Tumor-infiltrating CD8+ T cells are correlated with prolonged progression-free and overall survival in epithelial ovarian cancer (EOC). A significant fraction of EOC patients mount autoantibody ...responses to various tumor antigens, however the relationship between autoantibodies and tumor-infiltrating T cells has not been investigated in EOC or any other human cancer. We hypothesized that autoantibody and T cell responses may be correlated in EOC and directed toward the same antigens.
We obtained matched serum and tumor tissue from 35 patients with high-grade serous ovarian cancer. Serum samples were assessed by ELISA for autoantibodies to the common tumor antigen NY-ESO-1. Tumor tissue was examined by immunohistochemistry for expression of NY-ESO-1, various T cell markers (CD3, CD4, CD8, CD25, FoxP3, TIA-1 and Granzyme B) and other immunological markers (CD20, MHC class I and MHC class II). Lymphocytic infiltrates varied widely among tumors and included cells positive for CD3, CD8, TIA-1, CD25, FoxP3 and CD4. Twenty-six percent (9/35) of patients demonstrated serum IgG autoantibodies to NY-ESO-1, which were positively correlated with expression of NY-ESO-1 antigen by tumor cells (r = 0.57, p = 0.0004). Autoantibodies to NY-ESO-1 were associated with increased tumor-infiltrating CD8+, CD4+ and FoxP3+ cells. In an individual HLA-A2+ patient with autoantibodies to NY-ESO-1, CD8+ T cells isolated from solid tumor and ascites were reactive to NY-ESO-1 by IFN-gamma ELISPOT and MHC class I pentamer staining.
We demonstrate that tumor-specific autoantibodies and tumor-infiltrating T cells are correlated in human cancer and can be directed against the same target antigen. This implies that autoantibodies may collaborate with tumor-infiltrating T cells to influence clinical outcomes in EOC. Furthermore, serological screening methods may prove useful for identifying clinically relevant T cell antigens for immunotherapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Spatial skills have been shown in various longitudinal studies to be related to multiple science, technology, engineering, and math (STEM) achievement and retention. The specific nature of this ...relation has been probed in only a few domains, and has rarely been investigated for calculus, a critical topic in preparing students for and in STEM majors and careers. We gathered data on paper-and-pencil measures of spatial skills (mental rotation, paper folding, and hidden figures); calculus proficiency (conceptual knowledge and released Advanced Placement AP calculus items); coordinating graph, table, and algebraic representations (coordinating multiple representations); and basic graph/table skills. Regression analyses suggest that mental rotation is the best of the spatial predictors for scores on released AP calculus exam questions (β = 0.21), but that spatial skills are not a significant predictor of calculus conceptual knowledge. Proficiency in coordinating multiple representations is also a significant predictor of both released AP calculus questions (β = 0.37) and calculus conceptual knowledge (β = 0.47). The spatial skills tapped by the measure for mental rotation may be similar to those required to engage in mental animation of typical explanations in AP textbooks and in AP class teaching as tested on the AP exam questions. Our measure for calculus conceptual knowledge, by contrast, did not require coordinating representations.
Abstract
BACKGROUND
Checkpoint inhibitors have shown efficacy in other solid tumors and are being studied in glioblastoma. For patients treated with anti-PD-1 monoclonal antibodies, such as ...pembrolizumab, CSF concentrations and blockade of PD-1 on T cells present in the CSF have not been reported. Such information would provide valuable context for applying checkpoint inhibitors for the treatment of CNS malignancies.
METHODS
CSF and blood samples were obtained from 6 glioblastoma CAR T cell study patients who received intraventricularly administered CAR T cells. These patients were also treated with pembrolizumab 200 mg intravenously every 3 weeks. Pembrolizumab levels in CSF and blood were measured using an ELISA assay. FACS analysis for PD-1 blockade was performed on endogenous and CAR T cells detected in CSF samples, and the results were compared to cells in CSF without pembrolizumab treatment.
RESULTS
Data analyzed from 3 patients samples so far show that average pembrolizumab levels in the CSF and serum were 330 ± 114 ng/mL and 64 ± 8 µg/mL, respectively. The average CSF/serum ratio was 0.5 ± 0.1%. In 1 patient from whom multiple CSF/blood samples were obtained over 3 months, steady-state CSF levels ranged from 155–394 ng/mL throughout each 21 day cycle of pembrolizumab. PD-1 was completely blocked on both endogenous T cells as well as CAR T cells that were delivered directly into the CSF.
