bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inducing mammaglobin-A (mamA) specific HLA class I tetramer positive CD8+cytotoxic T-lymphocytes (CTL) against breast cancer by DNA vaccination
Authors: Bharat A. , Narayanan K. , Benshoff N. , Dietz J. , Gillanders W. , Fleming T. , Mohanakumar T. 
Published: March 2020

2522 Background: We recently reported that DNA vaccination using MamA, a highly expressed human (hu) breast cancer specific protein, leads to immunity against breast cancer. Here we demonstrate that the induction of breast cancer immunity following MamA DNA vaccination occurs through the expansion of CD8+ CTL by using HLA class I MamA peptide tetramers. Methods: HLA-A2+huCD8+ double transgenic mice received four (100μg) two-weekly IM injections of PCI-neo vector cloned with hu MamA gene. HLA-A2 tetramers (tet) carrying an immunodominant Mam2.1 peptide (LIYDSSLCDL) were used to monitor development of mam-A specific CD8+ T cells. Specificity of tetramers was tested against CD8+ CTL lines developed in vitro by stimulation of normal hu HLA-A2+ peripheral blood lymphocytes with TAP-2 deficient T2 cells pulsed with pooled MamA HLA-A2 binding peptides. Results: There was a sequential expansion of Mam2.1 tet+CD8+ T cells during stimulation of hu PBLs with MamA peptides in vitro (<1% pre-stimulation to >15% after six stimulations). These Mam2.1 tet+CD8+ T cells were HLA-A2 restricted and MamA specific since they revealed cytotoxicity only towards UACC-822 (HLA-A2+MamA+, 75% lysis) but not MCF-7 (A2+MamA−) or DU-4475 (A2−MamA+) breast cancer cell lines. In contrast, there was no binding of MamA peptide tetramers to control Flu-specific CD8+ CTL lines (<1%). MamA DNA vaccination, but not PCI-neo vector alone, of HLA-A2+huCD8+ mice lead to the expansion of Mam2.1 tet+CD8+ T cells (<0.7% pre-vaccination to >2.5% post-vaccination) in the peripheral blood that revealed in vitro cytotoxicity against UACC-822 (70% lysis) but not against DU-4475 or MCF-7 breast cancer cell lines. Adoptive transfer of both whole splenocytes or fractionated CD8+ T cells from vaccinated mice into immunodeficient SCID-beige mice with previously established subcutaneous hu breast cancer colonies lead to tumor infiltration of tet+CD8+ CTLs and, at 4-weeks, at least 80% tumor regression of UACC-822 but not DU4475 or MCF-7 colonies. Conclusions: MamA DNA vaccination resulted in the expansion of CD8+ CTL. The CD8+ CTL were HLA class I MamA peptide tetramer positive, HLA class I restricted and specifically lysed mamA+ human breast cancer cells both in vitro and in vivo. No significant financial relationships to disclose.
T regulatory cells (Treg) in patients with metastatic renal cell carcinoma (mRCC) decrease during sunitinib treatment: Correlations with clinical responses and T helper 1/T helper 2 (Th1/Th2) bias
Authors: Suppiah R. , Finke J. , Rini B. I. , Richmond A. , Wood L. , Elson P. , Shaheen P. , Garcia J. , Dreicer R. , Bukowski R. 
