bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adoptive T-cell therapy (ACT) with TILs for metastatic melanoma: Clinical responses and durable persistence of anticancer responses in peripheral blood.
Authors: Donia Marco , Andersen Rikke , Ellebaek Eva , Iversen Trine Zeeberg , Andersen Mads Hald , thor Straten Per , Svane Inge Marie 
Published: March 2020

3028 Background: TIL treatment holds the promise to introduce a new treatment paradigm into oncology practice. To demonstrate the logistical feasibility of this complex approach in Europe, at Herlev Hospital, Denmark, we have initiated a trial for patients with metastatic melanoma and evaluated the melanoma-specific immunity in the peripheral blood. Methods: We present the updated results of trial NCT00937625. The study takes place in a medium-size academic center (30 in-patient oncology beds) equipped with a 36 square meters cGMP cell production lab integrated in a hematopoietic stem cell transplantation unit. Patients were treated with autologous TILs preceded by standard lymphodepleting chemotherapy but followed by attenuated regimens of IL-2 (n=6 low-dose s.c. for 14 days; n=9 i.v. intermediate decrescendo dose). Melanoma-specific responses were assessed with intracellular cytokine staining. Results: We have generated TILs from 28/31 patients, with 15 patients treated so far and many TILs cryopreserved for future use. Patients were treated with an average of >50x109 CD4+, CD8+and a small but consistent fraction of γδ TILs. The lower doses of IL-2 have significantly decreased the classical toxicity of the treatment associated with more harsh IL-2 regimens, and response evaluation showed the achievement of three CR lasting > 1 year and four PR. Clinical responses were associated with high numbers of tumour reactive T-cells infused. Importantly, in most responding patients we observed induction and durable persistence (up to 1 year) of anti-melanoma T-cell responses in the peripheral blood. Conclusions: A high response rate including durable complete responses can be induced after treatment with TILs followed by an attenuated regimen of IL-2, which significantly reduced the occurrence of severe side effects. Effective TIL treatment is associated with induction and long-term persistence in the blood of T cells producing in vitro anticancer responses. By showing that TIL-based ACT is logistically feasible and accessible to medium-size academic centers, we open the possibility for testing this treatment in a large randomized setting in Europe. Clinical trial information: NCT00937625.
Allogeneic dendritic cell (DC) vaccination as an “off the shelf” treatment to prevent or delay relapse in elderly acute myeloid leukemia patients: Results of phase I study.
Authors: van den Loosdrecht Arjan A , Santegoets Saskia , Wetering Sandra van , Singh Satwinder Kaugh , Koppes Malika , Hall Anthony , de Gruijl Tanja D. , Ossenkoppele Gert J. , Kruisbeek Ada M 
Published: March 2020

3029 Background: Vaccines against tumor-associated antigens represent an appealing strategy for preventing tumor recurrence. A novel immunotherapy platform is represented by the DCOne cell line, which originates from a human myeloid leukemia cell line, endogenously expresses a range of tumor associated antigens and can be differentiated into mature dendritic cells. Methods: A phase I study enrolled 12 AML patients (age range 58-71) who were either in CR1/CR2 (n=5) or had smouldering disease (n=7), at high risk of relapse and ineligible for available post-remission therapies, in a 3+3 design, starting with 4 bi-weekly intradermal DCOne DC vaccinations of 10E6 cells (n=3), 25E6 (n=3) or 50E6 (n=6). Patients were monitored for clinical and immunological responses for 126 days and surviving patients were followed up after study completion. Results: Treatment was well tolerated in all patients, with expected toxicities of injection site reactions (< grade 2). During the study 3 patients died: 2 from infections and 1 from leukemia. Patients who survived more than 6 months post-vaccination showed remarkable survival (22 mo after the first patient was recruited, 3 patients have been alive for 22, 20 and 16 months respectively). One patient with smouldering AML at entry achieved CR2 after vaccination; one patient who was in CR2 at entry, relapsed 8 mo after vaccination and entered CR3 following a single low dose of 5-AZA. Remarkably, 1/5 patients that were evaluable by IFNg ELIPOTs showed vaccination-induced specific T cell responses to WT-1 and PRAME, antigens present in DCOne DC. In addition, increased post vaccination delayed type hypersensitivity reactions were observed in all cohorts. Furthermore, induction of systemic immune responses, with increases in CD4+ and CD8+ T cell proliferative responses and/or seroconversion to DCOne DC and/or AML blasts was seen in 5 out of 9 patients. Conclusions: Vaccination with DCOne derived DC is feasible in AML, generated cellular and humoral immune responses, and interesting clinical responses. The hypothesis that immune responses correlate with clinical benefit will be investigated in a randomised phase II trial. Clinical trial information: NCT01373515.
Risk of HCC recurrence with cellular immunotherapy following radiofrequency ablation.
Authors: Cui Jiuwei , Li Wei , Wang Nanya , Zhao Hengjun , Jin Haofan , Niu Chao , Wang Guanjun 
Published: March 2020