CONCLUSIONS
To our knowledge, this is the first report of pembrolizumab concentrations in the CSF after intravenous administration. CSF levels were 0.5% of serum concentrations and remained stable throughout a 21 day cycle of pembrolizumab. PD-1 was found to be blocked on endogenous T cells in the CSF. Furthermore, even though they were relatively low, pembrolizumab levels in the CSF were sufficient to block PD-1 on intraventricularly administered CAR T cells.
Hong Kong's resistance to be a signatory of the 1951 Geneva Convention and lack of domestic policies in this area has resulted in restrictions on access to healthcare amongst asylum seekers and ...refugees (ASRs). Using social determinants of health framework this study sought to identify health practices, problems and needs of African ASRs in Hong Kong.
A cross-sectional survey comprising of six domains including health status, health-seeking behaviour and social experience targeted at adult African ASRs in Hong Kong was conducted through three local non-governmental organisations between February and April 2013. Outpatient care and inpatient care in the past 12 months were used as proxy measures of general and severe ill health respectively. Associations between the determinants of health factors with general or severe health was explored through logistic regressions.
Majority of 374 participants were young, single, educated males having been in Hong Kong for over 5 years. A third of ARS (36.1 %) screened positive for depression. Most reported problems related to basic necessities (64.7-78.6 %) and access to health services (72.2 %). ASRs with relatively less education, health awareness or higher risk behaviours were less likely to have obtained outpatient or inpatient services. African ASRs reporting problems with case officers (aOR = 2.80; 95 % CI = 1.35-5.79) or illness in the past 30 days (aOR = 6.00; 95 % CI = 2.94-12.25) were more likely to report general ill health. Similarly, problems with the case officers (aOR = 3.76; 95 % CI = 1.97-7.18) and self-reported illness in the past 30 days (aOR = 3.32; 95 % CI= 1.68-6.57) were also significantly associated with severe ill health. At the health system level, those who reported experiencing difficulties accessing the medical services in Hong Kong are 3.29 (95 % CI = 1.48-7.31) and 4.12 (95 % CI = 1.73-9.79) times as likely to report general and severe ill health respectively.
The host government should have moral and ethical obligations to attend to the health needs of ASRs. Evidently a number of structural and health system factors have significantly impacted the health of African ASRs in Hong Kong. Changes to current policies regarding how African ASRs are handled whilst in Hong Kong but, more immediately, improvements in healthcare access are needed.
Background: Novel targeted treatment options with fixed or minimal residual disease (MRD) guided duration are warranted for patients with R/R CLL. Post-treatment MRD has proven to predict outcome in ...patients receiving chemo-immunotherapy (CIT). With the BTK inhibitor ibrutinib as a single agent, rarely undetectable MRD (uMRD) is seen despite high long-term efficacy. The Bcl-2 inhibitor venetoclax + CD-20 targeting antibody results in a significant proportion of patients with uMRD; early data indicating correlation of MRD status with progression free survival in R/R CLL.
Aim: The aim of the VISION / HOVON 141 phase 2 study is to evaluate feasibility of MRD-guided treatment cessation and reinitiation in patients with R/R CLL upon venetoclax + ibrutinib combination treatment.
Methods: Patients received ibrutinib monotherapy (420 mg daily) for two (28-days) cycles. Venetoclax ramp up initiated during cycle 3, reaching full dosage of 400 mg daily from start of cycle 4 with continued combination treatment for a further 12 cycles; totaling 15 cycles. Patients reaching at least partial remission (PR) and uMRD in blood and bone marrow (by central flow cytometry, <10-4 level) at cycle 15 day 15 are randomized 1:2 between maintenance ibrutinib or observation (stopping therapy); patients becoming MRD positive (>10-2) during observation reinitiate combination treatment with the same regimen. Patients MRD positive at cycle 15 remain on ibrutinib maintenance therapy until progression. Registered at clinicaltrials.gov: NCT03226301.