Published: March 2020

2526 Background: High numbers of regulatory T cells (Treg) and high expression of forkhead box transcription factor (FoxP3) in Treg are associated with decreased survival in various malignancies, likely via immunosuppression. Studies demonstrate Th1 suppression (IFN-γ) and Th2 (Il-4) promotion in metastatic renal cell carcinoma (mRCC) patients (pts). The aim of the present study was to determine the profile of Th1, Th2, and Treg at baseline and after 28 days of therapy with the multi-targeted tyrosine kinase inhibitor, sunitinib malate (SU11248). Further, correlation of changes in these parameters and tumor shrinkage (TS) was examined. Methods: Blood was obtained from cytokine-refractory, clear cell mRCC pts on day 1 (pre-treatment) and after 28 days of sunitinib 50mg daily. T cell cytokine expression (IL-4, IFN-γ), percentage in peripheral blood mononuclear cells of CD3+/CD4+/CD25hi+/FoxP3+ cells, and percentage of Treg that were FoxP3+ were evaluated using flow cytometry. Tumor measurements were performed after 2 cycles of therapy. Correlations between immune parameters and TS were assessed with Spearman rank correlations. Results: Ten pts were evaluable for Th1/Th2 responses; 9 for Treg. At baseline 7/10 had Th2 bias and 3/10 had Th1 bias. On day 28, pts maintained Th1 bias (n=3), switched to Th1 bias (n=3), or had decrease in magnitude of Th2 response (n=4). Additionally, a median 74.5% decrease occurred after 28 days of sunitinib in the percentage of CD3/CD4/CD25hi+/FoxP3+ in peripheral blood mononuclear cells, with a median 68.0% decrease of FoxP3+ Treg (CD3/CD4/CD25hi+) cells. Decrease in number of Treg correlated with relative change in Th1 response and Th2 bias (p<.05 for all correlations). All pts had TS including 2 pts with partial response. Degree of TS correlated with relative change in Th1 response (p=.03), and Th2 bias (p=.06), as well as the relative change in FoxP3+ Treg (p=.06). Conclusions: Our results suggest that sunitinib promotes an immunostimulatory Th1 bias and reduces Treg. This immunostimulatory mechanism may contribute to the anti-tumor effect in mRCC. Further studies are on-going. [Table: see text]
A phase I/II study of a HER2/neu (HER2) peptide vaccine plus concurrent trastuzumab
Authors: Webster D. J. , Waisman J. , Macleod B. , Dela Rosa C. , Higgins D. , Fintak P. , Childs J. , Slota M. , Salazar L. G. , Disis M. L. 
Published: March 2020

2528 Background: HER2 is a tumor antigen in breast and ovarian cancer. Vaccines targeting both Class I and II epitopes of HER2 can elicit long-lived cellular immunity. Trastuzumab increases the activity of HER2-specific T cells in vitro. This study examines the safety and immunogenicity of a HER2 peptide vaccine given with trastuzumab to augment HER2-specific immune responses in vivo. Methods: 20 HLA-A2+ subjects will be enrolled on this Phase I/II single institution trial. Eligible subjects must have stage IV HER2 overexpressing breast or ovarian cancer, stable or no evident disease on maintenance trastuzumab and a normal baseline MUGA. Subjects must have ECOG performance status 0–1, creat ≤ 2.0, bili < 1.5 × ULN, SGOT < 2 × ULN. The HER2 vaccine used in this study has been previously reported and is composed of 3 HER2 Class II epitopes encompassing Class I epitopes in their natural sequence. (Knutson et al, J Clin Investigation 107:477–484, 2001). Subjects receive 6 vaccinations + GM-CSF at monthly intervals. Primary endpoints are safety and immunogenicity. Results: To date, 14 of 20 subjects have been enrolled. A total of 77 vaccinations have been given. Of 276 reported toxicities, 88% were Grade 1; most common were constitutional symptoms (25%), injection site reactions (14%), and cytopenias (14%). 11% of toxicities were Grade 2; most common were lymphopenia (34%) and headache (19%). There was one Grade 3 toxicity (syncope 5 hours after vaccination) and one Grade 4 toxicity (stroke secondary to brain metastases in long-term follow up). Cardiac toxicity included two Grade 2 asymptomatic decreases in LVEF (54 to 49% and 64 to 45%.) The average decrease in LVEF between baseline and 9 month post-vaccine follow up was 5% ± 5.85 (n = 10). Of the 10 patients who have had immunologic analysis performed at multiple time points, 5 have developed significant T cell immunity to either HER2 overlapping peptide pools and/or HER2 peptides. Complete immunologic analysis will be presented. Conclusions: Subjects with HER2 overexpressing Stage IV cancer can be safely immunized with a HER2 peptide vaccine while receiving concurrent trastuzumab without additional cardiac toxicity. In addition, the approach is immunogenic, generating significant levels of HER2-specific T cells in the peripheral blood. No significant financial relationships to disclose.