3031 Background: Although radiofrequency ablation (RFA) has brought promising therapeutic outcome in hepatocellular carcinoma (HCC) treatment, the curative rate was compromised by high recurrence and metastasis after RFA. Immunosupression in patients with HCC is an important factor leading to its recurrence and metastasis. This study was designed to observe the efficiency and safety of application of cellular immunotherapy (CIT) after RFA for HCC patients. Methods: Sixty-two patients with HCC who were treated with radical RFA were divided into two groups: RFA alone (32 patients) and RFA/CIT (30 patients). Autologous mononuclear cells were collected from the peripheral blood and separated by apheresis, and then induced into natural killer cells, γδT cells, cytokine-induced killer cells. These cells were identified by flow cytometry with their specific antibodies and then were infused intravenously to RFA/CIT patients for 3 or 6 courses. The tumor recurrent status of these patients was evaluated with computed tomography (CT) every 3 months after RFA. Progression-free survival (PFS), liver function, viral load, and adverse effects were examined. Results: The median PFS in RFA group was 12.0 (9.1-14.8) months while median PFS in RFA/CIT group has not yet been reached. It indicated that sequential RFA/CIT significantly reduced the risk of HCC recurrence [hazard ratio (HR) = 0.136]. In RFA/CIT group, six courses had better survival prognosis than three courses (P <0.05). Viral load of hepatitis C decreased in two of three patients without antiviral therapy in RFA/CIT group, but was increased in RFA alone group. The RFA/CIT group maintained the hepatic function at the level before CIT. The hepatic function in 28.1% (9/32 cases) patients in RFA group was deteriorated. Only one developed fever (38.5 °C) after one infusion and recovered 2 hours later. Otherwise, there was no toxic effect in the RFA/CIT group. Conclusions: These preliminary results suggested that combination of sequential CIT with RFA for HCC patients was efficient and safe, and may be helpful in the prevention of the recurrence for the patients with HCC after RFA. It also suggested that the CIT may reduce the risk of recurrence by dual effects of anti-tumor and anti-virus.
Correlative biomarker analysis of sequential tumor biopsies in a ph I mode of action (MoA) study in neoadjuvant head and neck squamous cell carcinoma (HNSCC) patients (pts) treated with RG7160 (GA201), a novel dual-acting, monoclonal antibody (mAb) designed to enhance antibody-dependent cellular cytotoxicity (ADCC), with cetuximab (C) as reference.
Authors: Mancao Christoph , Di Scala Lilla , Delmar Paul , Temam Stéphane , Soria Jean-Charles , Spicer James F. , McGurk Mark , Delord Jean-Pierre , Sarini Jerome , Halama Niels , Evers Stefan , Passioukov Alexandre 
Published: March 2020

