bluuebunny/crossref_metadata_2025_split huggingface dataset:
WT1-targeted dendritic cell vaccination as a postremission treatment to prevent or delay relapse in acute myeloid leukemia.
Authors: Berneman Zwi N. , Van de Velde Ann , Anguille Sebastien , Cools Nathalie , Van Driessche Ann , Nijs Griet , Stein Barbara , Vrelust Inge , Gadisseur Alain P. , Schroyens Wilfried A. , Van Tendeloo Viggo F. , Smits Evelien L. 
Published: March 2020

2506 Background: Vaccination with tumor antigen-loaded dendritic cells (DC) holds promise for the adjuvant treatment of cancer. Methods: In a phase I/II trial, we investigated the effect of autologous DC vaccination in 17 patients with acute myeloid leukemia (AML) in remission but at very high risk of full relapse. Wilms’ tumor 1 protein (WT1) was chosen as immunotherapeutic target and introduced into the DC by mRNA electroporation. We are continuing a phase II trial, which is still recruiting. Results: Two out of 3 patients, who were in partial remission with chemotherapy-refractory disease, were brought into complete remission following 4 biweekly intradermal injections of WT1 mRNA-electroporated DC. In those 2 patients as well as in 6 other patients who were in complete remission but who had molecularly demonstrable residual disease, there was a return to normal of the AML-associated WT1 mRNA tumor marker following DC vaccination, compatible with reaching clinical and molecular remission in 8/17 patients. Among the 8 responders, there have been 2 relapses and 2 deaths. Of the 9 non-responders, 8 have relapsed and 7 have died. Of the 2 patients in partial remission who were brought into complete remission by DC vaccination, 1 has died following relapse. Median overall survival was 6 months in non-responders and 52 months in responders (p=0.0007). Median relapse-free survival was 3 months in non-responders as compared to 47 months in responders (p<0.0001). Clinical responses overall were correlated with elevated levels of activated natural killer (NK) cells post-vaccination. Long-term clinical responses, lasting for at least 3 years, were significantly correlated with an increase in polyepitope WT1-specific tetramer+ CD8+ T-cell frequencies. Conclusions: DC-based immunotherapy elicits both innate (NK) and adaptive (T cells) cellular responses correlated with clinical benefit. WT1 mRNA-transfected DC emerge as a feasible and effective strategy to control residual disease in AML, in particular as a post-remission treatment to prevent full relapse.
Costimulatory effect of agonistic 4-1BB antibody on proliferation and effector phenotype of tumor-infiltrating lymphocytes in melanoma.
Authors: Sarnaik Amod , Bilotto Anthony , Jure-Kunkel Maria , Hall MacLean S , Wang Wenshi , Younos Ibrahim , Pilon-Thomas Shari , Weber Jeffrey S. 
Published: March 2020

2511 Background: Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) is a promising form of immunotherapy with a 20-30% durable response rate. Its widespread implementation is limited by the relatively long time needed to establish TIL in vitro and the lack of effective tumor reactivity. Our objective was to incorporate co-stimulation with 4-1BB agonism to optimize TIL growth preparation time and tumor reactivity to improve outcomes. Methods: 7 metastatic melanoma patients were consented to an IRB-approved tissue procurement protocol. For each specimen, TIL were propagated in vitro from 4 melanoma tumor fragments per condition with standard 6000 IU/mL of IL-2 and either 10 ug/mL of 4-1BB agonistic antibody (BMS-663513) or its isotype control. After 3 weeks, TIL were counted and phenotyped using flow cytometry. TIL were re-stimulated with HLA-matched melanomas and assessed for interferon-γ (IFNγ) release by ELISA. Statistical comparisons involved the 2-tailed, paired t test using GraphPad Prism software. Results: 4-1BB treatment yielded a median 4.3x107 TIL (range 1.1x107-8.4x107) compared to a median 2.3x107 cells in the control (range 1.5x106-5.3x107, p = 0.009). This is clinically significant as the initial minimum target number for TIL generation is 3x107. On phenotypic analysis compared to control, 4-1BB treatment resulted in a 1.5X higher CD8+ cell numbers (p=0.02), a 6X lower CD4+ cell numbers (p=0.02), and 5.5X lower CD4+CD25+FoxP3+ Treg cell numbers (p=0.09). A paired sample was re-stimulated in triplicate with HLA-matched tumor target, and ELISA of the supernatant treated with 4-1BB yielded 1.6 fold higher IFNγ (p=0.05). A paired sample was then assayed for known markers of T cell cytolytic activity: EOMES and perforin. 4-1BB treatment resulted in 34.5% EOMES and perforin double positive TIL compared to 18.8% in the control group. Conclusions: 4-1BB agonism is associated with enhanced kinetics of TIL proliferation, increased yield of CD8+ TIL, lower Treg numbers, increased markers of cytolysis, and enhanced IFNγ release upon tumor re-stimulation. 4-1BB agonism may be a useful adjuvant in the generation of TIL in future clinical trials.
