Journal articles on the topic 'Penny stocks'

The paper attempts to explain the impact of penny stock on pricing in light ofthe ICAPM as stock exchanges introduce restrictions on penny stocks trading.The study is conducted using stocks listed on the Warsaw Stock Exchange (WSE)between 1995–2012. The systematic risk and risk prices components are simulated by two chosen ICAPM applications, using different procedures of portfolio construction.The main market WSE stocks are sorted into queintile portfolios usingtwo procedures. It is assumed that elimination of penny stocks contributes to morecorrect pricing, observed with ICAPM validity, however only when simulatingalgorithm uses appropriate construction of tested portfolios. The tests were carriedout in four modes. All WSE stocks were analyzed in mode 1. Penny stockswith market values lower than 1.50, 5.00 and 10.00 PLN were excluded from thestudy in modes 2, 3 and 4. The analysis indicates that the results are in line withthe extended conjectures.

Abstract Oryginality and objective – Research on the pricing of stocks listed on developed markets shows inexplicable deviation from the pricing that could be observed with CAPM validity. A similar anomaly is found on the Polish market. Reasons for inconsistent pricing with CAPM are unknown, and they are the main objective of this research. Method – The study is conducted using stocks listed on the Warsaw Stock Exchange in 1995–2012. Quintile stock portfolios are formed on the basis of strategies widely used by investors. The study is carried out in several modes. In the subsequent modes penny stocks with the market values below 0.5, 1.5, 5.0 and 15.0 PLN are eliminated. Results – It is conjectured that both penny stocks and improper procedures for the test portfolios forming contribute to inconsistent stock pricing in light of the CAPM. The studies show that results are in line with the extended conjectures. Also, study results indicate that speculative stocks are mostly penny stocks, however, it is not possible to explicitly state that penny stock are speculative.

Penny stocks at times makes the investors wealthy by turning to be a multi-bagger stocks or erode the wealth of the investors with poor performance in volatile conditions. While there are many machine learning-based prediction models that are used for stock price evaluation, very few studies have focused on the dynamics to be considered in penny stock conditions. Though the pattern might remain the same for normal stocks and the penny stock classification, still some of the parameters to be evaluated in the process needs changes. The model discussed in this report is a comprehensive solution discussed as scope for evaluation of the penny stock pick, using trading and reporting financial metrics. Experimental study of the test data indicates that the model is potential and if can be used effectively with reinforcement learning pattern, it can turn to be sustainable solution.

There has been a steady increase in institutional ownership of penny stocks over the past decades. Nevertheless, we show that penny stocks bought by institutional investors significantly underperform other penny stocks in subsequent four quarters. This poor performance is mainly driven by quasi-indexers, i.e., institutions with passive and widely diversified investment strategies. In comparison, dedicated institutions, i.e., those with low turnover but large average investments in portfolio firms and a commitment to “relationship investing”, have marginally significant ability in trading penny stocks.

Purpose – The purpose of this paper is to explore some commonly held beliefs about individuals investing in over-the-counter (OTC) stocks (those traded on Over-the-counter Bulletin Board (OTCBB) and Pink Sheets), a fairly pervasive activity. The authors frame the analysis within the context of direct gambling, aspirational preferences in behavioral portfolios, and private information. Design/methodology/approach – Contrary to popular perceptions, the modeling of the deliberate act of buying OTC stocks at a discount brokerage house finds that unlike the typical lottery buyers/gamblers, OTC investors are older, wealthier, more experienced at investing, and display greater portfolio diversification than their non-OTC investing counterparts. Findings – Behavioral portfolio investors (Shefrin and Statman, 2000) invest their money in layers, each of which corresponds to an aspiration or goal. Consistent with sensation seeking and aspirations in behavioral portfolios, OTC investors also display higher trading activity. Penny stocks seem to have different characteristics and trading behavior than other OTC stocks priced over one dollar. Irrespective of the price of OTC stocks, the authors find little evidence of information content in OTC trades. Originality/value – The paper provides insight into individual investor decision making by empirically exploring the demographic and portfolio characteristics of individuals trading in OTC stocks.

Walruses in Canada are currently subdivided into seven stocks based on summering areas; Western Jones Sound (WJS), Baffin Bay (BB), Penny Strait-Lancaster Sound (PS-LS), North Foxe Basin (N-FB), Central Foxe Basin (C-FB), Hudson Bay Davis Strait (HB-DS) and Southern and Eastern Hudson Bay (SE-HB). In this study, walrus were sampled from six of the seven stocks (SE-HB samples were not available) and genotyped at 10 microsatellite loci. All stocks were genetically diverse (average heterozygosity of 0.58) with no evidence of inbreeding (average FIS of 0.03). We detected significant genetic differentiation among the stocks and a pattern of genetic spatial autocorrelation that suggests a moderate effect of geographic distance on gene flow among stocks. Bayesian clustering suggested the six recognized stocks were elements of two larger genetic clusters - a northern Arctic population (containing BB, WJS, and PS-LS stocks) and a central Arctic population (containing C-FB, N-FB, and HB-DS stocks). These populations are moderately differentiated (FST = 0.07), but based on evidence of contemporary movement from assignment tests, are not completely isolated. There was support for maintaining the WJS stock and a combined BB+PS-LS stock, although the latter conclusion is based on a small sample size. Similarly, there was some evidence suggesting separation of the Foxe Basin stocks from the HB-DS but not the N-FB from the C-FB stock. However, given that there are morphological and chemical differences between N-FB and C-FB stocks, there is currently insufficient evidence to support a revision of the current stock designations.

In presenting economic puzzles, I have three goals in mind: some puzzles are chosen to stimulate research; others offer examples that will help undergraduate and graduate teaching; all should provide quality distractions during seminars. This feature begins with reader's comments on the first “Puzzles.” Next are several speed puzzles, with answers provided at the end. Here we have two Fischer Black problems in finance and a dot game from Richard Zeckhauser. Following are several longer puzzles, for which readers are challenged to submit their own answers. This issue's longer problems give you a chance to think about strategies for staying ahead (in sailboat racing to R&D racing) and not losing your head at an auction. The responses will be discussed in a future issue.

Surveys to estimate walrus abundance at terrestrial haulout sites in the Penny Strait-Lancaster Sound (PS-LS) and West Jones Sound (WJS) stocks were conducted in 1977 and 1998-2009. The Minimum Counted Population (MCP) was similar in 1977 (565) to recent years (557) for the PS-LS stock. The MCP for the WJS stock was higher in recent surveys (404) than in 1977 (290). Regression analysis of MCP and density (number of walrus divided by number of haulouts surveyed) showed no significant trends over time. We also calculated bounded count estimates for comparison. Finally, we used broad-scale behavioural data to estimate the proportion of the total stock that could be considered countable, to produce two adjusted estimates. We selected recent surveys with good coverage and ignored adjusted estimates that were lower than MCP. For the PS-LS stock, the adjusted MCP (with 95% CL) was 672 (575-768) and 727 (623-831) walrus in 2007 and 2009, respectively. For WJS, the best estimates were the adjusted MCP of 503 (473-534) in 2008 and the adjusted bounded count of 470 (297-1732) in 2009. While both stocks appear to have remained stable over three decades, differences in survey coverage and possible differences in walrus distribution make precise population estimation difficult.

<span style="font-family: Times New Roman; font-size: small;"> </span><p style="margin: 0in 0.5in 0pt; text-align: justify;" class="MsoNormal"><span style="font-family: Times New Roman;"><span lang="EN-GB" style="color: black; font-size: 10pt; mso-ansi-language: EN-GB;">This research investigates the market reaction to an information-based manipulation called stock spams. The impact is focused on the liquidity variable which is measured by </span><span lang="EN-GB" style="font-size: 10pt; mso-ansi-language: EN-GB;">Amivest ratio. Using the event study methodology on a sample of penny stocks for the period February 2006 through October 2008, our findings suggest <span style="color: black;">positive and significant abnormal liquidities for stocks targeted by manipulators during the event window. Robustness checks were performed using a non-parametric test. These results support the thesis that this kind of manipulation is a very flourishing business that manipulators exploit by simply purchasing stocks at low prices and selling them at higher prices. </span></span></span></p><span style="font-family: Times New Roman; font-size: small;"> </span>

abstract With millions of Americans leaving the workplace during the Great Resignation, Arthur Miller’s 1980 play The American Clock continues to be a relevant and prescient barometer for our current socioeconomic climate. Whether Americans were speculating in penny stocks leading up to the Great Depression or using online platforms to bet on “meme stocks” and cryptocurrency today, or whether naively trusting in Rockefeller or Elon Musk as economic saviors spouting esoteric pecuniary wisdom, Miller’s play is a timeless mirror reflecting the foibles of human nature. Miller’s adaptation of historical figures such as Jesse Livermore not only scrutinizes the greed and gullibility of 1920s America but also informs current economic and social dynamics. Like much of Miller’s work, the play includes autobiographical elements, with the Baum family corresponding to the Miller family’s experience during the Depression. This article demonstrates how The American Clock remains relevant in the twenty-first century.