3035 Background: GA201 is a novel humanized anti-epidermal growth factor receptor (EGFR) mAb with a dual MoA: glycoengineered to enhance ADCC on top of inhibition of EGFR signaling. In an open-label, multi-center trial of pts with HNSCC, an exploratory biomarker analysis of sequential tumor biopsies was performed to investigate the single/duplex marker correlation structure. Methods: Pts received 2 doses of 700 or 1,400 mg GA201 or C (day 1, 8). Tumor biopsies were taken at baseline (BL) and pre-surgery (day 15). Immunohistochemistry immune-cell counts (single/duplex markers), EGFR-pathway markers and intra-tumoral cytokines (LUMINEX) were assessed. Advanced exploratory statistical methods were used to analyse inter-relationship between BL and on treatment markers, and with response (as determined by FDG-PET). Results: All immune markers (single and duplex) presented highly heterogeneous median values at BL, but cluster analysis emphasized their strong inter-correlation. These markers were unrelated to the BL tumor EGFR and pERK expression. Strongest bivariate correlation was seen between (CD16, CD68), (CD3, 4, 8) and (CD4, NKp46). GA201 treatment induced positively correlated dynamic changes (chg) between (CD8, CD68), while C did so for (CD4, CD16) and (CD16, CD68). Strong and negative correlation between (CD56chg, PETchg) was seen only in pts treated with 1,400 mg GA201. Intra-tumoral cytokines like CXCL12 showed good correlation with BL CD3, 16 and 68 infiltration. Principle component analysis also confirmed a good association between most BL immune markers and was able to differentiate strongest PET responders in the 700 mg GA201 cohort. Conclusions: Multivariate statistical methods were used to demonstrate strong interdependencies between immune-effector markers and to highlight their promising associations with response to GA201 treatment, likely due to ADCC processes in the tumors. Clinical trial information: NCT01046266.
Relationships of peripheral blood lymphocyte counts (PBLC) with antitumor activity of NGR-hTNF given in combination with chemotherapy (CT).
Authors: Bulotta Alessandra , Gregorc Vanesa , Rossoni Gilda , Todisco Gabriele , Viganò Maria Grazia , Ammannati Cristina , Mazzola Giulia , Lambiase Antonio , Bordignon Claudio 
Published: March 2020

3038 Background: Antitumor effects of NGR-hTNF (N), a tumor-targeted antivascular agent, are driven at low dose by an early vessel stabilization that greatly enhances both intratumoral CT uptake and T-cell infiltration. Synergism with CT was shown in immunocompetent mice, but not in nude mice lacking functional T cells. Methods: By an individual patient pooled analysis of 396 patients (pts) from 7 ph II trials in 6 tumor types, we estimated the effects of baseline PBLC on the antitumor activity of N (with or without CT) and CT alone. Low dose N (0.8 μg/m2) was given in combination with CT in 171 pts. Control groups of 140 and 85 pts receiving N and CT alone, respectively, were also analyzed. CT was doxorubicin or a platinum-based regimen. In all trials, response to therapy was assessed every 6 weeks by RECIST. Endpoints of interest were response rate (RR, complete plus partial response), disease control rate (DCR, RR plus stable disease), duration of response (DOR) and progression-free survival (PFS). In logistic and Cox regression analyses, PBLC data were dichotomized in high or low levels by the median cutpoint (1.5/mL; 95% CI, 1.4-1.6). Multivariate models included age, sex, PS and tumor type as covariates. Results: In both N-alone and CT-alone groups, there was no statistically significant difference in treatment effect according to baseline PBLC. Conversely, high PBLC were related to better treatment outcome in the N plus CT group, compared to low PBLC. In this N plus CT group, high PBLC (vs low) were associated with higher RR (OR=2.8; 95% CI, 1.2-6.3; p=.01) and DCR (OR=2.6; 1.3-4.9; p=.004), and with longer DOR (HR=0.39; 0.16-0.96; p=.04) and PFS (HR=0.60; 0.43-0.85; p=.004). For high vs low PBLC, RR was 29% vs 14%, DCR 76% vs 57%, median DOR 8.2 vs 6.3 months, and median PFS 5.0 vs 3.0 months, respectively. On multivariate analyses, high PBLC remained an independent predictor of increased RR (OR=2.7; p=.01) and DCR (OR=2.6; p=.005), and improved DOR (HR=0.36; p=.04) and PFS (HR=0.60; p=.005). Conclusions: Consistently with preclinical data, these results highlight the potential value of PBLC in predicting tumor response to NGR-hTNF in combination with CT, which merits further clinical validation Clinical trial information: NCT00994097-NCT00484432-NCT00484276-NCT00484211-NCT00483509-NCT00483080-NCT01358071.
Effect of vaccination with autologous tumor-loaded dendritic cells on intratumoral regulatory T cells in metastatic melanoma patients.
Authors: Guidoboni Massimo , Granato Anna Maria , Ancarani Valentina , Pancisi Elena , Petrini Massimiliano , Riccobon Angela , Fiammenghi Laura , Drago Francesco , Ridolfi Laura , De Rosa Francesco , Nanni Oriana , Valmorri Linda , Lanza Giovanni , Serra Luigi , Verdecchia Giorgio Maria , Migliori Giuseppe , Amadori Dino , Ridolfi Ruggero 
Published: March 2020