Radiotherapy plus the anti-EGFR mAb nimotuzumab or placebo for the treatment of high-grade glioma patients.
Authors: Solomon Maria Teresa , Selva Julio Cesar , Figueredo Javier , Vaquer Jose , Toledo Carolina , Quintanal Nelson , Salva Silvia , Dominguez Rafael , Alert Jose , Marinello Jorge Juan , Catala Mauricio , Gonzalez Griego Martha , Luaces Patrcia Lorenzo , Iznaga Normando , Bach Ferdinand , Crombet Ramos Tania 
Published: March 2020

2515 Background: Despite remarkable advances in multimodal therapy, high grade glioma (HGG) patients still face a poor prognosis. EGFR is well validated as a primary contributor of HGG initiation and progression. Nimotuzumab is a humanized monoclonal antibody (mAbs) that recognizes the EGFR extracellular domain. While it has similar preclinical and clinical activity when compared to other anti-EGFR mAbs, it does not induce skin toxicity or hypomagnesemia. Methods: A randomized, double blind, multicentric clinical trial was conducted in 70 anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) patients that received radiotherapy (RT) plus nimotuzumab or placebo. Patients received 6 weekly doses of nimotuzumab or placebo together with radiotherapy. Treatment was maintained every 3 weeks, until completing 1 year of treatment. GBM patients did not receive temozolomide since the drug cannot be sold to Cuba. The objectives of this study were to assess the overall survival, progression free survival (PFS), response rate, immunogenicity and safety in both treatment groups. Results: Seventy patients were included in the study: 41 AA and 29 GBM. The median cumulative dose was 3600 mg of nimotuzumab and the median antibody number of doses was 16. The combination of nimotuzumab and radiotherapy was very safe. The most prevalent related adverse events included grade 1-2 nausea, fever, tremors and anorexia. There was no increasing toxicity with repeated drug exposure. No anti-idyotipic response was detected. The mean and median survival time for subjects treated with nimotuzumab and RT was 31.06 and 17.76 months while the mean and median survival time for controls was 21.07 and 12.63 months, respectively. For the evaluable patients of the AA stratum, the median survival time was 44.56 months (active drug) vs. 14.6 months (control). For the evaluable patients in the GBM cohort, the median survival time was 16.06 months (nimotuzumab arm) vs. 8.36 months (placebo arm). Median PFS was 18.23 vs. 6.25 months. Conclusions: In this randomized trial, nimotuzumab continues showing an excellent safety profile and positive efficacy results in patients with high grade glioma in combination with irradiation.
Assessment of a novel immunological biomarker SNP panel from a phase III trial of Bacillus Calmette-Guérin (BCG) adjuvant treatment in stage III melanoma patients.
Authors: Chiu Connie Ging Ting , Morton Donald L. , Chong Kelly , Hoshino Mirei , Huang Sharon , Nicholl Michael Bruce , Elashoff David , Hoon Dave S. B. 