An autologous Vγ9Vδ2 T lymphocytes cell therapy product generated by BrHPP (INNACELL Gamma Delta [IGD]) in metastatic renal cell carcinoma patients: Phase I clinical trial results
Authors: Bompas E. , Neidhardt E. M. , Rolland F. , Philip I. , Galéa C. , Salot S. , Tiollier J. , Saiagh S. , Negrier S. , Bennouna J. 
Published: March 2020

2550 Background: Vγ9Vδ2 (γδ) T lymphocytes, a peripheral blood lymphocyte subset, have shown to be directly cytotoxic against renal carcinoma cells. Lymphocytes γδ can be selectively expanded ex vivo with BrHPP (Phosphostim) and IL-2. We conducted a phase I trial, to define the dose limiting toxicities (DLT), characterize the safety profile, the pharmacodynamics and potential efficacy. Methods: Patients (pts), with progressive mRCC, PS of 0–1 and no organ dysfunction, were included. A one hour iv infusion of IGD was administered alone at cycle 1, and combined with low dose of sc IL-2 (2 MIU/m2 d1 to d7) in the 2 subsequent cycles (every 3 weeks). IGD dose was escalated from 1, up to 8 billions cells (bil). Results: 10 mRCC pts were treated in the study at 3 IGD dose levels: 1 patient at 1 bil, 6 pts at 4 bil, 3 pts at 8 bil. One patient experienced a grade (G)3 hypotension (4 bil, cycle 3), and one patient presented reversible signs of biological disseminated intravascular coagulation (8 bil, cycle 2) graded as a serious adverse event and fulfilling a DLT criteria. At all doses the treatment was well tolerated during the product alone infusion (cycle 1). The most frequent type of adverse events presented was mild to moderate flue like symptomes as fever, chills and asthenia reported during the second and third cycles in the IL-2 combined cycles. Patients presented also gastrointestinal symptoms as nausea and vomiting of grade 1 or 2. Preliminary efficacy assessment evaluation shows: 2 pts were not evaluable, 3 pts were withdrawn for disease progression at 3, 8 and 11 weeks, 2 pts maintained a stable disease for 36 and 63 weeks, and 2 pts are still under follow up with a stable disease at >91 and >124 weeks post treatment. Of note, one patient showed a 19% decrease in tumour size and another one presented a significant pain decrease leading to quality of life improvement. One other patient recently treated, is still under follow-up without progression after >16 weeks post treatment. Conclusion: IGD in combination with sc low dose IL-2 is safe, well tolerated, and shows promising antitumor signs of efficacy. These results warrant further product evaluation in phase 2 clinical trials. [Table: see text]
Evaluation of interferon-alfa 2b in a model of acute respiratory distress syndrome and pulmonary fibrosis induced by intratraqueal bleomycin in Wistar rats
Authors: Ferreira Filho A. F. , Rossari J. R. , Silva V. D. , Da Silva D. L. , Prolla J. C. 