3040 Background: Vaccination with dendritic cells (DC) is still a valid experimental option for metastatic melanoma (MM). However, only a few patients experience long-lasting objective responses and the majority of clinical responders afterwards relapse and die. Which mechanisms are actually responsible for this “secondary resistance” to whole tumor antigens-loaded DC vaccines is largely unknown. It has been hypothesized that suppressive immune cell subpopulations, regulatory T cells in particular, may progressively accumulate in tumor tissues thus hampering therapy-induced antitumor immune responses along time. To elucidate this issue we evaluated changes induced by immunologically effective DC vaccination in the composition of tumor-associated T cell subpopulations. Methods: 12 patients with MM previously enrolled in a phase I/II DC vaccine trial and for which tumor tissue taken before and after at least 4 induction vaccine doses were available, were included in the study. Intratumoral lymphocytes were evaluated by CD3, CD4, CD8, FoxP3 and GrB immunostainings, and quantified by a computer-assisted method. A nonparametric two-tailed Wilcoxon signed-rank test was utilized for evaluating differences in the distribution of the number of cell positive for each marker on the total cell counts in pre- and post-vaccine biopsies. Results: Our data showed a considerable and statistically significant decrease of intratumoral FoxP3+regulatory T cells in melanoma tissues after DC vaccination. In addition, the concurrent increase of intratumoral activated cytotoxic T lymphocytes, as shown by CD8 and Granzyme B stainings, indicated that this decrease has likely a functional relevance. Conclusions: Our findings that vaccination with DC loaded with autologous tumor lysate strongly reduces the intratumoral content of regulatory T cells add strength to the rationale for the development of potentially more effective combination schedules where whole tumor antigen-loaded DC vaccine prime and partially activate tumor-specific low-affinity T cells in a first tumor antigen-focusing step, followed by boosting with non-maximal doses of anti-CTLA-4 antibodies.
T-regulatory cell function analysis in locally/regionally advanced melanoma patients treated with ipilimumab.
Authors: VanderWeele Robert Alan , Butterfield Lisa H. , Lin Hui-Min , Cunningham Diana E. , Lin Yan , Kirkwood John M. , Tarhini Ahmad A. 
Published: March 2020

3041 Background: We conducted an immunogenicity and biomarker analysis in stage IIIB-C melanoma patients treated with neoadjuvant ipilimumab (ipi) and reported a significant increase in the frequency of circulating T-regulatory cells (T-reg) (CD4+CD25hi+ Foxp3+; p=0.02 CD4+CD25hi+CD39+; p=0.001) from pre-ipi (baseline) to post-ipi (6 weeks) in treated patients (Tarhini et al., ASCO 2012). Also, increases in T-reg were associated with improved PFS (p=0.034; HR=0.57). We hypothesized that ipi induces its clinical activity in part through its effect on T-reg, and despite the observed increase in circulating T-reg frequency; their suppressor function is reduced. Methods: Patients were treated with ipi (10 mg/kg IV q3weeks x 2doses) bracketing definitive surgery. PBMC were collected at baseline and at 6 weeks. T-reg were isolated from pre-ipi (baseline) and post-ipi (6 weeks) PBMC samples utilizing Miltenyi Biotec T regulatory isolation kit (CD4+CD25+CD127dim/-). Isolated T-reg were incubated with OKT3/IL-2/CD28-stimulated and CFSE-labeled CD4+CD25- responder T-cells from the same patient time point at 1:1, 1:2 and 1:5 ratios. Flow cytometery was used to evaluate the number of cell divisions of CFSE labeled responder cells and, therefore, the degree of T-reg proliferation suppression. Results: Thirty-five patients were enrolled in the study; of those, 18 patients had adequate PBMC samples with sufficient T-reg isolated for T-reg functional analysis. Preliminary analysis of the first 13 patients shows a trend toward decreased suppressive function of T-reg after treatment with ipi. Expressed as “percent of maximum inhibition”, pre- vs. post-ipi T-reg showed 61% vs. 47% suppressive activity (p=0.15) at the 1:1 ratio. Conclusions: There was a trend toward decreased suppressive function of T-reg after treatment with ipi, supporting the function modulation hypothesis. T-reg functional analysis for the remaining 5 patients is ongoing and we will perform comparative studies of changes in T-reg function with changes in T-reg frequency and clinical outcomes in the entire cohort.
A trial of autologous ex vivo expanded NK cell-enriched lymphocytes with docetaxel in patients with advanced NSCLC as second- or third-line treatment: Phase IIa study.
Authors: Park Suk-Young 
Published: March 2020