This work focuses on Value at Risk (VaR) and Expected Shortfall (ES) in conjunction with the so called, low price effect. In order to improve forecasts of risk measures like VaR or ES when low price effect is present, we propose the low price correction which does not involve additional parameters and instead of returns it relies on asset prices. The forecasting ability of the proposed methodology is measured by appropriately adjusted popular evaluation measures, like MSE and MAPE as well as by backtesting methods. For illustrative and comparative purposes a real example from the Athens Stock Exchange as well as a number of penny stocks from Nasdaq, NYSE and NYSE MKT are fully examined. The proposed technique is always applicable, but its superiority and effectiveness is evident in extreme economic scenarios and severe stock collapses. The proposed methodology that pays attention not only to the asset return but also to the asset price, provides sufficient evidence that prices could contain important information which could if taken under consideration, results in improved forecasts of risk estimation.

The economic crisis has forced managers of joint stock companies to look for short-term solutions for the sharp changes in stock prices of their companies. Even the companies of the V4 countries are not the exception. The authors have focused on those companies where have been used either reverse stock split or stock split. They analyzed the effects of the reverse stock split or stock splits on the abnormal returns of stocks. In this paper, the authors analyzed a dataset from 1993 until 2015 with 124 reverse stock splits and 184 stock splits in total focused on the stock market in V4. Based on their own research they conclude that when reverse stock splits were used stock returns significantly decreased one day around the announcement date. They conclude that managers of a company might use this instrument to move the stock price back to the optimal trading range outside of the penny stock area. In the case of stock splits, the authors concluded that the use of this tool results in a significant increase in the returns of a stock after the announcement date. However, the results are in contrast to some former studies which found no positive effect on the returns caused by stock splits. The authors conclude that managers of a company might use this instrument to transport information content of future (positive) performance of a company to the traders. Keywords: Vysegrad group countries, normal stock split, reverse stock split, abnormal returns. JEL Classification: G11, G23, G32

This study examines several aspects of the momentum strategies, such as profitability, risk-based explanation, and decomposition of the momentum profits. For this purpose, we use weekly and monthly data of 581 firms listed at the Pakistan Stock Exchange (PSX) for the period 2004-2014. We found the presence of momentum profits over short and long-horizons, while majority of the contrarian profits were observed only in the presence of penny stocks that have share prices of PKR 10 or less. As a robustness check, we computed returns through the weighted relative strength scheme (WRSS) procedure and average cumulative abnormal returns (ACARs). Interestingly, the results reported through WRSS have shown a similar pattern to that obtained through average cumulative abnormal returns (ACARs). Further, to know which factor contributes more to momentum and contrarian profits, we used the model proposed by Lo and MacKinlay (1990). Our findings show that the overreaction effect is the largest contributing factor of contrarian profits in PSX, while cross-sectional risk is the second largest factor and negatively affects the contrarian profits. Moreover, the lead-lag effect contributes positively to the contrarian profits. Similarly, the largest contributing factor for momentum profits is the underreaction effect, whereas cross-sectional risk is the second largest factor that positively affects momentum profits. Unlike contrarian profits, lead-lag effect reduces the momentum profits in the PSX.

Keynes (The General Theory of Employment, Interest and Money, Harcourt Brace and Co., New York, 1936) had rightfully argued that picking stocks is akin to a beauty contest. The chances of winning are amplified if one's choice matches the likelihood of the panel's choice. In this era of financialization, where profit-making has shifted to speculative sways rather than fundamental trade and commodity production measures (Krippner, Socio-Econ Rev 3(2): 173-208, 2005), similar beauty contests have become even more acute. Online, real-time media channels along with pervasive investments applications have ushered in unprecedented online financial information and retail investor interest, ranging from dealing in penny stocks to sentiment-based trading. More than information sources, similar investment sites compete to recommend investment directions and strategies, not driven by strict fundamentals used by “arbitrageurs” or rational speculators but on pseudo-signals proffered by various information investment channels with varying degrees of credibility. This behavior, referred to herein as information activism, concomitantly adds a sociopsychological dimension to the concept of financialization (Lagoarde-Segot, Int Rev Financial Anal 2016) – wherein technology-driven information reach and range contribute to financial dominance of financial actors and practices. Using information activism as a lens, this research empirically evidences the extent to which information activism affects retail investor behavior under various market conditions. This study examines the differential effects of two primary, albeit reputable, sources of information activism: an investment news channel (CNBC – Mad Money) and an online financial blog (SeekingAlpha), and the effect on investor behavior during the 2008 financial crisis. In identifying the specific downstream effects of information activism on capital markets and investor behavior, factors related to investor behavior, such as trading volume and price reaction, are analyzed surrounding information activism events. Results indicate that retail investors appear to rely on online information activists during uncertain economic conditions. Findings denote that abnormal returns are associated with information activism during uncertain economic conditions and for buy recommendations when information asymmetry is high. Abnormal trading volume is also associated with information activism during economic uncertainty and with buy recommendations when information asymmetry is high particularly for stocks exchanges where unsophisticated investors tend to trade more heavily.

Purpose: The main aim of the article is to assess the financial standing of penny companies listed on the Warsaw Stock Exchange. Design/methodology/approach: To determine the financial condition of the analyzed entities, the evaluation system was used in two analytical dimensions, i.e. economic and financial analysis in the area of operational efficiency, debt, financial liquidity and profitability, as well as statistical measures to assess the diversity of individual indicators. Findings: The results of the analysis showed that penny companies, to a large extent, were not characterized by a high degree of indebtedness, low financial liquidity or a lack of profits, which characterizes entities threatened with bankruptcy. Research limitations/implications: The result of the analysis carried out entitles us to conclude that penny companies are not entities that can be categorically classified as entities threatened with bankruptcy. Originality/value: The article is a study on the results of research in the area of the financial condition of penny companies listed on the Warsaw Stock Exchange.

Injurious nematodes were found in 201 of the investigated 670 plant stocks of 42 imported consignments. Infections by quarantine nematodes appeared in 100 stocks of 26 consignments, 15 there of including 3 or more infected plant stocks each. Root knot nematode, Meloidogyne spp., appeared in 81 stocks, i.e. 12 % of the investigated material. The infections were found in 40 plant species, relatively often in barberry, Berberis sp., and in peony, Paeonia sp.. Among garden roses, 26 out of 167 stocks investigated were infected by root knot nematodes. Root lesion nematode, Pratylenchus penetrans (Cobb) Chitwood & Oteifa, of P. convallariae Seinhorst was found in 28 plant stocks, i.e. 4 % of the investigated material. Several Pratylenchus-infected stocks were found among roses, raspberry and barberry. Potato rot nematode, Ditylenchus destructor Thorne, was found in one rose stock and related D. myceliophagus J. B. Goodey in 12 stocks of various plants. Several ectoparasitic species were found in very low numbers. Virus vectors, Trichodorus primitivus (de Man) Micoletzky and T. viruliferus Hooper, were detected in a total of four stocks, but too few for virus transmission tests. The transmissability ofthe detected nematodes was discussed, and the risks of introduction of nematode pests to the country was re-assessed.

The purpose of this study is to highlight issues of interest to researchers employing the I/B/E/S earnings and forecast data. I/B/E/S has traditionally provided per share data on a split-adjusted basis, rounded to the nearest penny. In doing so, per share amounts are comparable over time. However, because not all prior forecasts and earnings per share amounts divide precisely to a penny, adjusting for stock splits and rounding to the nearest penny can cause a loss of information. Researchers are prohibited in many cases from determining the amounts actually reported in prior years, leading to misclassified observations. We obtain actual (unadjusted) earnings and forecast data from I/B/E/S and compare results to those generated using the a djusted I/B/E/S data. We replicate prior studies and find that conclusions are affected when using the actual I/B/E/S data.