Results: Enrollment is complete with 230 patients; the first 24 patients with uMRD have been randomized between observation and ibrutinib maintenance after 15 cycles of treatment. This preplanned interim analysis includes data only for the first 51 eligible patients reaching the time point for 15 cycles of treatment. With a median age of 67 years (range 40-83), 71% male, 65% WHO performance status 0, 84% Binet stage B/C, 71% receiving prior standard CIT, 18% TP53 aberrations (deletions and/or mutations) and 57% IGHV unmutated status (both centrally assessed), the trial population is representative of previously published RR CLL trials. Of the 51 patients, 49 completed the first two cycles of ibrutinib monotherapy and 43 (84%) patients completed all 15 cycles of treatment; discontinuation due to refusal to continue (2), toxicity or intolerance (2), 2nd malignancy (2) and death (2: tick borne encephalitis and Richter's transformation). Grade 2 adverse events (AEs) were experienced as the highest grade by 16% of patients, while 50% and 26% experienced grade 3 and 4 AEs, respectively. For AEs of special interest (≥grade 2), 10 (20%) patients were reported with atrial fibrillation and 7 (14%) with bleeding (grade 2, except one grade 3 bleeding).
Response evaluation was available for 42 out of the 51 patients according to investigator assessed IWCLL criteria based upon CT and bone marrow assessment at cycle 15. Complete remission (CR) was reached for 29 patients and PR for the remaining 13 patients with full IWCLL assessment, while data collection is ongoing for the remaining patients (see figure 1). The depth of peripheral blood (PB) response continued to improve during the treatment period with 55% reaching uMRD at cycle 15 while 39% also obtained uMRD in bone marrow aspirate (intention to treat analysis, see figure 2). Thus, the concordance between uMRD status in PB and BM is 71% with the remaining 29% having low MRD+ (below 10-2) in BM while uMRD in PB (figure 2).
Conclusion: Treatment with ibrutinib and venetoclax in the setting of R/R CLL demonstrates a favorable benefit-risk profile consistent with the known safety profile for the individual drugs. An increasing uMRD rate reaching 55% in PB and 39% in bone marrow by cycle 15 was demonstrated. The uMRD rate in PB is similar to what has previously been reported with the venetoclax + obinutuzumab combination for R/R CLL (Seymour et al., NEJM, 2018), while the CR rate was more than doubled with ibrutinib + venetoclax. The concordance between PB and BM MRD status indicate that treatment response can be followed mainly by PB testing. The DSMB recommends continuing of the study. This ongoing trial will assess feasibility and outcome of MRD guided targeted therapy for R/R CLL.
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Niemann:Novo Nordisk Foundation: Research Funding; Astra Zeneca: Consultancy, Research Funding; Sunesis: Consultancy; Acerta: Consultancy, Research Funding; CSL Behring: Consultancy; Roche: Other: Travel grant; Janssen: Consultancy, Other: Travel grant, Research Funding; Gilead: Other: Travel grant; Abbvie: Consultancy, Other: Travel grant, Research Funding. Enggaard:Gilead: Other: Advisory board; Abbie: Other: Advisory board; Janssen: Other: Advisory board. Mous:Abbvie: Honoraria; Takeda: Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; MSD: Honoraria; Roche: Honoraria; Sandoz: Honoraria. Poulsen:Abbvie: Other: Ad Board; Janssen: Other: Ad Board; Gilead: Other: Ad Board. Frederiksen:Abbvie: Research Funding; Janssen Pharmaceuticals: Research Funding; Novartis: Research Funding; Alexion: Research Funding; Gilead: Research Funding. Janssens:Janssen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; idem consultancy: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; abbvie: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Levin:Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant ; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant . Kater:Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding.
Usage of the combination of ibrutinib and venetoclax in the relapsed/refractory setting for CLL. Both drugs are approved for this indication but not in combination.
Abstract
OBJECTIVES: Folate receptor alpha (FolRα) is a cell-surface glycoprotein, highly expressed in ovarian and endometrial adenocarcinoma, and thus a promising target for cancer therapy using ...antibody drug conjugates (ADCs). Most ADCs currently in development are generated by random attachment of the cytotoxic payload to the antibody and result in a heterogeneous mixture, comprised of many different forms that are likely to vary in stability and activity, and therefore may be suboptimal therapeutic agents. We have employed an E. coli cell-free expression system (XpressCFTM) and site-specific conjugation technology, to generate STRO-002, a novel homogenous FolRα-targeting ADC. STRO-002 was optimized by selection of the antibody, drug-linker, conjugation site and drug-antibody ratio (DAR) that conferred the best pharmacological properties. We have conducted preclinical studies to evaluate the stability of STRO-002 and characterize the pharmacological properties of the cytotoxic metabolite SC209. In vitro cytotoxicity assays and in vivo efficacy studies were conducted to evaluate the activity of STRO-002 in multiple ovarian cancer cell lines and xenografts. IND enabling toxicology studies were conducted to determine the safety profiles for STRO-002 and its metabolite SC209 in cynomolgous monkeys and rats, respectively.