Published: March 2020

2566 Background: The acute respiratory distress syndrome (ARDS) is a common clinical entity, characterized by severe and acute pulmonary dysfunction, caused by a non-cardiogenic pulmonary edema, secondary to an increased permeability in the alveolar-capillary barrier due to a local or systemic inflammatory reaction initiated and amplified by pro-inflammatory cytokines, mostly interleukin (IL) 1, 6 and 8, and TNF-α. Despite recent advances in intensive care, the mortality associated to this syndrome remains around 40–50%. Interferons are natural proteins with antiviral, antiproliferative, antiangiogenic and immunomodulatory properties. Interferon-α reduces the synthesis and deposition of collagen I and III in hepatic tissue in experimental models of hepatic fibrosis. Interferon-α also modulates inflammation by inhibiting the action of TNF-α. The objective of this study was to evaluate the effect of interferon-α 2b in an experimental model of bleomycin-induced pulmonary fibrosis in Wistar rats. Methods: We evaluated 34 Wistar rats that were anesthetized with ketamine 100 mg/kg by the intraperitoneal route and divided in two groups of 17 animals each. Both groups received an intratracheal instillation of 1,5U of bleomycin and 0,2ml of saline solution in the first day (D1). Starting on D1, Group B received subcutaneous interferon-α 2b in a dose of 100,000 U/Kg/day for 14 days. In the fifteenth day (D15), all rats in both groups were anesthetized with thiopental and sacrificed. Their right lungs medium lobes were prepared for histological evaluation. Hematoxylin eosin and picrosirius stains were performed on 4 μm cuts of each specimen under carefully controlled conditions. The areas of collagen in their lungs were quantified in (μm2) by digital image analysis with the Image Pro for Windows software. All statistical tests were two-sided, and P < .05 was used to indicate statistical significance. Results: The mean pulmonary fibrosis area in the group A was 28,432 μm2 versus 8,866 μm2 in group B who used interferon-α 2b (P = 0,037). Conclusions: These results shows that the use of interferon-α 2b, in this animal model of ARDS, reduced the development of pulmonary fibrosis. No significant financial relationships to disclose.
A phase II study of the cancer vaccine TG4010 alone and in combination with cytokines in patients with metastatic renal cell carcinoma (RCC)
Authors: Banu E. , Rixe O. , Linassier C. , Machiels J. P. , Baudard M. , Ringeisen F. , Velu T. , Lefrere-Belda M. A. , Limacher J. M. , Oudard S. 
Published: March 2020

2581 Background: MUC1 is a glycoprotein often over-expressed and underglycosylated in renal cell carcinoma (RCC) making it an attractive antigenic target for tumor-specific immunotherapy. TG4010 is a cancer vaccine based on a modified vaccinia virus, strain MVA, expressing both MUC1 and Interleukin 2 (MVA-MUC1-IL2). The objective of this phase II, non-randomized study was to determine the efficacy of TG4010 alone and in combination with cytokines. Methods: Thirty seven patients (pts) with progressive metastatic RCC expressing MUC1 in at least 50% of the tumour cells were treated by subcutaneous injections of TG4010, 108 pfu/inj weekly, for 6 weeks then every three weeks until progression. At progression, TG4010 was continued in combination with Interferon α2a (INF) and Interleukin 2 (IL2). Results: Treatment efficacy and toxicities were previously presented at ASCO 2005 (abstr 4653). No objective responses have been observed, however, 7 pts (19%) remained stable for more than 6 months with TG4010 alone, 3 of them more than 22 months. After progression on TG4010 alone 22 pts received TG4010 in combination with cytokines. Six pts (27%) have been stabilized more than 6 months. The median TTP were 2.6 months (95% CI, 2.4–2.9 months) for TG4010 alone and 3.5 months (95% CI, 0.2–6.7 months) for the combined treatment. There were 24 deaths, with a median OS of 19 months (95% CI, 10–27.9) for the whole population. Seven pts were treated by sorafenib after immunotherapy failure. After censoring pts at the introduction of sorafenib, the median OS was 16 months (95% CI, 6–26), with 41% of pts alive at 2-years. The most frequent adverse effects related to TG4010 were minor to moderate injection site reactions, fatigue and flu-like symptoms. Twelve out of 24 pts evaluable for MUC1 ELISpot show evidence for MUC1-specific CD8+ T cell response while 14 out of 21 evaluable for MUC1 specific T cell proliferation were responsive. Conclusions: The cancer vaccine TG4010 alone and in combination with IL2 and INF induces some disease stabilizations in pts with progressive metastatic RCC and can improve survival in a population selected for MUC1 positivity, which is a factor of poor prognosis. [Table: see text]
Phase I and pharmacological study of the novel aurora kinase inhibitor AZD1152
Authors: Schellens J. H. , Boss D. , Witteveen P. O. , Zandvliet A. , Beijnen J. H. , Voogel-Fuchs M. , Morris C. , Wilson D. , Voest E. E. 