ABSTRACTStarts with an excerpt from Michael Rundell and Penny Stock, The Corpus revolution (ET30, 1992). An update on the rise and rise of electronic language corpora and their impact on dictionaries. How dramatically the world has changed since Penny Stock and I wrote about the ‘Corpus Revolution’ in 1992.At the time, it was not hard to predict that computer processing power and storage capacity would carry on doubling each year. It was already clear, too, that the arrival of the corpus would revolutionize the work of dictionary-makers – hence the title of our articles. These changes were well under way in 1992 and, sixteen years on, their effects are still being felt. In the process, dictionaries have got dramatically better – if by ‘better’ we mean that the description of language they provide corresponds more closely to the way people actually use words when they communicate with one another.

As a commercial high-grade cut flower, the marketability of herbaceous peony (Paeonia lactiflora Pall.) is limited by its short vase life in water. Si (silicon) is an alternative to improve the postharvest life of cut flowers. However, the effects of the combined application of Si and preservatives on the postharvest performance of cut peony flowers are unknown. In this study, the effects of a Si application and a preservative alone and collegial on the longevity of the vase life, water loss, antioxidant defense system, and stock carbohydrates level of cut flowers of three peony cultivars were investigated. It was observed that Si effectively prolonged the vase life, while the preservative alone, to a lesser extent, but markedly induced an early flowering and a greater flower diameter (flower open degree). The simultaneous use of Si and the preservatives not only showed larger flowers, but also improved the postharvest performance as characterized by an extended vase life and delayed the water loss. In addition, the Si supplementation dramatically intensified the antioxidant defense system (ameliorated antioxidant enzymes and alleviated ROS accumulation) in petals but did not increase the stock carbohydrates (starch and soluble sugars) levels, as compared to the treatment with the preservative alone. We show that a Si supplementation to a preservative is highly recommended for a large-scale use to promote the postharvest performance and competitiveness of marketed cut flowers.

We describe the theory and practice of real GDP comparisons across countries and over time. Version 8 of the Penn World Table expands on previous versions in three respects. First, in addition to comparisons of living standards using components of real GDP on the expenditure side, we provide a measure of productive capacity, called real GDP on the output side. Second, growth rates are benchmarked to multiple years of cross-country price data so they are less sensitive to new benchmark data. Third, data on capital stocks and productivity are (re)introduced. Applications including the Balassa-Samuelson effect and development accounting are discussed. (JEL C43, C82, E01, E23, I31, O47)

Introduction. This study analyses the economic and management trends of the company Ferrovie Elettriche Abruzzesi SA (FEA), the owner of the concession granted to build and use the Tavo railway from Penne to Pescara, and the tramway service in the city of Pescara from 1925 to 1956. Aim of the work. This study highlights how the management of concessionary companies of secondary railway lines is interconnected with the more general Italian problems of passenger and freight railway traffic management. Methodological approach. An analysis of the company's financial statements, the content of the reports by the technical bodies and the Internal Works Com- mittee, and the company's correspondence with stakeholders facilitated the reconstruction of all the internal and external causes of the crisis. Main findings. The common denominator of the crisis was the associated and growing competition from road traffic and bus services, which led to increas- ingly poor operating results for FEA. The Penne-Pescara line had a low volume of traffic, which was part of the more general ‘rail problem' that characterised Italy. Originality. Delving into the interface of accounting and the history of local pub- lic transport, this study provides a case study of ‘bad practice', which is rarely available in the scientific literature on corporate crises.

Bagehot's conception of the last resort lending function of the central bank is shared by most economists today. On several occasions, the Federal Reserve has digressed from its overall strategy of monetary control to also undertake a tactical rescue of individual banks and segments of the capital market. On three other occasions, the Federal Reserve has intervened to counter systemic risks to the financial system beyond the arena of commercial banks. The events which prompted these actions were the threat to the commercial paper market triggered by the bankruptcy of the Penn Central Railroad in June 1970, the pressures on broker-dealer firms generated by the collapse of speculation in silver in early 1980, and the near failure of the clearing and settlement systems operated by stock and commodity exchanges which occurred during the stock market crash of 1987. I was a Member of the Board of Governors of the Federal Reserve System during the Penn Central episode, and I shared in the decisions to intervene. As a Public Governor of the Commodity Exchange, I helped to formulate the policies applied during the silver speculation and in the aftermath of the stock market collapse. The discussion which follows draws on those experiences.

Fifty of 58 walruses (Odobenus rosmarus rosmarus) instrumented with satellite-linked transmitters in four areas in eastern Smith Sound, Northwest Greenland, during May and June of 2010 – 13 and 2015 provided data for this study. These animals departed from the feeding banks along the Greenland coast in June – July (average 14th June), simultaneously with the disappearance of sea ice from these areas. Most of them moved to Canadian waters in western Smith Sound. The most frequently used summering grounds were along the coasts of Ellesmere Island: on the eastern coast, the area around Alexandra Fiord, Buchanan Bay, and Flagler Bay (west of Kane Basin) and Talbot Inlet farther south, and on the southern coast, Craig Harbour. This distribution of tagged walruses is consistent with prior understanding of walrus movements in summer. In addition, however, nine tracks of these tagged animals entered western Jones Sound and four entered the Penny Strait-Lancaster Sound area, crossing two putative stock boundaries. Since these 13 tracks were made by 12 animals, one walrus entered both areas. It is possible that some of the tracked walruses used terrestrial haul-out sites in the largely ice-free areas of Jones Sound and Lancaster Sound for short periods during the summer, though this cannot be confirmed with certainty. The return migration from western Smith Sound to the wintering area in eastern Smith Sound takes place in October. The tracked walrus showed high affinity to coastal areas, while walruses moving between Greenland and Canada also used offshore areas in Smith Sound. This study demonstrates that the walrus population that winters along the northwestern coast of Greenland is shared more widely in Canada than previously thought and should be managed accordingly.

Total factor productivity growth has played a significant role in uplifting the economic development process of nations in recent years. This paper uses the recently published data of Penn World Table (PWT, 9) for six emerging economies (China, India, South Korea, Malaysia, Thailand and Taiwan) to establish a relationship between the growth of total factor productivity and its various determinants. Panel data econometric techniques are employed and the data utilized were spanning from 1955 to 2012. We found that growth of real GDP and human capital are positively and significantly related with the growth of total factor productivity. Similarly physical capital stock is although positively impacted the growth of total factor productivity but however this relationship is not significant statistically. Lastly, an inverse and significant relationship is observed between employment level and total factor productivity growth for the selected emerging economies. The study concludes that relatively richer and highly educated economies have improved their productivity while employment level has adversely affected the growth of TFP. The results of the study imply that economies should focus on income and human capital increasing policies and further to translate the benefits the focus should be on efficiency of labor rather increasing the employment level.

Las bajas tasas de crecimiento económico están directamente relacionadas con las caídas de la producción, motivo por el cual es imprescindible la innovación y un marco normativo que proteja al aparato productivo, el objetivo de esta investigación es determinar la incidencia de la innovación y calidad institucional en el crecimiento económico según el nivel de ingresos de los países a través de un análisis de correlación y causalidad por el método de Mínimos Cuadrados Ordinarios (MCO), en un modelo de crecimiento endógeno, Las bases de datos utilizadas son: World Development Indicators (WDI), Worldwide Governance Indicators (WGI) y Penn World Table (PWT). Los principales resultados encontrados son una relación positiva entre las variables excepto en el caso de los países de bajos ingresos en los que la relación entre calidad institucional y el crecimiento económico es negativa, también se comprobó una relación causal bidireccional para todas las variables con excepción del stock de capital el cual indica causalidad en el crecimiento económico sin un efecto de ida y vuelta. En definitiva, los países deben enfocar su educación a la investigación aplicada generadora de patentes, así mismo se debe trabajar y afianzar las políticas dirigidas a fortalecer la democracia en los países de ingresos bajos y medios bajos.