Published: March 2020

2519 Background: Melanoma is an immunogenic cancer, whereby immunotherapy in stage III patients has shown some success. However, there are no effective immune biomarker tests to identify patients most likely to benefit from immunotherapy. BCG (Bacillus Calmette-Guérin) therapy is a form of immunomodulation. The objective was to assess the predictive clinical effect of a single nucleotide polymorphism(SNP) immune biomarker panel in stage III resected melanoma patients treated with BCG. Methods: MMAIT-III was a phase III prospective randomized international multicenter trial of BCG+melanoma vaccine vs BCG+placebo after complete resection of stage III melanoma patients (NIH #NCT00052130). 120/292 patients with palpable disease treated with resection and BCG+placebo had lymphocytes(PBL) from USA sites available for analysis. Endpoints were overall survival(OS) and disease-free survival(DFS), with a 10-yr follow-up. PBL DNA was assessed by MassARRAY MALDI-TOF for 28 SNPs associated with macrophage/monocyte-related immune response pathways to BCG/tuberculosis. A pilot study(n=34) from phase II BCG trial confirmed presence of the SNPs. A logistic regression determined a SNP score, and a cutoff was identified by ROC and used as a predictor in a Cox proportional hazard model in a verification study(n=120). Results: 9 SNPs in 6 genes had prognostic value: NRAMP1 and CD14, 18, 195, 209, 282. The 9-SNP panel distinguished patients in 2 survival groups(OS median 4.9-yrs vs 1.5-yrs, p=0.0008), AUC=0.77. SNP biomarker positivity demonstrates significant association with 10-yr OS (59.7% vs 15.7%; HR 1.97, CI 1.11-3.50, p=0.018) and DFS (47.2% vs 12.3%; HR 2.35, CI 1.43-3.92, p=0.0007). In Cox model, the SNP panel was a significant predictor of OS(HR 2.69, CI 1.56-9.00, p=0.0052) and DFS(HR 2.33, CI 1.49-5.16, p=0.0003) independent of known melanoma prognostic factors. Conclusions: The 9-SNP panel identified patients with an exceptionally favourable disease outcome, and may represent a stratifying predictive SNP panel for identifying patients that are inherently responsive to BCG therapy and potentially other immunomodulating agents in melanoma.
Adjuvant dendritic cell (DC)-based vaccine therapy of melanoma patients.
Authors: Petenko Natalia N. , Mikhaylova Irina N. , Chkadua George Z. , Baryshnikov Anatoly Y. , Demidov Lev V. 
Published: March 2020

2524 Background: Earlier DC vaccine therapy demonstrated clinical benefit in some patients (pts) with advanced melanoma although the effect was seen only in pts with minimal tumor burden (ASCO2007 abstract No: 3077). As there is no effective treatment for high risk resected melanoma we conducted an exploratory trial to assess the effectiveness of DC vaccine in stage III and IV melanoma pts after radical surgery in comparison with observation. Methods: 108 stage III and IV melanoma pts were enrolled in two comparative arms. The arms were well balanced in respect with demographic and prognostic factors. The vaccine was based on mature autologous monocyte-derived DC primed with autologous tumor lysate, administered intradermally every 2-6 weeks until the disease progression. Disease free survival (DFS) and overall survival (OS) were evaluated with Kaplan-Meier method and compared between the two arms using the log rank test. Safety of DC vaccine was also monitored. Results: The vaccine arm included 56 pts (stage III – 46, stage IV – 10 pts) who were surgically rendered free of disease and treated with DC vaccine. 52 pts were enrolled in the control arm (stage III – 47, stage IV – 5 pts), they were treated surgically and observed afterwards. At a median follow-up of 22 months, the HR (DC vs observation) for DFS was 0.45 (p < 0.05; 95%CI 0.29-0.69) and for OS was 0.71 (p=0.23; 95%CI 0.40-1.25). 60% of pts in the DC arm remained alive at this time point. Risk reduction significantly correlated with the strong delayed type hypersensitivity reaction induced by vaccine in 31 (55%) out of 56 vaccinated pts. The vaccine was safe and well tolerated although vitiligo was registered in 4 cases which was associated with more durable time to progression and OS. Conclusions: The immunotherapy with DC vaccine is safe and significantly improves DFS compared with observation in the adjuvant treatment of stage III and IV melanoma.