RESULTS: Based on optimization studies, the anti-FolRα human IgG1 antibody (H01/SP8166) conjugated to a proprietary cleavable drug-linker (SC239) was selected for the lead ADC STRO-002. SC239 contains a tubulin-targeting 3-aminophenyl hemiasterlin warhead, SC209, which has potent cytotoxic activity. Based on most favorable anti-tumor activity, positions 180 and 404 on each heavy chain were selected for conjugation of SC239 to SP8166 to yield an ADC with DAR of ~ 4.
The drug-linkage in STRO-002 is highly stable and the released warhead, SC209, is a very weak substrate for cellular drug-resistance efflux pumps and is cleared rapidly from plasma. STRO-002 has potent but highly specific cytotoxic activity (0.1-3 nM) on multiple FolRα-positive ovarian cancer cell lines in vitro and anti-tumor efficacy in ovarian xenograft models. STRO-002 exhibits dose-dependent tumor growth inhibition in Igrov-1 tumor xenografts at a single dose and complete regression is achieved in Igrov-1 and OVCAR-3 tumors with a single dose at 10 and 5 mg/kg, respectively. In addition, administration of STRO-002 in combination with carboplatin confers added benefit in efficacy in Igrov-1 tumors. Toxicology studies show favorable safety profiles for STRO-002 and SC209. The main toxicity finding in monkeys dosed up to 9 mg/kg consists of reversible hematopoietic/lymphoid tissue toxicity, which is considered antigen-independent and is consistent with the anti-proliferative effects of SC209 observed in single-dose toxicology studies in rats. No evidence of ocular toxicity due to SC209 were observed in either species.
CONCLUSIONS: STRO-002 is a highly specific FolRα targeting ADC with minimal drug moiety release in circulation and the potential for an improved safety and activity profile, and a reduced risk of tumor drug resistance. Our data supports the advancement of STRO-002 to the clinic as a potential treatment of FolRα expressing malignancies such as ovarian cancer.
Citation Format: Cristina Abrahams, Stellanie Krimm, Xiaofan Li, Sihong Zhou, Jeffrey Hanson, Mary Rose Masikat, Krishna Bajjuri, Tyler Heibeck, Dharti Kothari, Abigail Yu, Robert Henningsen, Cuong Tran, Gang Yin, James Zawada, Julie Hang, Maureen Bruhns, Willy Solis, Alexander Steiner, Adam Galan, Toni Kline, Ryan Stafford, Alice Yam, Venita I. De Almeida, Mark Lupher, Jr., Trevor Hallam. PRECLINICAL ACTIVITY AND SAFETY OF STRO-002, A NOVEL ADC TARGETING FOLATE RECEPTOR ALPHA FOR OVARIAN AND ENDOMETRIAL CANCER abstract. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-090.
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Background: Because treatment options for localized prostate cancer (PCa) have similar survival outcomes but varying side effects, it is important that patients are meaningfully ...involved in the decision-making process to ensure the chosen treatment aligns with their needs, wants and preferences. Here, we describe PCa patients’ experience with informed decision-making as well as treatment patterns and trends over time. Methods: Focus groups were conducted with 47 men treated for PCa across Canada to understand their cancer journey experience. Thematic analysis was conducted. A subset of this data on informed decision-making is described. Men (≥ 35 years) diagnosed with localized, low-risk PCa from 2011-2013 were identified using data from six provincial cancer registries. Treatment data were identified by linking hospital/cancer centre data with registry data. Descriptive statistics were generated to describe treatment patterns and trends. Results: Focus group participants expressed a desire to be involved in the treatment decision-making process. While many participants felt completely informed about the treatment choices available to them, others felt they had not been properly engaged in the treatment decision-making process. Some participants felt they had opted for surgery or radiation therapy (RT) without full knowledge of the trade-offs between potential benefits and side effects. Others felt they may have made different decisions about their care had they been more informed. From registry data, in 2013 surgery was the most common primary treatment for men with low-risk PCa ranging from 12.0% in New Brunswick to 41.7% in Nova Scotia. RT was the second most common ranging from 6.4% in New Brunswick to 18.3% in Saskatchewan. Varying majorities of men had no record of surgical or radiation treatment, a proxy for active surveillance. Treatment trends over time suggest an increase in the use of non-active treatment approaches from 60.7% in 2011 to 69.9% in 2013. Conclusions: System performance indicators yield useful information about oncology practice patterns and trends. This information is enhanced when combined with patient level information on how men felt about decision-making around their PCa care.