The very meaning of “culture” has gone through so many transformations over the last sixty years that it is necessary to take stock of developments in this field of cultural history before suggesting—with an eye to the promises and perils of earlier practices—what new possibilities might exist for the future of the field. The post-1945 period witnessed a powerful impulse to understand culture as something more pervasive than just literature and the arts—and as something more socially and politically reverberant than the shibboleth of “art for art's sake.” In 1957, at the very beginning of the modern practice of cultural history, Richard Hoggart'sThe Uses of Literacyfound the high and low hierarchies embedded in it. It focused on working-class culture (e.g., glossy magazines, films, “penny dreadfuls”), and on how reading was changing under the impact of mass media. By 1976, Raymond Williams needed to draw attention to the complexity of the wordculture, so extended had its purview become over the previous two decades. Linda Nochlin asked why they were no great women artists, and T. J. Clark, using a Marxist framework, sought to understand aesthetic modernism by interrogating the historic circumstances that had led to the breakdown of the academic system.The New Cultural History, edited by Lynn Hunt, came out in 1989. Its “models” for cultural history were the work of Michel Foucault, Clifford Geertz, Natalie Zemon Davis, E. P. Thompson, Hayden White, and Dominick LaCapra, and its “new approaches” came from Mary Ryan, Roger Chartier, Thomas Laqueur, and Randolph Starn. These scholars were legislators of discourse and narrative, of popular and working-class culture, of gender, epistemes, and thick description. With many other tendencies, often defined by their focus on theoretical explication and elaboration, these approaches had the effect of deterring scholars from reengaging with the traditional interests—even theraison d'etre—of cultural history, namely, art, architecture, theater, dance, music, and literature. This turning-away also affected the very composition of humanities and interpretive social science departments, which added many new subjects of study but, inevitably perhaps, let others wither away.

Abstract Background: CTL019 is an investigational therapy derived from autologous T-cells expressing a CD19-specific chimeric antigen receptor (CAR). A single center, phase I/IIa trial of CTL019 showed complete and durable remissions in pediatric/young adult patients (pts) with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) (Maude et al NEJM 2014); these results have yet to be reproduced in a multicenter setting. Here, we report results from a 6-month interim analysis of the first multicenter phase II trial of an engineered cell therapy in leukemia. Methods: 9 US sites participated in this single-arm phase II study in pediatric/young adult pts with R/R B-ALL. Leukapheresis products were shipped for centralized manufacturing according to the University of Pennsylvania (Penn) process in an academic-industry collaboration. T cells were transduced with a lentiviral vector encoding a CAR composed of anti-CD19 scFv, CD3ζ and 4-1BB domains. Following lymphodepletion with fludarabine and cyclophosphamide, a single dose of CTL019 cells was administered (target dose 2.0-5.0×106 cells/kg for ≤50 kg and 1.0-2.5×108 cells for >50 kg). The primary endpoint was overall remission rate (ORR = CR + CRi [CRi, complete remission with incomplete blood count recovery] maintained at 2 evaluations ≥28 days apart) as determined by an Independent Review Committee. Secondary objectives included minimal residual disease (MRD), relapse-free survival (RFS), overall survival (OS) and safety. All analyses were performed on infused patient set. Results: 29/35 pts enrolled (82.9%) were infused with CTL019; 6 withdrew prior to infusion (2 manufacturing failures [1 lack of growth, 1 contamination]; 4 deaths [median, 48 days from enrollment; 2 progressive disease, 1 multi-organ failure, 1 pneumonia]). Mean bone marrow involvement at enrollment was 68.2% (SD, 27.3%; Table 1). 2 pts did not receive lymphodepleting chemotherapy due to leukopenia. Collection, manufacturing and infusion were feasible in a multicenter setting with a median time from enrollment to infusion of 37 days. Target cell dose was met in 24/33 (72.7%) manufactured products. ORR in all infused pts was 69.0% (20/29 pts; 98.95% CI 43.6, 88.1). Of the 5 pts who received CTL019 below the target dose, 2 achieved CR/CRi. Of note, deep remission with no evidence of MRD (<0.01%) was achieved in 18/29 pts (62.1%; 95% CI 42.3, 79.3) within 6 months. Median RFS and median survival have not yet been reached. Median duration of follow-up was 6.4 months (range 0.4-14.0). CR/CRi was not achieved in 9 pts: 2 pts died before Day 28 (1 ALL; 1 embolic stroke not attributed to CTL019 at Day 25 after infusion), 6 did not respond and 1 pt achieved CRi at Day 28 but relapsed 17 days later. Of the 20 pts who achieved a CR/CRi, 8 pts relapsed 1.7-7.6 months after onset of remission; 2 were CD19 negative. RFS and OS at 6 months (Figures 1, 2) were 66.4% and 75.7%, respectively. Serious adverse events occurred in 79.3% of pts within 8 weeks of infusion. Overall 10 deaths occurred at 0.4-8.8 months (9 ALL; 1 embolic stroke); no deaths attributable to CTL019. The most common adverse event was cytokine release syndrome (CRS), which was graded on the Penn scale and managed according to a standardized algorithm. All 26 (89.7%) cases of CRS were reversible; 11 pts (37.9%) had grade 3 or 4 CRS, of which 7 (26.9%) required systemic anti-cytokine therapy, 9 (34.6%) required high dose vasopressors for hypotension, 6 (23.1%) required mechanical ventilation, 4 (15.4%) underwent dialysis. Reversible neuropsychiatric events occurred in 9 (31%) pts (1 grade 3; no grade 4), including seizures in 2 pts but no cases of cerebral edema. Conclusions: In this first multicenter trial of CAR-modified T cell therapy, CTL019 therapy was feasible and efficacious, showing a high ORR with durable remissions in pediatric/young adult pts with R/R B-ALL. Despite the high rate of toxicity with CTL019 in the R/R setting, the rate of grade 3 or 4 CRS was comparable to the single center study, and standardized management of CRS was successful in a multicenter trial with no deaths attributable to CRS. In this highly refractory population, a vast majority of eligible pts can be successfully infused in a timely fashion and outcomes appear reproducible in a multicenter setting despite a more heterogeneous population than the single center study. The trial is continuing under Novartis manufacturing. Disclosures Maude: Novartis: Consultancy. Pulsipher:Medac: Other: Travel support for a study group; Chimerix: Consultancy, Other: Advisory Board ; Jazz Pharmaceutical: Consultancy, Other: Advisory Board; Novartis: Consultancy, Other: Advisory Board, Steering Committee for Phase II Study. Grupp:Pfizer: Consultancy; Novartis: Consultancy, Research Funding. Davies:Novartis: Honoraria. Verneris:Bimogen: Other: Advisory Board. Schlis:Novartis: Honoraria. Driscoll:Novartis: Consultancy. June:Immune Design: Consultancy, Equity Ownership; Pfizer: Honoraria; Celldex: Consultancy, Equity Ownership; Novartis: Honoraria, Patents & Royalties, Research Funding; Johnson & Johnson: Honoraria; Novartis: Honoraria, Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership. Levine:GE Healthcare Bio-Sciences: Consultancy; Novartis: Patents & Royalties, Research Funding. Wood:Novartis Pharmaceuticals: Employment, Other: Stock. Yi:Novartis: Employment.