A mismatch between methods and objectives in phase I drug development: Statistical limitations and personalized medicine—A California Cancer Consortium (CCC) study.
Authors: Frankel Paul Henry , Shibata Stephen , Groshen Susan G. , Longmate Jeff , Pal Sumanta Kumar , Khoo Stella , Newman Edward M. 
Published: March 2020

2538 Background: Patient variation in drug response and toxicity impacts all phases of drug development. While detailed sample-size calculations and analysis based on statistical methodology are critical for addressing variation in late stage trials, phase I studies pose unique and largely unsolved challenges related to variability. Changes in patient selection during the study, small sample-sizes and large patient variation in toxicity are exactly the kind of problems that statistical methods cannot address in small, isolated phase I studies, regardless of apparent mathematical rigor. We have documented these problems via a physician survey. Methods: A 10-question anonymous survey was sent to 670 oncologists at National Comprehensive Cancer Network (NCCN) and CCC institutions via an online survey. 19 % (126/670) of the oncologists polled responded. 78/126 (62%) specialized in Medical Oncology. The number of years in practice varied from 2-45 yrs with a median of 17 yrs. Results: a) 66% of all respondents stated that non-DLT toxicities on one dose level would impact their patient selection on the following dose level, conflicting with the assumption of random patient selection implicit in simulations used in evaluating statistical designs. b) Only 13% stated a desire to target a non-heme toxicity as high as 20% grade 3, while 87% desired a 10% or less grade 3 rate; c) More than half the respondents would prefer not to escalate if 3/3 patients experienced grade 2 LFTs; d) 82% of the respondents thought the appropriate target toxicity differed for patients depending on their potential for becoming a surgical candidate, furthering the need for personalized dosing. Conclusions: Statistical methods in phase I trials are unable to address many of the salient features of phase I study conduct and investigator goals. We will present several approaches we have initiated to address these limitations, and present future plans to help produce a more reliable estimate of a recommended dose. Supported in part by NCI grants U01CA062505, N01-CM-62209, and NCCN data collection assistance.
Prediction of early death among patients (pts) enrolled in phase I trials: Development and validation of a new model based on platelet count and albumin level.
Authors: Ploquin Anne , Olmos David , Lacombe Denis A. , A'Hern Roger , Duhamel Alain , Twelves Christopher , Marsoni Silvia , Morales Rafael , Soria Jean-Charles , Verweij Jaap , Voest Emile E. , Schoffski Patrick , Schellens Jan H. M. , Kramar Andrew , Arkenau Hendrik-Tobias , Kaye Stanley B. , Penel Nicolas 
Published: March 2020

2540 Background: Selecting pts with “sufficient life expectancy” for phase I oncology trials remains challenging. The Royal Marsden Model (RMM; Arkenau, JCO 2009) identified high-risk pts as those with ≥2 of: albumin (ALB) <35g/l; LDH >ULN; more than 2 metastatic sites. The RMM was assessed in 1845 pts treated in phase I trials by members of the European New Drug Development Network (ENDDN). The present study aimed to develop an alternative prognostic model using a different methodology and to compare its performance with the RMM. Methods: The primary endpoint was 90-day mortality rate (90-DMR). The new model was developed from the ENDDN database using CHAID, an exploratory non-parametric data analysis method evaluating the relationship between a dependent variable (90-DMR) and possible predictive variables through a decision-tree analysis. The ROC characteristics and calibration of both methods were then validated in the independent EORTC Database (n=341 pts). Results: The CHAID method identified low and high-risk groups with 90-DMR of 9.5% vs 37.5%. High-risk pts had ALB<33g/L or ALB≥33g/L but platelet count ≥400.000/mm3. Applying both models to the validation dataset; the rates of correctly-classified pts were 0.86 [CI-95% 0.82-0.90] vs. 0.67 [CI-95% 0.60-0.74], with the CHAID model and RMM respectively. The CHAID model had higher specificity (0.90 vs. 0.65), but lower sensitivity (0.36 vs. 0.93) than the RMM. Discriminative slopes were similar for the CHAID model and RMM (19.4% and 19.3%, respectively). The negative predictive value (NPV; correct identification of pts surviving 90 days) was similar for the CHAID model and RMM (0.94 [0.91-0.97] and 0.99 [0.94-1.00] respectively). Calibration, assessed by the Brier score, was slightly better with the CHAID model (0.001 and 0.098, respectively). Conclusions: In selecting pts for phase I trials arguably an important criterion is NPV; the CHAID model and RMM provided a similar high level of NPV but the CHAID model gave a better rate of correctly-classified patients. Both models improved the screening process and reduce the attrition rate in phase I trials.
