blasts. This pro-oncogenic activity, together with high expression levels and a multitude of immunogenic epitopes, make it a promising target for T-cell based therapy approaches.
EGF-based cancer vaccine for advanced NSCLC: Results from a phase III trial.
Authors: Crombet Ramos Tania , Neninger Elia , Acosta Soraida , Amador Rosa Mari­a , Mendoza Silvia , Santiesteban Eduardo Rafael , Rodriguez Pedro Camilo , Garcia Beatriz , Popa Xitlally , Mazorra Zaima , Viada Carmen , Gonzalez Gisela , Lage Agustin 
Published: March 2020

2527 Background: The prognosis of patients with advanced non small cell lung cancer (NSCLC) remains dismal. Epidermal Growth Factor Receptor (EGFR) is overexpressed in epithelial tumors and its role in the development of NSCLC is widely proven. The EGF vaccine is a therapeutic cancer vaccine composed by recombinant Epidermal Growth Factor (EGF) conjugated to a carrier protein, P64K from Neisseria Meningitides and Montanide, as adjuvant. The vaccine is intended to induce antibodies against self EGF that would block EGF-EGFR interaction. Methods: A multicentric, randomized Phase III trial was designed to assess the efficacy, immunogenicity and safety of the EGF cancer vaccine in advanced NSCLC patients. Patients older than 18 years with histology or cytology proven NSCLC at stage IIIB and IV were enrolled in the trial. All patients received no less than 4 platinum-based cycles and achieved at least stable disease, before entering the trial. A low-dose of cyclophosphamide was administered 3 days before the first immunization. Then, patients received 4 quarterly immunizations followed by monthly re-immunizations. Control patients received best supportive care. Results: In total, 405 patients bearing stage IIIB/IV NSCLC were recruited in 21 sites. The vaccine was very well tolerated. The most frequent adverse events consisted in grade 1/2 injection site pain, fever, headache, vomiting and chills. The vaccine was immunogenic. Antibody titers against EGF significantly increased with vaccination and on the contrary, EGF concentration in sera showed a fast reduction after immunization. There was an inverse correlation between the anti-EGF antibody titers and the EGF concentration in sera. Baseline EGF concentration was a worse prognostic factor for the control patients and a predictive factor for vaccinated subjects. The overall survival was significantly better for vaccinated patients as compared to controls. There was a direct correlation between the antibody titers and survival. Conclusions: The EGF cancer vaccine was very well tolerated and significantly increased overall survival of the vaccinated patients. Baseline EGF concentration predicted survival benefit. The EGF vaccine is a new therapeutic option for advanced NSCLC patients.
Phase I clinical trial of a genetically modified and oncolytic vaccinia virus GL-ONC1 with green fluorescent protein imaging.
Authors: Corral Jaime Jesus , Young Anne Mary , Mateo Joaquin , Yap Timothy Anthony , Denholm Katie Ann , Shah Krunal Jitendrakumar , Tunariu Nina , Sassi Salem , Karapanegiotou Lena , Mansfield David , Molife L Rhoda , Harrington Kevin J. , De Bono Johann Sebastian 
Published: March 2020

2530 Background: GL-ONC1 is a genetically engineered vaccinia 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 F14.5L, J2R (thymidine kinase) and A56R (hemaglutinin) loci. A phase I clinical trial of iv GL-ONC1 was pursued to evaluate safety, tolerability, tumour delivery, neutralizing antibody development and anti-tumour activity. Methods: GL-ONC1 was administered to patients with advanced solid tumours at escalating doses (1×105, 1×106, 1×107, 1×108, 1×109, 3×109 plaque-forming units (pfu) on day 1; 1.667×107 and 1.667×108 pfu on day 1-3 of a 28-day cycle) using a 3+3 dose escalation design. Green fluorescent protein (GFP) imaging was performed on skin rash and mucosal tumour lesions at baseline and after each cycle. Optional tumour biopsies were obtained for pharmacodynamic and viral delivery evaluation. Results: 27 patients (21 males, median age 60 years) were treated. One of six patients at the 1x109 pfu dose level developed a dose-limiting, grade 3 rise in aspartate transaminase levels after a single infusion. Other reported adverse events (grade 1/2) included pyrexia (21), musculoskeletal pain (9), fatigue (8), nausea (7), and vomiting (4). Two patients developed skin rash during the first week of treatment, which appeared green by GFP and were positive to viral plaque assay (VPA). VPA of blood, urine, stool and sputum were negative for viral shedding in all but one patient who had positive shedding for 11 days. Increased neutralizing antibody titres were detected in all tested patients apart from one. Best response by RECIST was stable disease at 48 weeks (1), 24 weeks (3) and 8-12 weeks (5). A patient with squamous cell carcinoma of the tongue had a biopsy after 4 cycles which showed positive IHC staining of vaccinia virus. This is the first time that a virus is shown to be delivered to solid tumour after iv delivery. Conclusions: GL-ONC1 administered iv is well tolerated, with documented colonisation in patient tumour, and preliminary evidence of anti-tumour activity.
A first-in-human, phase I safety and pharmacokinetic study of genz-644282, a non-camptothecin topoisomerase I inhibitor, in patients with advanced solid tumors.
Authors: Han Hyo S. , Tan Antoinette R. , Weiss Glen J. , Sullivan Daniel , Strosberg Jonathan R. , Collins Sara , Moss Rebecca Anne , Wu Jingyang , Ewesuedo Reginald , LoRusso Patricia 
Published: March 2020