3045 Background: Cancer immunotherapy has been attractive for a long time with diverse clinical attempts and results. In particular, NK cells have received considerable attention because of their potential role in immune surveillance in vivo. MICA/B on tumor cells, known as the representative ligand for NKG2D receptor on NK cell, has been reported to be modulated by a variety of stresses including some chemotherapeutic agents and it is anticipated that enhancing MICA/B expression is contributory to anti-cancer treatment. With recent development of expanding autologous ex-vivo NK cell enriched lymphocytes (NKL), we designed a trial to augment the anti-cancer effect by co-administering NKL and docetaxel (D), one of the second-line agents in patients with advanced NSCLC. Methods: We first identified some chemotherapeutic agents, such as cisplatin and D, that induce peak MICA/B expression on HeLa cell during the 24-36 hours and designed a trial of combination of NKL with D administered within the same day. Eligible patients were 20-75 years old, ECOG PS 0-2, previously received one chemotherapy, and had stage IIIB/IV histologically proven NSCLC with measurable lesions. NKL were prepared and provided from NKBIO CO. Feasibility, adverse effect, and PFS were evaluated and compared with historical control of weekly D. Results: 19 patients were enrolled before early closure. NKL production and administration were feasible in all cases even with disseminated disease. No additional AE was observed in addition to that reported in D alone. PFS 3M and RR 10.5% with 2 PR were observed and similar to historical control (PFS 2.9M, RR 8.8%). Conclusions: To our knowledge, it seems to be the first report on the combination of NKL with D in patients with advanced NSCLC. Autologous NKL production and co-administration with D were feasible without further toxicity or complication. Benefit in PFS and RR, as compared with historical control, was not detected in this study population with advanced NSCLC, but further study to see whether the combination of NKL and chemotherapy has anti-cancer effect is desirable to be performed in low tumor burden state, such as less advanced or remission induced state.
Double-loaded mature dendritic cell (DC) therapy for non-HLA-restricted patients with advanced ovarian cancer: Final results of a clinical phase I study.
Authors: Imhof Marianne , Lipovac Markus , Angleitner-Boubenizek Lukas , Barta Johannes , Gomez Ivan , Hrdina Astrid , Krupa Ewa , Lafleur Judith , Lang Istvan , Pieta Katharin , Rottmann Heike , Imhof Martin ,   Hospital Korneuburg Gynecology Nurses
Published: March 2020

3052 Background: Prognosis of ovarian cancer remains poor after initial responsiveness to surgery and chemotherapy followed by high recurrence and mortality rates and new experimental approaches are warranted. Our goal was to evaluate a novel DC-based vaccine, which exploits a unique dual loading strategy to amplify specific anti-tumor short- and long-term immune responses to delay or even prevent recurrent and metastatic disease. Methods: Monocytes were collected via apheresis, matured into DCs and pulsed with two universal tumor associated antigens (uTAA) in our GMP facility. DCs were loaded with TERT and Survivin via two different pathways (mRNA and peptide) to elicit CD8+ and CD4+T cells directly. Endpoints of the study were tolerability and safety, immunological and clinical responses. T cell responses against the IMP and loaded antigens were evaluated by cytokine bead array (CBA) and intracellular staining assays. Results: 15 non HLA-restricted patients with advanced ovarian cancer were enrolled 8 weeks after standard treatment (surgery and chemotherapy). Each patient was vaccinated intradermally on a weekly or fortnightly basis with a maximum of 8 doses of 13*106 double loaded DCs. The majority of treatment related side effects were grade 1 fever and erythema. Overall the therapy was well tolerated. Immune response data is available for 14/15 patients, 1 was withdrawn after the first administration. The IMP leads to strong immune responses with high frequency (>90%), which is proven for both uTAAs in CD8+ as well as CD4+ T cells. A clear positive trend in progression free survival is demonstrated compared to matched historical control. Conclusions: Therapy with our unique double loaded DC vaccine was feasible, safe and well-tolerated by patients. The vaccine was highly immune stimulatory and elicited both, long-term and short-term anti-tumor immune responses, establishing a promising platform for immune therapy for ovarian cancer and all solid tumors in general. The first two authors contributed equally. Clinical trial information: NCT01456065.