Hereditary transthyretin (ATTRv) amyloidosis is an autosomal dominant disease linked to transthyretin gene mutations which cause instability of the transthyretin tetramer. After dissociation and ...misfolding they reassemble as insoluble fibrils (i.e. amyloid). Apart from the common Val30Met mutation there is a very heterogeneous group of non-Val30Met mutations. In some cases, the clinical picture is dominated by a rapidly evolving restrictive and hypertrophic cardiomyopathy.
A case series of four liver recipients with the highly clinically relevant, rare and particularly aggressive Val122del mutation is presented. Medical and surgical therapeutic options, waiting list policy for ATTRv-amyloidosis, including the need for heart transplantation, and status of heart-liver transplantation are discussed.
Three patients needed a staged (1 patient) or simultaneous (2 patients) heart-liver transplant due to rapidly progressing cardiac failure and/or neurologic disability. Domino liver transplantation was impossible in two due to fibrotic hepatic transformation caused by cardiomyopathy. After a follow-up ranging from 3.5 to 9.5 years, cardiac (allograft) function was maintained in all patients, but neuropathy progressed in three patients, one of whom died after 80 months.
This is the first report in (liver) transplant literature about the rare Val122del ATTRv mutation. Due to its aggressiveness, symptomatic patients should be prioritized on the liver and, in cases with cardiomyopathy, heart waiting lists in order to avoid the irreversible neurological and cardiac damage that leads to a rapid lethal outcome.
Abstract
Simultaneous assessment of cell surface phenotypic markers, activation markers such as CD69 and apoptosis related markers such as CD95/FAS can provide deeper understanding of mechanism and ...impacts of in vitro mitogenic stimulation on immune cell populations.. Kinetic and dose response studies of PBMC’s with different stimulants was performed and followed with novel simplified assays that could assess levels of CD69 and CD95 on T and B cells followed by plate-basedmicrocapillary flow cytometry. Information on the CD4, CD8, CD3,CD19, CD45 expression levels was also obtained. Our results demonstrate that while CD4 expression on CD4 T cells was rapidly downregulated with phorbol myristate acetate or combinations with ionomycin, but was not impacted by PHA treatment. Tracking of CD95 expression levels demonstrate the elevation of CD95 on T and B cells with PHA treatment with no significant loss in CD4 expression levels. Correlation of T celll activation markers and apoptotic markers and expression levels of phenotypic markers would facilitate further elucidation of the mechanism of T cell activation.
Objective
To develop and test the validity of an Objective Structured Assessment of Technical Skills (OSATS) tool for breech presentation delivery.
Materials and methods
Monocentric prospective study ...conducted in the Department of Gynecology, Obstetrics, Fetal Medicine and Reproductive Medicine at the University Hospital of Nice. The study consisted of two parts, the development of the OSATS scoring system and its objective validation. Several experts in obstetrics from university hospital centers and private French hospitals were invited to participate in the development phase of the scoring system. For the validation phase, we formed a group of 20 novices and a group of 20 experts, who had to perform a breech presentation delivery on a simulator, according to a standardized scenario. Each participant was filmed and two experts would then evaluate their performance by viewing anonymized videos and using the OSATS score.
Results
The scores obtained by the expert group were significantly higher than those of the novice group, with a total score of 21.73/25 versus 6.95/25 (
p
< 0.0001), a task-specific score of 87.2/110 versus 44.3/110 (
p
< 0.0001) and an overall score of 108.93/135 versus 51.25/135 (
p
< 0.0001), respectively.
Conclusion
The OSATS score developed in this study for breech presentation delivery is a reliable model to assess the competence level in procedural skills using a simulator.
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