BackgroundUpadacitinib (UPA) is an oral reversible Janus kinase inhibitor. In patients (pts) with RA, UPA 15 mg once daily (QD) demonstrated better clinical responses at 12 weeks (wks) vs adalimumab (ADA) 40 mg every other week (EOW) in the phase 3 SELECT-COMPARE study; these were maintained through 3 years (yrs) in the ongoing long-term extension (LTE), along with an acceptable safety profile.[1,2]ObjectivesTo assess the safety and efficacy of UPA vs ADA through 5 yrs in the SELECT-COMPARE LTE.MethodsPts receiving background methotrexate were randomized 2:2:1 to UPA 15 mg QD, placebo (PBO), or ADA 40 mg EOW. Rescue (PBO to UPA, UPA to ADA, or ADA to UPA) was mandated for lack of response (<20% improvement in tender or swollen joint counts at wks 14, 18, or 22), or failure to achieve Clinical Disease Activity Index (CDAI) low disease activity (LDA) at wk 26. All remaining PBO pts switched to UPA at wk 26. Pts who completed the 48-wk double-blind period could continue to receive open-label UPA or ADA in the LTE for up to 10 yrs total. Rates of treatment-emergent adverse events (TEAEs) and AEs of special interest were calculated per 100 pt-yrs through 5 yrs for all pts receiving UPA or ADA. Efficacy assessments at 5 yrs were performed by original randomized group for CDAI LDA (≤10) and remission (≤2.8), and disease activity score for 28-joints C-reactive protein (DAS28[CRP]) ≤3.2 and <2.6. Radiographic progression (change from baseline in modified total Sharp score [mTSS]) and proportion of pts with no radiographic progression (change from baseline in mTSS ≤0) were assessed at 192 wks (latest available timepoint; data collected at wks 96/192/520 only) by treatment sequence. No formal statistical comparisons were performed.ResultsThrough 5 yrs, 1417 pts were exposed to UPA (4497 pt-yrs) and 579 to ADA (1472 pt-yrs). UPA was generally well tolerated, with similar rates of TEAEs, serious TEAEs, TEAEs leading to discontinuation of study drug, and COVID-related TEAEs vs ADA (Figure 1). Rates of most AEs of special interest with UPA were similar vs ADA, except for numerically higher rates of herpes zoster, creatine phosphokinase elevation, lymphopenia, and hepatic disorder (mainly transaminase elevations) with UPA. In the 651 and 327 pts originally randomized to UPA and ADA, respectively, greater proportions of pts achieved CDAI LDA and remission, and DAS28(CRP) scores ≤3.2 and <2.6, with UPA vs ADA (Table 1). Through 192 wks, similar proportions of pts treated with UPA vs ADA had no radiographic progression; mean changes from baseline in mTSS were similar, except for a numerically smaller change with continuous UPA (Table 1).ConclusionThe safety profile of UPA over 5 yrs was consistent with the 3-yr results and the integrated phase 3 safety analysis.[1,2]Consistent with the 3-yr analyses,[2]UPA continued to show numerically better clinical responses than ADA at 5 yrs. Radiographic progression remained similarly low through 192 wks with UPA and ADA.References[1]Cohen SB, et al.Ann Rheum Dis2020. doi:10.1136/annrheumdis-2020-218510[2]Fleischmann R, et al.RMD Open2022. doi:10.1136/rmdopen-2021-002012Table 1.Efficacy endpointsAt 5 yrs, by original randomized group (non-responder imputation)UPA N=651a,bADA N=327a,cCDAI ≤1036.4 (32.7, 40.1)26.9 (22.1, 31.7)CDAI ≤2.824.6 (21.3, 27.9)18.7 (14.4, 22.9)DAS28(CRP) ≤3.234.7 (31.1, 38.4)24.8 (20.1, 29.4)DAS28(CRP) <2.631.8 (28.2, 35.4)23.2 (18.7, 27.8)At 192 wks, by treatment sequence (as observed)PBO to UPA N=442UPA N=288UPA to ADA N=150ADA N=109ADA to UPA N=111Radiographic progression (change from baseline in mTSS, mean [95% CI])1.3 (0.8, 1.7)0.5 (0.2, 0.9)1.7 (0.7, 2.8)1.2 (0.5, 1.9)0.9 (0.2, 1.5)No radiographic progression (mTSS change from baseline ≤0)77.1(73.2, 81.1)80.9(76.4, 85.4)74.0(67.0, 81.0)78.0(70.2, 85.8)77.5(69.7, 85.2)Data are % of pts (95% confidence interval) unless otherwise stated.aPts rescued at or before wk 26 were considered non-responders.b252 rescued.c159 rescued.AcknowledgementsAbbVie funded this trial and participated in the trial design, research, analysis, data collection, interpretation of data, and the review and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. Medical writing support was provided by Laura Chalmers, PhD, of 2 the Nth (Cheshire, UK), and was funded by AbbVie.Disclosure of InterestsRoy M. Fleischmann Consultant of: AbbVie, Amgen, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galapagos, Galvani, Gilead, GSK, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, Biosplice, Bristol-Myers Squibb, Flexion, Gilead, Horizon, Eli Lilly, Galvani, Janssen, Novartis, Pfizer, Sanofi-Aventis, Selecta, Teva, UCB, Viela, and Vorso, Jerzy Swierkot Speakers bureau: AbbVie, Accord, BMS, Janssen, MSD, Pfizer, Roche, Sandoz, and UCB, Consultant of: AbbVie, Accord, BMS, Janssen, MSD, Pfizer, Roche, Sandoz, and UCB, Grant/research support from: AbbVie, Accord, BMS, Janssen, MSD, Pfizer, Roche, Sandoz, and UCB, Sara Penn Employee of: AbbVie, and may hold stock or options, Patrick Durez Speakers bureau: AbbVie, Galapagos, Lilly, Nordimed, and Thermofischer, Louis Bessette Speakers bureau: AbbVie, Amgen, Bristol-Meyers Squibb, Celgene, Eli Lilly, Fresenius Kabi, Gilead, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Teva, and UCB, Consultant of: AbbVie, Amgen, Bristol-Meyers Squibb, Celgene, Eli Lilly, Fresenius Kabi, Gilead, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Teva, and UCB, Grant/research support from: AbbVie, Amgen, Bristol-Meyers Squibb, Celgene, Eli Lilly, Fresenius Kabi, Gilead, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Teva, and UCB, Xianwei Bu Employee of: AbbVie, and may hold stock or options, Nasser Khan Employee of: AbbVie, and may hold stock or options, Yihan Li Employee of: AbbVie, and may hold stock or options, Charles Peterfy Shareholder of: Spire Sciences, Inc, Consultant of: Daiichi Sankyo, Eli Lilly, Five Prime, Genentech, Gilead, GlaxoSmithKline, Istesso, Labcorp, Paradigm, SetPoint, Sorrento, and UCB, Employee of: Spire Sciences, Inc, Yoshiya Tanaka Speakers bureau: AbbVie, Asahi Kasei, Astellas, BMS, Chugai, Daiichi-Sankyo, Eisai, GSK, Janssen, Lilly, Mitsubishi Tanabe, MSD, Novartis, Ono, Pfizer, Sanofi, Taisho Toyama, Takeda, UCB, and YL Biologics, Grant/research support from: AbbVie, Asahi Kasei, Astellas, BMS, Chugai, Daiichi-Sankyo, Eisai, GSK, Janssen, Lilly, Mitsubishi Tanabe, MSD, Novartis, Ono, Pfizer, Sanofi, Taisho Toyama, Takeda, UCB, and YL Biologics, Eduardo Mysler Speakers bureau: AbbVie, Amgen, AZ, BMS, Janssen, Lilly, Novartis, Pfizer, Roche, Sandoz, and Sanofi, Paid instructor for: AbbVie, Amgen, AZ, BMS, Janssen, Lilly, Novartis, Pfizer, Roche, Sandoz, and Sanofi, Grant/research support from: AbbVie, Amgen, AZ, BMS, Janssen, Lilly, Novartis, Pfizer, Roche, Sandoz, and Sanofi.