2534 Background: The approved topoisomerase I (TopI) inhibitors (irinotecan and topotecan) are camptothecin derivatives. The lactone ring structure of camptothecins negatively impacts their clinical potential.Genz-644282 is a novel non-camptothecin that induces TopI-DNA cleavage complexes at similar as well as unique genomic positions; that are more persistent. This study was designed using a pharmacokinetic-pharmacodynamic (PK-PD) model to predict the maximum tolerated dose (MTD). Methods: A PK-PD relationship of Genz-644282 to inhibit tumor growth was derived (Simeoni, Can Res 2004). Using an accelerated titration design, cohorts of 1, 3 or 6 patients received 3 weekly doses of Genz-644282 on a 28 day schedule starting with 0.5 mg/m2. After MTD on the 28 day schedule was exceeded, 21 day schedule was initiated. Results: 49 patients (N=44 data available: 26M :18F) were dosed. Tumor types were colorectal (15), breast (5), small cell lung (SCLC 3), non-small cell lung (4), others (17). As predicted from the PK-PD model 8 cohorts were evaluated on the 28 day schedule before defining the MTD. The MTD was 8 mg/m2 and 9 mg/m2 for the 28 day and 21 day schedules, respectively. Dose limiting toxicities that determined the MTD were: gr 4 thrombocytopenia (n=2); gr 2 thrombocytopenia (n=1) and gr 4 neutropenia (n=1) both of which resulted in ≥72h delays in initiating cycle 2. Treatment emergent adverse events (>10%) were nausea (45%), fatigue (39%), anorexia (32%), anemia (27%), vomiting (23%), thrombocytopenia (18%), diarrhea (16%), dehydration (16%), hyperglycemia (16%), cough (16%), dyspnea (14%), depression (11%) and hyponatremia (11%). Efficacy data suggest 2 responders with SCLC (1 minor response;1 complete response), and 2 patients (breast, gastric) with stable disease (≥ 6 months). PK data show a Genz-644282 half-life of approximately 50 h, a linear dose-exposure relationship, and no accumulation in between doses. Conclusions: Genz-644282 is a non-camptothecin TopI inhibitor in phase I development with ongoing expansion phase. The emerging pk, efficacy and safety data are suggestive of a distinct clinical profile of Genz-644282 from the camptothecins.
Phase Ib study of plitidepsin (APL) with gemcitabine (GEM) in refractory solid tumors and lymphoma patients.
Authors: Stein Mark N. , Ribrag Vincent , Gomez-Roca Carlos Alberto , Salles Gilles A. , Carella Angelo Michele , Gyan Emmanuel , Szyldergemajn Sergio A. , Kahatt Carmen Maria , Luque Manuel , Extremera Sonia , De Miguel Bernardo , Fernandez-Garcia Eva , Soria Jean-Charles 
Published: March 2020