Published: March 2020

3008 Background: AZD1152 is a specific aurora kinase inhibitor, selective for Aurora B, currently undergoing Phase I evaluation in patients with advanced solid malignancies. AZD1152 induces p53 independent cellular multinucleation and polyploidy, resulting in apoptosis. It is rapidly converted to the active moiety (AZD1152-HQPA) in plasma. This is the first human study, aimed at determining the maximum tolerated dose, dose limiting toxicities (DLT), pharmacokinetic profile (PK), and to recommend a dose and schedule for further clinical evaluation. Methods: AZD1152 is being administered as a 2-hour IV infusion given weekly in a dose-escalating manner, utilizing an accelerated titration design in patients for whom no other therapy of proven benefit exists. Patients with WHO-PS of 0-2 and adequate bone marrow, liver and renal function were eligible. Results: To date, a total of 13 patients have been recruited: 10M/3F, median age 58 yrs (range 52–71). Patients had colon cancer (n = 3), melanoma (n = 2), or various other solid tumors. Doses were escalated from 100 mg to 200, 300 and 450 mg. DLT was CTC grade 4 neutropenia in 3 patients at 450 mg, signifying a non-tolerated dose on this schedule. Bone marrow recovery was generally noted by 2 wks post-dose. Problematic non-hematological toxicities have not been reported to date. Five patients have remained on therapy for >12 wks (2 × 12+ wks, 16+ wks, 20+ wks and 28+ wks, respectively). AZD1152 is rapidly converted to AZD1152-HQPA with an apparent dose proportional increase in the systemic exposures of both. Population PK analysis of AZD1152-HQPA in the first eight patients revealed a linear three compartment model with clearance 22.4 ± 1.03 L/h. Interoccasion variability was low (CV 5.7%). Conclusions: To date, AZD1152 has been well tolerated when administered IV over 2 hours on a weekly schedule at doses up to 300 mg, however further patients are being enrolled to confirm. Neutropenia is the DLT at 450 mg and no other clinically significant toxicities have been reported. Both AZD1152 and AZD1152-HQPA appeared to have linear kinetics. Significant disease stabilization observed in this rapidly progressive disease setting supports continued clinical development. [Table: see text]
Phase I, pharmacokinetic (PK), & pharmacodynamic (PD) study of 17-dimethylaminoethylamino-17-demethoxygeldanamycin, (17DMAG, NSC 707545) in patients with advanced solid tumors
Authors: Egorin M. J. , Belani C. P. , Remick S. C. , Erlichman C. , Teneyck C. J. , Holleran J. L. , Ivy S. P. , Ramalingam S. , Naret C. L. , Ramanathan R. K. 