Abstract Introduction: Cellular immunotherapy with CD19-targeted chimeric antigen receptor (CAR) T cells has provided new therapeutic options for patients with high-risk hematologic malignancies. Following this therapy, patients may experience disease relapse or CAR-mediated toxicity due to cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Recent studies have confirmed that the intestinal microbiome can modulate the anti-tumor immune response to chemotherapy, immune checkpoint blockade, graft-versus-host disease after allogeneic hematopoietic cell transplantation, and adoptive cellular therapy. The contribution of the intestinal microbiome on the function of CAR T cells in vivo both with respect to their anti-tumor function and their propensity to induce toxicities is not known. Hence, in a multi-center study we analyzed the association between clinical outcomes and (1) antibiotic exposure prior to CAR T cell infusion and (2) the composition and diversity of the fecal microbiome. Methods and Results: We retrospectively collected clinical data and antibiotic exposures from patients with acute lymphoblastic leukemia (ALL, n=91) and non-Hodgkin lymphoma (NHL, n=137) treated with investigational or commercial CD19 CAR T cells at Memorial Sloan Kettering Cancer Center (MSK) and the University of Pennsylvania (Penn). We considered any antibiotic exposure between day -30 and the day of CAR T cell infusion. We focused our analysis on anaerobe-targeting antibiotics used in the setting of neutropenic fever: piperacillin-tazobactam, imipenem-cilastatin, and meropenem (here referred to as "P-I-M"). We found that forty-seven (20.6%) of 228 patients were exposed to P-I-M in the four weeks before CAR T cell infusion. Patient characteristics at the time of CAR T cell infusion were similar between the P-I-M-exposed and not-exposed groups, although a worse performance status was observed in patients with NHL treated with P-I-M. We found that overall survival (OS) was significantly decreased following CAR T cell infusion in patients exposed to P-I-M (Fig 1A; OS HR, 2.58; 95% CI, 1.68 - 3.98; p= &lt;0.001). A subgroup analysis of the patients with NHL also demonstrated decreased OS associated with P-I-M exposure whether the costimulatory domain was CD28 or 4-1BB (data not shown). Next, we queried whether patients exposed to P-I-M had more aggressive disease. We evaluated potential confounders for the findings in uni- and multi-variable models. Importantly, exposure to P-I-M remained a strong predictor of decreased OS (HR, 2.58; 95% CI, 1.55 - 4.3; p= &lt;0.001) (Table 1). Exposure to P-I-M was also associated with increased ICANS (p= 0.023) but not CRS (p= 0.058) in patients in the combined NHL and ALL cohort as well as in patients with NHL (CRS: p= 0.154, ICANS: p= 0.002) (data not shown). We also prospectively collected baseline fecal samples prior to cell infusion from CD19 CAR T cells recipients (n=48) at MSK and Penn. Samples were submitted for 16S RNA sequencing of the V4-V5 region on the Illumina MiSeq platform and the amplicon sequence variants (ASVs) were annotated according to the NCBI 16S database using BLAST. In comparison to healthy controls (n=30), we found that alpha-diversity was significantly lower in fecal samples from CAR T cell patients (p= 0.0023, Fig 1B) and the composition of fecal samples was significantly different (p= &lt;0.001, Fig 1C). Finally, linear discriminant analysis effect size (LEfSe) identified an increased abundance of Lachnospiraceae, Ruminococcaceae, and Bacteroidaceae in patients who achieved a Day 100 complete response (CR) and those who experienced CAR-mediated toxicity (data not shown). Conclusion: Our results suggest that exposure to antibiotics, in particular P-I-M, in the four weeks before therapy was associated with worse survival. Profiling of the baseline fecal microbiome samples by 16S revealed that CD19 CAR T cell patients presented with evidence of an altered fecal microbiome as measured by lower alpha-diversity and a composition that is distinct from that of healthy controls. Finally, we identified bacterial taxa that were associated with Day 100 CR and CAR-mediated toxicity. Our findings indicate that the intestinal microbiome can affect the efficacy of CD19 CAR T cell therapy and provides a rationale to target the intestinal microbiome to improve clinical outcomes of patients treated with cellular therapies. Figure 1 Figure 1. Disclosures Smith: Janssen: Consultancy, Honoraria. Gomes: Xbiome: Current Employment. Schluter: Postbiotics Plus LLC: Other: cofounder. Park: Kura Oncology: Consultancy; BMS: Consultancy; Servier: Consultancy; Autolus: Consultancy; Curocel: Consultancy; Artiva: Consultancy; Kite Pharma: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Affyimmune: Consultancy; Intellia: Consultancy; Innate Pharma: Consultancy; Minerva: Consultancy; PrecisionBio: Consultancy. Palomba: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Jain: Targeted Healthcare Communications: Consultancy; Bristol Myers Squibb: Other: for advisory board participation; CareDx: Other: for advisory board participation; CTI Biopharma: Research Funding; Syneos Health: Research Funding. Pennisi: Gilead Sciences: Consultancy. Perales: Miltenyi Biotec: Honoraria, Other; Novartis: Honoraria, Other; Omeros: Honoraria; NexImmune: Honoraria; Bristol-Myers Squibb: Honoraria; Merck: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Kite/Gilead: Honoraria, Other; Medigene: Honoraria; Nektar Therapeutics: Honoraria, Other; Cidara: Honoraria; Servier: Honoraria; Sellas Life Sciences: Honoraria; Karyopharm: Honoraria; MorphoSys: Honoraria; Equilium: Honoraria; Incyte: Honoraria, Other. Garfall: Amgen: Honoraria; CRISPR Therapeutics: Research Funding; GlaxoSmithKline: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Research Funding; Tmunity: Research Funding. Landsburg: Triphase: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member; Incyte: Membership on an entity's Board of Directors or advisory committees; ADCT: Membership on an entity's Board of Directors or advisory committees; Curis: Research Funding; Takeda: Research Funding. Gerson: Kite: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy; TG Therapeutics: Consultancy. Svoboda: Imbrium: Consultancy; Genmab: Consultancy; Astra Zeneca: Consultancy, Research Funding; Atara: Consultancy; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Incyte: Research Funding; Merck: Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; TG: Research Funding. Giralt: AMGEN: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; SANOFI: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; JENSENN: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees. Gill: Interius Biotherapeutics: Current holder of stock options in a privately-held company, Research Funding; Novartis: Other: licensed intellectual property, Research Funding; Carisma Therapeutics: Current holder of stock options in a privately-held company, Research Funding. Rivière: FloDesign Sonics: Other: Provision of Services; Centre for Commercialization of Cancer Immunotherapy: Other: Provision of Services; Fate Therapeutics: Other: Provision of Services, Patents & Royalties; The Georgia Tech Research Corporation (GTRC): Other: Provision of Services (uncompensated); Juno Therapeutics: Patents & Royalties. Porter: Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Wiley and Sons Publishing: Honoraria; Tmunity: Patents & Royalties; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; ASH: Membership on an entity's Board of Directors or advisory committees; DeCart: Membership on an entity's Board of Directors or advisory committees; Genentech: Current equity holder in publicly-traded company, Ended employment in the past 24 months; American Society for Transplantation and Cellular Therapy: Honoraria; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees. Schuster: Abbvie: Consultancy, Research Funding; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; Adaptive Biotechnologies: Research Funding; BeiGene: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; DTRM: Research Funding; Genetech: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Incyte: Research Funding; Juno Theraputics: Consultancy, Research Funding; Loxo Oncology: Consultancy; Merck: Research Funding; Nordic Nanovector: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Pharmaclcyclics: Research Funding; Tessa Theraputics: Consultancy; TG Theraputics: Research Funding. Sadelain: NHLBI Gene Therapy Resource Program: Other: Provision of Services (uncompensated); Fate Therapeutics: Other: Provision of Services (uncompensated), Patents & Royalties; Atara Biotherapeutics: Patents & Royalties; Ceramedix: Patents & Royalties; Mnemo Therapeutics: Patents & Royalties; Takeda Pharmaceuticals: Other: Provision of Services, Patents & Royalties; St. Jude Children's Research Hospital: Other: Provision of Services; Juno Therapeutics: Patents & Royalties; Minerva Biotechnologies: Patents & Royalties. Frey: Novartis: Research Funding; Kite Pharma: Consultancy; Sana Biotechnology: Consultancy; Syndax Pharmaceuticals: Consultancy. Brentjens: Gracell Biotechnologies, Inc: Consultancy, Ended employment in the past 24 months; BMS: Consultancy, Patents & Royalties, Research Funding; sanofi: Patents & Royalties; Caribou: Patents & Royalties. June: AC Immune, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Consultancy; Novartis: Patents & Royalties; Tmunity, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Current equity holder in publicly-traded company. Pamer: Diversigen: Other: Advisory board; Bristol Myers Squibb, Celgene, Seres Therapeutics, MedImmune, Novartis and Ferring Pharmaceuticals: Honoraria. Peled: DaVolterra: Consultancy; MaaT Pharma: Consultancy; CSL Behring: Consultancy; Seres Therapeutics: Research Funding. Ruella: BMS, BAYER, GSK: Consultancy; Novartis: Patents & Royalties; AbClon: Consultancy, Research Funding; Tmunity: Patents & Royalties; viTToria biotherapeutics: Research Funding. van den Brink: WindMILTherapeutics: Honoraria; Pluto Therapeutics: Current holder of stock options in a privately-held company, Other: has consulted, received honorarium from or participated in advisory boards ; Priothera: Research Funding; Forty-Seven, Inc.: Honoraria; MagentaTherapeutics: Honoraria; GlaskoSmithKline: Other: has consulted, received honorarium from or participated in advisory boards; Ceramedix: Other: has consulted, received honorarium from or participated in advisory boards ; Merck & Co, Inc: Honoraria; Synthekine (Spouse): Other: has consulted, received honorarium from or participated in advisory boards; Kite Pharmaceuticals: Other; Amgen: Honoraria; Frazier Healthcare Partners: Honoraria; Seres: Other: Honorarium, Intellectual Property Rights, Research Fundingand Stock Options; Rheos: Honoraria; Therakos: Honoraria; Jazz Pharmaceuticals: Honoraria; Notch Therapeutics: Honoraria; Nektar Therapeutics: Honoraria; Wolters Kluwer: Patents & Royalties; Juno Therapeutics: Other; DKMS (nonprofit): Other; Pharmacyclics: Other; Da Volterra: Other: has consulted, received honorarium from or participated in advisory boards; Novartis (Spouse): Other: has consulted, received honorarium from or participated in advisory boards; Lygenesis: Other: has consulted, received honorarium from or participated in advisory boards .