2539 Background: Combination chemotherapy (CT) regimens may improve the outcome of patients with advanced metastatic disease. APL (a marine-derived cyclodepsipeptide) is a cytotoxic agent that induces apoptosis by JNK-pathway activation and increased oxidative stress; it has also shown anti-angiogenic properties in vitro. GEM has a different mechanism of action and toxicity profile from APL, making this combination appropriate for clinical testing. Moreover, APL has been shown pre-clinically to potentiate the anti-tumor effect of GEM. Methods: Patients with ECOG-PS ≤ 1 received escalating doses of APL/GEM (1.8/750, 1.8/1000, 2.4/1000 and 3.0/1000 mg/m2) on days 1, 8 and 15 every four weeks. The primary objective was to determine of the maximum tolerated dose (MTD) and the recommended dose (RD) for APL/GEM. Secondary objectives included characterization of safety profile, pharmacokinetics (PK) and anti-tumor activity of APL/GEM. Results: 34 patients were included and 33 treated (23 solid tumors and 11 lymphomas) with a median age of 59 years (r: 28–86), median prior CT lines 3 (r:1-7) and a median of 2 cycles (r:1-12). Relative dose intensity was 66.7% (r: 37.7-85.7%) and 80.9% (r: 56.1-100.6%) for APL and GEM, respectively. The MTD was 3.0/1000 mg/m2, as 2/6 patients experienced dose limiting toxicities (DLTs) [grade (G) 4 thrombocytopenia and 2 missed doses due to G2 ALT/AST]. The RD was 2.4/1000 mg/m2, with no patients experiencing DLTs. Adverse events (AEs) were mainly G 1-2 anemia, thrombocytopenia and ALT/AST increase. Six patients with solid tumors had stable disease (SD) ≥ 3 months, one patient with NK T-cell lymphoma had a complete response, a patient with Hodgkin disease (HD) had a partial response and three other patients with HD had SD ≥ 3 months with tumor decrease at the RD. No relevant drug-drug interaction was observed for the dose levels tested. Conclusions: APL/GEM at the RD can be safely combined. Objective responses were observed in patients with HD and NK T-Cell lymphoma. Further studies of this combination in lymphoma are warranted.
A multicenter phase II neoadjuvant trial of bevacizumab combined with docetaxel plus carboplatin in the treatment of triple-negative breast cancer: Korean Cancer Study Group (KCSG-BR 0905, NCT 01208480).
Authors: Kim Hye Ryun , Jung Kyung Hae , Im Seock-Ah , Im Young-Hyuck , Kang Seok Yun , Park Kyong Hwa , Lee Keun Seok , Lee Soohyeon , Ahn Jin-Hee , Kim Sung-Bae , Lee Kyung-Hun , Park Yeon Hee , Ahn Jin Seok , Kim Ku Sang , Lee Hye Yoon , Ro Jungsil , Park Byeong-Woo , Kim Seung Il , Sohn Joo Hyuk 
Published: March 2020

2542 Background: Triple negative breast cancer (TNBC) is dismal disease that is ineligible for endocrine or anti-HER2 therapy. We have conducted a phase II neoadjuvant trial to evaluate efficacy and tolerability of bevacizumab combined with docetaxel plus carboplatin in TNBC. Methods: Women with a histologically confirmed stage II or III TNBC were eligible. Hormone receptors and HER2 negativity were confirmed by immunohistochemistry and/or fluorescence in situ hybridization. Patients received 6 cycles of docetaxel 75 mg/m2, carboplatin AUC 5, and bevacizumab 15 mg/kg on day1 every 21 days. Bevacizumab was omitted in the last cycle to avoid wound complication. The primary endpoint was pathologic complete response (pCR) rate in both breast and axillary lymph node and secondary endpoints were clinical response rate, toxicity profiles, and breast conserving surgery (BCS) rate. Results: Forty-five TNBC patients were recruited from 7 institutes in the Korean Cancer Study Group (KCSG) between October 2010 and August 2011. The median age of the patients was 45 years (30-72 years). The T1, T2, and T3 were 4.4 %, 68.9 %, and 26.7 %, respectively and axillary lymph node was positive in 80% by breast MRI. Among 45 patients, 44 patients completed 6 cycles of therapy followed by surgery and one patient was withdrawn due to patient’s refusal of further therapy after 3rd cycle. The pCR rate was 42.2 % (19/45) and clinical response rate was 95.5 % (43/45) (CR, n= 6; PR, n=37; SD, n=1; not evaluable, n=1) based on RECIST criteria 1.1. BCS was undertaken in 77.7 % (35/45). The grade 3 or 4 adverse events were neutropenia (38), febrile neutropenia (4), vomiting (3), nausea (2), anemia (1), thrombocytopenia (1), stomatitis (1), gastrointestinal bleeding (1), and increased ALT (1). Only one patient experienced delayed wound healing after breast surgery. Conclusions: Bevacizumab in combination with docetaxel and carboplatin as neoadjuvant treatment provided an encouraging pCR rate (42.2 %) and a negligible wound healing problem after surgery. The adverse events were manageable.