How to run survival-endpoint phase II trials with 25% to 40% fewer patients.
Authors: Schell Michael J. , Haura Eric B. , Kim Jongphil , Han Gang , Simon George R. 
Published: March 2020

2544 Background: New molecular information, whether arising from expression profiling, identification of key mutations, or proteomic analyses is making the personalization of therapy increasingly feasible. This leads to the fragmentation of common disease entities into multiple molecular subtypes. Having sufficient numbers of patients to demonstrate the effectiveness of novel targeted therapies for each subtype has therefore become challenging, essentially impeding progress. Methods: Use of sample size determination software allows for comparison of phase II trials with a target survival proportion at a given time T based upon Kaplan-Meier versus exponential survival methods. Results: The use of exponential survival fitting methods, in lieu of the currently implemented trial designs, to single arm phase II studies can routinely reduce patient numbers by 25-40% (Table) without compromising the statistical power. The biggest advantage is that survival information both before and after time T reduces the variability for the exponential fit estimate. This approach will lead to the saving of financial and patient resources for researchers. Moreover, the time saved will accelerate the approval of agents making the proposed trial designs ethically attractive. However, this approach is only applicable if the exponential distribution assumption behind the approach is valid. Conclusions: The exponential survival fitting method should replace the current standard approach in all instances unless the exponential distribution assumption is known to be false. Detailed examples and analysis will be presented. [Table: see text]
First-in-human phase I and pharmacokinetic study of DTS-108 in patients with advanced carcinomas.
Authors: Coriat Romain , Faivre Sandrine J. , Dreyer Chantal , Mir Olivier , Bouattour Mohamed , Goldwasser Francois , Raymond Eric 
Published: March 2020

2557 Background: DTS-108 is a soluble pro-drug of SN38, the active metabolite of irinotecan, where the SN38 moiety is covalently linked to a 20AA peptide through a specific cross-linker that releases SN38 by esterase bond cleavage. DTS-108 was designed to achieve therapeutic levels of SN38, while reducing diarrhea. Methods: This trial identified the pharmacokinetics, the adverse event (AE) profile (NCI-CTCv3 criteria), the dose limiting toxicities (DLT) at cycle 1, the maximum tolerated dose (MTD), and the recommended phase II dose (RD) of intravenous DTS-108 (1-2 hours) every two weeks (q2w) in patients (pts) with advanced/metastatic carcinomas, ECOG:0-1, and adequate hepatic, marrow, and kidney functions. Results: Forty-Two pts received DTS-108 across 14 dosing cohorts (range: 3-416 mg/m2). All grade AEs were asthenia (43%), nausea (43%), diarrhea (41%), vomiting (33%), anemia (31%), rash (21%), anorexia (21%), alopecia (19%), abdominal pain (19%), and neutropenia (19%). Grade 3 diarrhea was only reported in two pts with either partial bowel obstruction or recent history of a total colectomy. Neutropenia was the dose limiting toxicity of DTS-108. Neutropenia started to be observed at doses >56 mg/m2. At 416 mg/m2, 3/6 pts had grade 4 neutropenia. Infusion related reactions (itching urticaria) were observed with increasing frequency and severity at doses >75 mg/m2 and required antihistamine premedications. At 313 mg/m2 and 416 mg/m2, infusion skin reactions were 2/6 pts and 6/6 pts, respectively. Fluorescence HPLC was initially used to quantify DTS-108 and its metabolites (SN-38 and SN-38G). Sample stability analysis of this method showed that SN38 values were inaccurate as DTS-108 degraded forming ex-vivo SN-38 during the blood collection, plasma storage, and/or sample extraction. New processes and analytical LC/MS/MS methods for testing SN-38 were implemented. At the dose of 313 mg/m2, mean DTS-108, SN38, and SN38G AUCINF (CV%) were 439293 (24%), 1992 (34%), and 4538 (46%) h*ng/mL. Tumor stabilization (RECIST) was observed in 9 pts and confirmed in 6 pts. Conclusions: DTS induced neutropenia and infusion skin reactions but no dose-limiting diarrhea. The MTD was 416 mg/m2 and the RD was 313 mg/m2 q2w.
Phase II trial of a GM-CSF-producing and CD40L-expressing cell line combined with allogeneic tumor antigen as a novel vaccine for metastatic lung adenocarcinoma.
Authors: Creelan Ben C. , Antonia Scott , Noyes David , Hunter Terri B. , Simon George R. , Bepler Gerold , Williams Charles C. , Tanvetyanon Tawee , Haura Eric B. , Schell Michael J. , Dessureault Sophie , Chiappori Alberto 
Published: March 2020

2559 Background: We created a vaccine in which irradiated allogeneic lung adenocarcinoma cells are combined with a bystander K562 cell line transfected with hCD40L and hGM-CSF. By recruiting and activating dendritic cells, we hypothesized the vaccine would induce tumor regression in metastatic lung adenocarcinoma. Methods: Intradermal vaccine was given every 14 days x3, followed by monthly x3. Cyclophosphamide (300 mg/m2 IV) was administered before 1st and 4th vaccines to deplete regulatory T-cells. All-trans retinoic acid was given (150/mg/m2/day) after 1st and 4th vaccines to enhance dendritic differentiation. Peripheral blood mononuclear cells (PBMCs) were collected at baseline and after each vaccination. T-cell activation profiles were analyzed by ELISpot assay and tested by generalized Wilcoxon for correlation to survival. Results: 24 participants were accrued at a single center from 10/2006 to 6/2008, with median age 64 and median of 3 previous lines of chemotherapy prior to entry. 20 were former smokers and 4 had brain metastases. A total of 101 vaccines were administered. Common toxicities of any grade were joint pain (79%) and fatigue (75%). Significant adverse events included a grade 3 hypotension and a grade 3 acute respiratory distress. No confirmed complete or partial radiologic responses were observed. Median overall survival (OS) was 8.0 mo (95% CI 3.5 – 12.5) and median time-to-progression was 2.4 mo (95% CI 0.3 – 4.6). Presence of HLA-A2 conferred reduced risk of progression (HR 0.37, 95% CI 0.14 -0.89, p=0.02) and trend to improved OS (HR 0.59, p = 0.06). Of 14 participants with evaluable PBMCs, 5 demonstrated sustained tumor peptide-specific T-cell activation after vaccination. Ex vivo peptide immune response correlated with improved OS compared to non-responders (23 vs. 7 mo, HR 0.48, p = 0.04). Conclusions: Vaccine administration was feasible and tolerable in a heavily pretreated population of metastatic lung cancer. These data suggest the vaccine has clinical activity in the subset with peptide-induced T-cell immune responses and warrants further investigation. A randomized trial of the vaccine is currently in development.