Abstract A single-center trial of CD19 directed, lentiviral transduced chimeric antigen receptor (CAR) T cells (CTL019) for relapsed and refractory (r/r) B-ALL pediatric patients showed rates of CR >90% with prolonged CAR T cell persistence/CR without further therapy in the majority of patients infused (Maude NEJM 2014). We report here the feasibility, safety and efficacy of the first multicenter global pivotal registration CAR T cell trial. Features of this trial include: i) the first trial in which industry-manufactured cells were provided to all patients; ii) enrollment across 25 centers in the US, EU, Canada, Australia, and Japan; iii) successful transfer and manufacturing of cells in a global supply chain; and iv) successful implementation of cytokine release syndrome (CRS) management across a global trial. All patients had CD19 positive B-ALL with morphologic marrow tumor involvement at registration (>5% blasts), and were either primary refractory; chemo-refractory after first relapse, relapsed after second line therapy; or ineligible for allogeneic SCT. CTL019 was manufactured from patient PBMC under GMP conditions in the US, at a centralized "sponsor-owned" manufacturing facility, and supplied to all sites. The primary endpoint of overall remission rate (CR+CRi) within 3 months and secondary endpoints (EFS, DOR, OS and safety) were assessed by an independent review committee. Based on preliminary data as of March 2016, 57 patients were enrolled. There were 3 manufacturing failures (5%), 5 patients were not infused due to death or adverse events (9%), and 15 patients were pending infusion at the data cut off. Following fludarabine/cyclophosphamide lymphodepleting chemotherapy in the majority of the patients, 34 patients (median age 11 [3-23], 50% with prior HSCT) were infused with a single dose of CTL019 at a median dose of 2.9 x106 transduced CTL019 cells/kg (0.2 to 4). Among 29 patients reaching D28 prior to the data cutoff, 83% (24/29) achieved CR or CRi by local investigator assessment, all of which were MRD-negative. Two early deaths occurred prior to initial disease assessment, one due to disease progression and one due to intracranial hemorrhage. Two patients did not respond. One patient was in CR by BM at D28, but CSF was not assessed, therefore this patient was classified as "incomplete" assessment. Safety was managed by a protocol-specified CRS algorithm with no cases of refractory CRS. Using the Penn CRS grading scale, 82% of patients experienced CRS, with 7 grade 3 (21%) and 8 grade 4 (24%) events. 44% patients with CRS required anti-cytokine therapy; all received tocilizumab with or without other anti-cytokine therapy, with complete resolution of CRS. Besides CRS, the most common grade 3 and 4 non-hematologic AEs were febrile neutropenia (29%), increased bilirubin (21%), increased AST (21%), and hypotension (21%). 21% of patients experienced grade 3 or 4 neuropsychiatric events including confusion, delirium, encephalopathy, agitation and seizure; no cerebral edema was reported. CTL019 in vivo cellular kinetics by qPCR demonstrated transgene persistence in blood in responding patients at and beyond 6 months. Overall exposure (AUC 0-28d) and maximal expansion (Cmax) of CTL019 DNA measured by qPCR was higher in responding compared with non-responding patients. In summary, this pivotal global study in pediatric and young adult patients with r/r B-ALL receiving CTL019, confirms a high level of efficacy and a similar safety profile to that shown in the prior single center experience. Safety was effectively and reproducibly managed by appropriately trained investigators. The study has completed accrual. At the meeting, updated data from a planned formal interim analysis including safety, efficacy (primary and selected secondary endpoints), cellular kinetics, and impact of anti-cytokine therapy will be presented for more than 50 patients infused at 25 global sites. Disclosures Grupp: Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy. Laetsch:Novartis: Consultancy; Loxo Oncology: Consultancy. Bittencourt:Seattle Genetics: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Educational Grant. Maude:Novartis: Consultancy. Myers:Novartis Pharmaceuticals: Consultancy. Rives:Novartis: Consultancy; Jazz Pharma: Consultancy. Nemecek:Medac, GmbH: Research Funding; Novartis: Consultancy; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees. Schlis:Novartis: Honoraria. Martin:Jazz Pharmaceuticals: Other: One time discussion panel; Novartis: Other: Support of clinical trials. Bader:Medac: Consultancy, Research Funding; Riemser: Research Funding; Neovii Biotech: Research Funding; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Peters:Novartis: Consultancy; Jazz: Speakers Bureau; Amgen: Consultancy; Pfizer: Consultancy; Medac: Consultancy. Biondi:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Cellgene: Other: Advisory Board; BMS: Membership on an entity's Board of Directors or advisory committees. Baruchel:Servier: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Jazz: Consultancy; Baxalta: Research Funding. June:University of Pennsylvania: Patents & Royalties; Johnson & Johnson: Research Funding; Celldex: Consultancy, Equity Ownership; Pfizer: Honoraria; Immune Design: Consultancy, Equity Ownership; Novartis: Honoraria, Patents & Royalties: Immunology, Research Funding; Tmunity: Equity Ownership, Other: Founder, stockholder . Sen:Novartis: Employment. Zhang:Novartis: Employment. Thudium:Novartis: Employment. Wood:Novartis Pharmaceuticals: Employment, Other: Stock. Taran:Novartis: Employment. Pulsipher:Chimerix: Consultancy; Jazz Pharmaceutical: Consultancy; Novartis: Consultancy, Other: Study Steering Committee; Medac: Other: Housing support for conference.