Published: March 2020

3021 Background: 17DMAG is a water-soluble analog of 17-allylamino-17-demethoxygeldanamycin (17AAG), the first geldanamycin compound to enter clinical trials. 17DMAG causes oncoprotein degradation by binding to heat shock protein 90 (HSP90) & has greater in-vitro activity than 17AAG. In animals treated with 17DMAG, liver toxicity is dose-limiting. The objectives of this first-in-human study are to: establish the dose-limiting toxicity (DLT); recommend a phase 2 dose; & characterize the PK & PD of 17DMAG. Methods: Using a modified accelerated schema, escalating doses of 17DMAG are given IV over 1 h daily x 5 (schedule A) or daily x 3 (schedule B) every 3 weeks. Plasma 17DMAG concentrations during cycle 1 are quantitated by LC/MS. HSP70 & ILK levels in peripheral mononuclear cells are measured by western blot at baseline & 24 h on d 1. Results: 37 pts have been enrolled. On schedule A, dose levels are 1.5, 3, 6, 9, 12 & 16 mg/m2/d (n = 20). On schedule B, the starting dose was 2.5 mg/m2/d. Based on safety information from schedule A, subsequent schedule B dose levels were 14, 19, 25 & 34 mg/m2/d (n = 17). One DLT was noted in schedule A (16 mg/m2) & consisted of reversible liver enzyme elevation. End-of-infusion (EOI) 17DMAG concentrations (33–2074 ng/ml) & AUC0–24 (200–5200 ng/ml x h) increase linearly with dose. Interpatient PK variability was substantial, with CV% of 16–59%. The daily administration schedule precluded precise definition of 17DMAG t1/2 & clearance, but estimates of t1/2 & clearance ranged from 10.8 to 77 h & 19–160 ml/min/m2, respectively. Between 0 & 24 h, 20.5 ± 8.6% (range 4–43.8%) of the administered dose was excreted in urine. HSP70 increased between 0.2 & 3.7 fold above baseline in PBMCs at 24 h at 12, 16, & 25 mg/m2. There is an indication of ILK degradation in 3 of 4 patients evaluated at 25 mg/m2. Conclusions: 17DMAG is well tolerated at current dose levels & maximal tolerated dose has not been reached. 17DMAG plasma PK are linear over the doses delivered to date, & there is evidence of a target effect as manifested by↑HSP70 & ↓ILK. Support: U01CA099168–01, U01CA62502, U01CA69912, R01CA90390 & NIH/NCCR/GCRC grants #5M01 RR 00056 & M01 RR00080 No significant financial relationships to disclose.
Differential circulation kinetics during antiangiogenic therapy of four distinct blood cell populations expressing endothelial markers
Authors: Duda D. G. , Cohen K. S. , Di Tomaso E. , Scadden D. T. , Willett C. G. , Jain R. K. 
Published: March 2020

3038 Background: Circulating endothelial cells (CECs) are evaluated as potential biomarker of antiangiogenic therapy. CD146 is an endothelial marker, but its use as a single marker to detect CECs is questionable. In addition, several sub-populations of CECs are thought to exist. Methods: We analyzed the expression of CD31, CD34, CD45, CD133 and CD146 on mononuclear blood cells and primary tissue endothelial cells by flow cytometric and immunohistochemical analyses. Furthermore, we investigated by flow cytometry the phenotype of blood cells expressing endothelial markers and evaluated their changes VEGF blockade by bevacizumab in ten rectal cancer patients enrolled in a Phase I trial. Percent values obtained at days 3 and 12 after bevacizumab infusion were compared with pre-treatment values in individual patients using the Wilcoxon signed-rank test. Results: In the blood, CD146 primarily marked cells with lymphoid markers (CD3 and CD4). CD146 was largely undetectable on blood CD31+CD45- CECs or CD34+CD133+ progenitor cells. In contradistinction, CD146 was detectable in tissues on both cellular components of the vessel wall: CD31brightCD45- endothelial cells and CD31-CD45- pericytes. The CD31+CD45- CEC population contained two distinct populations: CD31brightCD34+CD45- (viable CECs) and CD31dimCD45- (mostly non-viable CECs). Unlike CD31brightCD45- CECs and CD34+CD133+ progenitor cells, CD146+ and CD31dimCD45- cell concentration in the peripheral blood of cancer patients did not decrease during VEGF blockade. Conclusions: In the blood of cancer patients, we identified 4 distinct populations using endothelial markers. CD146 identified T lymphocytes. Within the CD31+CD45- CEC population, there were 2 distinct subpopulations, while the rare progenitor populations localized primarily within the CD45+ hematopoietic cell pool. The changes in blood concentration of these 4 cell types during anti-VEGF therapy were distinct in individual patients. These results underscore the need for further characterization and identification of new markers for CEC subpopulations for their development as biomarkers of antiangiogenic therapy. [Table: see text]