De Waal Research Articles

Kesiapan Adaptasi Metode Beyond Budgeting Sebagai Upaya Pembaharuan Manajemen Kinerja (Studi pada Urban Style by Front One Hotel, Lampung, Sumatera Selatan)

This study aims to test the possibility of implementing control management using the beyond budgeting method. The method consists of 12 principles consisting of 6 principles of adaptive management and 6 principles of flexible organizational structure. This research was conducted with qualitative research by conducting a case study on a company in the hospitality sector (Urban Style by Front One Hotel in Lampung). Urban Style by Front One Hotel still uses a traditional budgeting system whose method does not create satisfaction for management in achieving it. Therefore, researchers try to introduce adaptive control management for the business environment, namely beyond budgeting Respondents in this study were the Management Team (GM and Staff) of Urban Style by Front One Hotel which consisted of General Manager, Human Resource Development, Front Office, Food and Baverage, Accounting and Finance, House Keeping, and Engineering. The data is primary data obtained by distributing questionnaires and interviews to the management team at Urban Style by Front One Hotel, respondents filled out questionnaires and interviews through zoom media because during the COVID-19 pandemic they could not conduct interviews directly. Data analysis using calculations introduced by de Waal (2003) which is symbolized by 3 colors, namely Green (ready), Orange (medium) and Red (not ready). The results showed that Urban Style by Front One Hotel could not apply the Beyond Budgeting method even though there was a desire to apply this method, relatively low readiness for change and there were corporations that had higher authority to change methods in management control.Keywords: Traditional Budget; Beyond Budgeting.

The Power of Books: Wafaa Bilal’s 168:01 and Edmund de Waal’s library of exile

This essay examines two installations: Wafaa Bilal's 168:01 (2016–) and Edmund de Waal's library of exile (2019–2020). Both are starkly white spaces, which come alive with the intervention of the viewer/participant. In both, books are accumulated over time, and will eventually be shipped to Iraq where they will help to replenish Iraqi libraries that have been destroyed during the Second Gulf War, or the violence that has followed it. Bilal encourages members of the public viewing 168:01 online, or visiting the exhibition in person, to exchange one of the blank white books that line its shelves for a book on the wish-list of the University of Baghdad's Faculty of Fine Art, his own alma mater. The contents of de Waal's library of exile will be shipped to Mosul where they will help to replace the contents of libraries in that city, most recently destroyed by daesh or IS fighters. This essay explores each installation's meditation on exilic longing, the way each reflects on the sorrow of losing a homeland or watching its people suffer from afar. I argue that in contrast to the profound sadness that each of these works evokes, it is the indefatigability of hope and the power of human resilience that each most powerfully conveys. While poignantly inviting us to reflect on grief and loss, both 168:01 and library of exile carefully avoid the pitfalls of a nostalgic gaze, not least by gesturing toward a brighter future.

Territorial Conflict, Domestic Crisis, and the Covid-19 Pandemic in the South Caucasus. Explaining Variegated EU Responses.

Territorial Conflict, Domestic Crisis, and the Covid-19 Pandemic in the South Caucasus. Explaining Variegated EU Responses.

Science and the Good: The Tragic Quest for the Foundations of Morality

Science and the Good: The Tragic Quest for the Foundations of Morality

Alex de Waal, New Pandemics, Old Politics: Two Hundred Years of War on Disease and Its Alternatives

Alex de Waal, <i>New Pandemics, Old Politics: Two Hundred Years of War on Disease and Its Alternatives</i>

Migrating Objects and Wanderers between Worlds: Cosmopolitan Selves in Edmund de Waal’s The Hare with Amber Eyes

Edmund de Waal‘s widely acclaimed family memoir The Hare with Amber Eyes (2010) is a hybrid text that fuses biography, autobiography and the biography of objects and interlaces these with critical reflections on art, transnationality, cross-cultural communication and the development of cosmopolitan identities. This article examines the central role of the collection of netsuke synecdochally evoked in the book’s title that not only provides the pivotal structural element but also the major conceptual focus of the text. I argue that this idiosyncratic gravitational centre effects the permeability of generic boundaries by establishing an intricate relationality between the narrative’s different protagonists, who continuously decentre and reconfigure each other. Moreover, the art objects’ own history of migration and multiple belonging becomes a blueprint for de Waal’s construction of his Jewish ancestors’ highly mobile and cosmopolitan selves, which sidesteps the narrowly circumscribed vision of national or religious identities. The full extent of these connections is revealed through an examination of the author’s artistic vision, his ceramic art and art criticism. Finally, I will read The Hare with Amber Eyes as an act of restitution in a two-fold sense: as an attempt to undo the politically motivated erasure of some of his ancestors’ traces and as a historical reminder of lived forms of cosmopolitanism that can speak to contemporary debates around globalisation and migration.