Background: Tisagenlecleucel, an anti-CD19 chimeric antigen receptor (CAR)-T cell therapy, has demonstrated durable responses and a manageable safety profile in adult patients (pts) with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). We report the correlation of pre- and post-infusion factors and biomarkers with efficacy in tisagenlecleucel-treated pts with r/r DLBCL. Methods: Results from JULIET, a global, single-arm, pivotal, phase 2 trial of tisagenlecleucel in adult pts with r/r DLBCL, were analyzed to identify baseline disease and pt characteristics and serum biomarkers that may correlate with efficacy. The relationships between markers such as lactate dehydrogenase (LDH), baseline tumor volume (TV, within 30 days prior to infusion) using positron emission tomography/computed tomography, pre-treatment C-reactive protein (CRP) and thrombocytopenia, as well as cytokine release syndrome (CRS; Penn scale)/neurological events (NE; CTCAE v4.03) severity, and month 3 response (complete or partial response [CR, PR]), progression-free survival (PFS), and overall survival (OS) were assessed. Results: As of December 11, 2018, 115 pts were infused with tisagenlecleucel and evaluable for efficacy. Baseline TV did not correlate with month 3 response; we then examined additional pre-treatment candidate factors. Median LDH levels at enrollment, pre-lymphodepleting chemotherapy (LDC), and pre-infusion were higher in nonresponders (NRs) compared with pts achieving CR/PR. 15/16 pts with pre-infusion grade 3/4 thrombocytopenia (<50 x 109/L) were NRs. Pre-infusion CRP levels did not associate with month 3 response. Univariate and multivariate logistic regression analyses showed that high pre-infusion LDH levels (defined as higher than 2-fold the upper limit of normal [ULN]) were independently associated with NRs. Compared with pts with normal levels of LDH at pre-infusion, pts with LDH 1-2-fold above the ULN and >2-fold above the ULN had poorer PFS and OS (Figure 1). Similar separations of PFS and OS were observed with LDH levels at enrollment and pre-LDC. Pts with pre-infusion platelet levels <50 x 109/L also had significantly worse PFS and OS compared with pts with platelet levels ≥50 x 109/L. Pre-infusion high TV, high CRP, high ferritin, and low serum albumin associated with worse OS, but not PFS. Additional analyses including factors at enrollment and pre-LDC will be presented. Post-infusion, correlations between severe (grade 3/4) CRS/NE and efficacy were examined. All 13 pts with severe NE were NRs. 9/17 pts with grade 3 CRS and all 9 pts with grade 4 CRS were also NRs. In addition, pts with severe CRS had worse PFS and OS compared with pts with grade 0-2 CRS. Similarly, pts with severe NE had worse PFS and OS compared with pts with grade 0-2 NE. High pre-infusion LDH and pre-infusion grade 3/4 thrombocytopenia and severe NE were independently associated with poorer PFS in Cox regression analyses. Severe CRS did not correlate with PFS in a multivariate Cox model. Pts with severe CRS who were also NRs had higher median baseline TV compared with other pts. Notably, the highest levels of serum biomarkers (eg, ferritin, IL4, IL8, IL10), highest LDH, and lowest platelet counts within 1 month post-infusion were observed in pts with severe CRS who were also NRs, compared with pts with severe CRS who achieved CR/PR and pts with grade 0-2 CRS. Analyses of the impact of tocilizumab and steroids usage are ongoing. Conclusions: Multivariate analyses identified that high levels of pre-infusion LDH, a known marker of tumor burden, metabolic activity, and disease aggressiveness, was associated with NRs at month 3 as well as worse PFS and OS. Grade 3/4 thrombocytopenia at pre-infusion and grade 3/4 NE were also associated with poor efficacy outcomes. Furthermore, the highest serum biomarker profiles post-infusion appeared to associate with pts with severe CRS who were also NRs. Overall, these analyses suggest that a subset of pts with aggressive disease at infusion and/or pts with severe CRS/NE had poorer outcomes in the JULIET trial. These analyses may reinforce the rationale for current and future directions of using CAR-T cell therapy in an earlier line of therapy (during less aggressive/less advanced disease), optimizing pt care, and developing interventions to prevent severe CRS and/or NE. Clinical trial information: NCT02445248. Disclosures Westin: Genentech: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; Juno: Other: Advisory Board; MorphoSys: Other: Advisory Board; Unum: Research Funding; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding. Tam:Roche: Honoraria; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BeiGene: Honoraria; Novartis: Honoraria. Jaeger:Novartis, Roche, Sandoz: Consultancy; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding. McGuirk:Bellicum Pharmaceuticals: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding. Holte:Novartis: Honoraria, Other: Advisory board. Waller:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Other: Travel expenses, Research Funding; Cerus Corporation: Other: Stock, Patents & Royalties; Chimerix: Other: Stock; Cambium Oncology: Patents & Royalties: Patents, royalties or other intellectual property ; Amgen: Consultancy; Kalytera: Consultancy. Jaglowski:Juno: Consultancy, Other: advisory board; Unum Therapeutics Inc.: Research Funding; Kite: Consultancy, Other: advisory board, Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding. Bishop:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Andreadis:Celgene: Research Funding; Juno: Research Funding; Novartis: Research Funding; Genentech: Consultancy, Employment; Kite: Consultancy; Gilead: Consultancy; Jazz Pharmaceuticals: Consultancy; Pharmacyclics: Research Funding; Merck: Research Funding; Roche: Equity Ownership. Foley:Janssen: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau. Fleury:Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; AstraZeneca: Consultancy. Ho:Janssen: Other: Trial Investigator meeting travel costs; Celgene: Other: Trial Investigator meeting travel costs; La Jolla: Other: Trial Investigator meeting travel costs; Novartis: Other: Trial Investigator meeting travel costs. Mielke:EBMT/EHA: Other: Travel support; IACH: Other: Travel support; Celgene: Honoraria, Other: Travel support (via institution), Speakers Bureau; Kiadis Pharma: Consultancy, Honoraria, Other: Travel support (via institution), Speakers Bureau; GILEAD: Consultancy, Honoraria, Other: travel (via institution), Speakers Bureau; Miltenyi: Consultancy, Honoraria, Other: Travel and speakers fee (via institution), Speakers Bureau; Jazz Pharma: Honoraria, Other: Travel support, Speakers Bureau; DGHO: Other: Travel support; Bellicum: Consultancy, Honoraria, Other: Travel (via institution); ISCT: Other: Travel support. Teshima:Novartis: Honoraria, Research Funding. Schuster:AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Patents & Royalties: Combination CAR-T and PD-1 Inhibitors, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Loxo Oncology: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Nordic Nanovector: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding. Bachanova:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Incyte: Research Funding; GT Biopharma: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Research Funding; Celgene: Research Funding. Maziarz:Kite: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Incyte: Consultancy, Honoraria; Celgene/Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Van Besien:Miltenyi Biotec: Research Funding. Izutsu:Eisai, Symbio, Chugai, Zenyaku: Research Funding; Eisai, Chugai, Zenyaku: Honoraria; Chugai, Celgene, Daiichi Sankyo, Astra Zeneca, Eisai, Symbio, Ono, Bayer, Solasia, Zenyaku, Incyte, Novartis, Sanofi, HUYA Bioscience, MSD, Astellas Amgen, Abbvie, ARIAD, Takeda, Pfizer: Research Funding; Kyowa Kirin, Eisai, Takeda, MSD, Chugai, Nihon Medi-physics, Janssen, Ono, Abbvie, Dainihon Sumitomo, Bayer, Astra Zeneca, HUYA Japan, Novartis, Bristol-Byers Squibb, Mundi, Otsuka, Daiichi Sankyo, Astellas, Asahi Kasei: Honoraria; Celgene: Consultancy. Kersten:Bristol Myers Squibb: Other: Travel grants, honorarium, or advisory boards; Gilead: Other: Travel grants, honorarium, or advisory boards; Roche: Consultancy, Research Funding, Travel grants, honorarium, or advisory boards; Amgen: Other: Travel grants, honorarium, or advisory boards; Novartis: Consultancy, Other: Travel grants, honorarium, or advisory boards; Roche: Other: Travel grants, honorarium, or advisory boards; Celgene: Other: Travel grants, honorarium, or advisory boards; Kite: Consultancy, Other: Travel grants, honorarium, or advisory boards; Janssen/Cilag: Other: Travel grants, honorarium, or advisory boards; MSD: Other: Travel grants, honorarium, or advisory boards; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Wagner-Johnston:Bayer: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees. Corradini:Jazz Pharmaceutics: Honoraria; KiowaKirin: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; Servier: Honoraria; Takeda: Honoraria, Other: Travel Costs; BMS: Other: Travel Costs; Celgene: Honoraria, Other: Travel Costs; AbbVie: Consultancy, Honoraria, Other: Travel Costs; Janssen: Honoraria, Other: Travel Costs; Gilead: Honoraria, Other: Travel Costs; Amgen: Honoraria; Daiichi Sankyo: Honoraria. Han:Novartis: Employment. Tiwari:Novartis: Employment. Agoulnik:Novartis: Employment. Eldjerou:Novartis Pharmaceuticals Corporation: Employment. Bubuteishvili Pacaud:Novartis: Employment. Salles:Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Other: Educational events; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria.

Penny stocks at times makes the investors wealthy by turning to be a multi-bagger stocks or erode the wealth of the investors with poor performance in volatile conditions. While there are many machine learning-based prediction models that are used for stock price evaluation, very few studies have focused on the dynamics to be considered in penny stock conditions. Though the pattern might remain the same for normal stocks and the penny stock classification, still some of the parameters to be evaluated in the process needs changes. The model discussed in this report is a comprehensive solution discussed as scope for evaluation of the penny stock pick, using trading and reporting financial metrics. Experimental study of the test data indicates that the model is potential and if can be used effectively with reinforcement learning pattern, it can turn to be sustainable solution.

Penny stock manipulation refers to unethical and illegal practices in the stock market which involve the manipulation of share prices and trading volumes with the aim of generating undue profits for the manipulators. The purpose of this study is to detect manipulation of penny stocks in Islamic stocks registered on ISSI in 2022. This type of research is qualitative research using technical analysis of candlestick indicators, moving averages, and volume. The results showed that there was manipulation of penny stocks in Islamic stocks including shares of PT Winner Nusantara Tbk (WINR), PT Wahana Pronatural Tbk (WAPO), PT Damai Sejahtera Abadi Tbk (UFOE), and PT Sunter Lakeside Hotel Tbk (SNLK) companies. This stock has a low market cap and liquidity, candlestick patterns and volume detects movements that tend to fluctuate, and is included in the UMA (Unusual Market Activity) list which has unusual transactions. In the context of Sharia, penny stock manipulation can lead to doubts and distrust in the Islamic capital market as a source of investment that is in accordance with Islamic values. This underscores the importance of upholding the integrity of Sharia-compliant capital markets and implementing strong supervisory mechanisms to protect investors from manipulative practices while adhering to Shariah principles.