Old politics in pandemic management

New Pandemics, Old Politics: Two Hundred Years of War on Disease and Its Alternatives, written by political scientist and Africanist Alex de Waal, is a clarion call to rethink the way in which societies respond to pandemic diseases. De Waal uses historical case studies of cholera, 1918 influenza, and HIV/AIDS to challenge readers to recognise the limitations of the current “war on disease” rhetoric that has dominated pandemic planning and responses since the late 19th century. Using the current COVID-19 pandemic to frame his analysis, de Waal dissects the historical choices which have produced the current policies of mass sequestration, reliance on curative services, and faith that medical technology through vaccination will bring “victory”.

Abstract 54: Cryo-EM structure of the PDE3A-SLFN12 complex reveals requirements for the activation of SLFN12 RNase and DNMDP-induced cancer cell killing

Abstract We have identified a novel mechanism of selective cancer cell-killing, whereby small molecules such as DNMDP induce complex formation between phosphodiesterase 3A (PDE3A) and a poorly characterized protein, SLFN12, that leads to downstream cell death (de Waal et al., Nat Chem Biol 2016; Lewis et al., ACS Med Chem Letters, 2019; Wu et al., J Bio Chem 2020). This process therefore relies on the presence and interaction of these two proteins, rather than a pre-existing dependency, as is the mechanism of many currently available cancer therapies. While complex formation is required for cancer cell killing, the molecular basis for complex induction and the activity of the complex that leads to cell death have not been described. In this study, we employed cryogenic electron microscopy (cryo-EM) to deduce the high-resolution structure of the DNMDP-induced PDE3A-SLFN12 complex. The solved structure includes DNMDP-bound PDE3A at 2.97 Å, as well as the structure of the full length SLFN12 at 2.76 Å. We found that the entire complex consists of a 2:2 hetero-tetramer with the C-terminal alpha-helix of SLFN12 reaching into the DNMDP-occupied substrate binding pocket of PDE3A and contacting both DNMDP and active site residues of PDE3A. The binding of DNMDP to PDE3A does not induce structural changes, but rather creates an adhesive surface at the entrance of the substrate binding pocket, which allows for stable binding of SLFN12. We have named DNMDP and similar PDE3A-SLFN12 complex inducing compounds “velcrins”, after the adhesive fabric. Site-directed mutagenesis confirmed that residues on the SLFN12 C-terminal helix are required for DNMDP-induced cell death. Based on homology to the SLFN13, we predicted that SLFN12 would also encode an RNase. Indeed, purified SLFN12 protein cleaved ribosomal RNA in vitro and mutation of the putative catalytic residues abolished this activity. Importantly, catalytically dead SLFN12 mutants failed to mediate DNMDP-induced cell killing while retaining the ability to complex with PDE3A. Consistent with the requirement of SLFN12 RNase activity for DNMDP-induced cell death, overexpression of wild-type SLFN12 alone was cytotoxic, whereas overexpression of catalytically dead SLFN12 was not. The RNase activity of SLFN12 in vitro was stimulated in the presence of DNMDP and PDE3A, suggesting that the mechanism of DNMDP-induced cell killing involves activation of the SLFN12 RNase. Intriguingly, SLFN12 homodimer interface mutants were no longer cytotoxic when overexpressed, but still supported DNMDP-induced cell killing. We hypothesize that PDE3A, an obligate dimer, activates SLFN12 RNase activity by stabilizing the dimeric form of SLFN12. Citation Format: Xiaoyun Wu, Colin Garvie, Sooncheol Lee, Steven Horner, Andrew Baker, Marcus Toetzl, Joseph McGaunn, Bethany Kaplan, Luc de Waal, Martin Lange, Timothy Lewis, Chris Lemke, Matthew Meyerson, Heidi Greulich. Cryo-EM structure of the PDE3A-SLFN12 complex reveals requirements for the activation of SLFN12 RNase and DNMDP-induced cancer cell killing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 54.

Abstract 1512: OrthoCARs: Engineered human IL-2/IL-2Rb orthogonal pairs selectively enhance CAR T cell antitumor efficacy by driving T cell expansion and fitness

Abstract CAR T cell therapy (CAR) has demonstrated remarkable clinical efficacy in hematological malignancies. However, barriers such as poor T cell effector function, lack of proliferation, and limited persistence prevent CARs from reaching their full curative potential. IL-2 is a potent stimulator of T cell proliferation, survival, and cytotoxic function, making it an attractive cytokine to support CARs. However, therapeutic use of IL-2 is limited by systemic toxicity due its promiscuous activation of undesired immune cell populations. To facilitate selective expansion and activation of CARs we have developed a human orthogonal ligand/receptor system consisting of a pegylated IL-2 mutein (STK-009) that does not significantly activate the wild type IL-2 receptor and a mutated IL-2 Receptor Beta (hoRb) that is fully activated by STK-009, but does not respond to the native IL-2 ligand. This system enables in vivo IL-2 signaling in CARs engineered to express hoRb while avoiding signaling bystander T cells and NK cells. Here, we demonstrate the ability of the STK-009/hoRb receptor pair to selectively enhance the anti-tumor efficacy of hoRb expressing CD19 CARs (SYNCAR-001) in preclinical lymphoma mouse models at will. We also demonstrate, in non-human primates (NHP), that STK-009 is selective for hoRb expressing cells. SYNCAR-001 + STK-009 can lead to complete responses in subcutaneous Raji mouse models, even with SYNCAR-001 dosed at sub-efficacious levels (400,000 CAR-Ts/mouse). Subcutaneous dosing of STK-009 expands SYNCAR-001 systemically and drives infiltration of SYNCAR-001 into tumors. UMAP analysis of STK-009 treated SYNCAR-001 reveal a small PD1+LAG3+ subpopulation during tumor rejection which disappeared once tumors are controlled. The majority of T cells showed no exhaustion markers. Further, an IL-7R+ population arises and remains after tumor control, indicating long term memory development. Nanostring analysis confirms upregulation of IL-7R and other critical genes involved in cytotoxic activity and persistence in SYNCAR-001 when treated with STK-009. These data demonstrate that STK-009 treatment expands SYNCAR-001 and delivers a gene signature indicative of enhanced T cell fitness and activity. Subcutaneous administration of STK-009 in NHP shows no evidence of toxicity or physiological IL-2 mediated activity on immune cells, including Teffs, Tregs, and NK cells. Pharmacokinetic analysis of STK-009 shows stable exposure with minimal clearance, demonstrating the selectivity of STK-009. These findings validate an orthogonal platform that selectively drives potent T cell effector functions of engineered cells without the toxicities mediated by NK cells or non-tumor specific T cells associated with high dose IL-2 therapy. These results demonstrate the ability of this orthogonal platform to improve the efficacy and durability of CARs. Citation Format: Paul-Joseph P. Aspuria, Sandro Vivona, Michele Bauer, Marie Semana, Navneet Ratti, Scott McCauley, Romina Riener, Rene de Waal Malefyt, Deepti Rokkam, Jan Emmerich, Patrick J. Lupardus, Rob A. Kastelein, Martin Oft. OrthoCARs: Engineered human IL-2/IL-2Rb orthogonal pairs selectively enhance CAR T cell antitumor efficacy by driving T cell expansion and fitness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1512.

Abstract 1744: STK-012, an alpha/beta selective IL-2 mutein for the activation of the antigen-activated T cells in solid tumor

Abstract Interleukin-2 (IL-2) is a potent stimulator of T and NK cell proliferation, survival, and cytotoxic function. High dose IL-2 induces complete responses as a single agent in certain cancers. Its use is limited due to toxicities such as severe hypotension and vascular leak syndrome (VLS). A better understanding of the mechanisms of IL-2 efficacy and toxicity and development of more selective therapies are needed to improve the use of IL-2. Next generation IL-2 therapeutics have been engineered to bias activity towards the dimeric form of the IL-2 receptor, which consists of IL-2Rβ (CD122) and IL-2Rγ (CD132), and away from the high affinity trimeric form of the receptor, which also includes IL-2Rα (CD25). This approach is designed to stimulate NK cells and naïve effector T-cells, which express the dimeric, and not the trimeric, form of the receptor. However, this approach largely misses antigen-activated and tumor-specific T-cells, which have high expression of both CD25 and CD122. In addition, this approach expands peripheral NK cells, which have been shown in mice to cause VLS (1-3).To specifically stimulate antigen-activated CD25+ effector T cells in cancer patients and avoid systemic NK and naïve T cell activation, we have developed a PEGylated, CD25/CD122-selective IL-2 mutein (STK-012) and its mouse surrogate (STK-014). Here we present efficacy and safety of STK-014 compared to wild type IL-2 (wtIL-2) and a CD122/CD132 biased IL-2 (βγIL-2). We also present safety of STK-012 in non-human primates (NHP). STK-012/STK-014 selectively induced STAT5 phosphorylation and proliferation in antigen activated T cells but not in NK cells and naïve T cells. In mice, STK-014 showed reduced toxicity compared to wtIL-2 and βγIL-2. In particular, wtIL-2 and βγIL-2 induced VLS while STK-014 did not. Moreover, STK-014 demonstrated complete responses both as single agent and in combination with a PD-1 antibody in syngeneic tumor models. In general, STK-014 demonstrated improved efficacy compared to wtIL-2 and βγIL-2. STK-014 dramatically increased intratumoral T cells and intratumoral cytotoxic activity compared wtIL-2 and βγIL-2 while avoiding T cell activation in the spleen. STK-014 treatment drastically increased the CD8+ T cell to Treg ratio within the tumor when compared to control tumors (25-fold), but also in comparison to wtIL-2 (2.75-fold) and to βγIL-2 (5.2-fold).In NHP, STK-012 was well tolerated at doses supra-efficacious in mice. Weekly dosing of STK-012 led to continuous elevated serum concentrations, demonstrating selectivity for CD25/122+ T cells. STK-012 selectively induced memory T cell expansion, including CD28+ CD95+ CD8 T cells. In summary, STK-012 avoids IL-2 mediated toxicity and may enable the specific expansion of antigen activated memory T cells in cancer patients, leading to durable tumor response. 1 Peace DJ and Cheever MA. JEM, 1989.2 Gatley MK et al. JI, 1988.3 Assier E et al. JI; 2004. Citation Format: Jan Emmerich, Michele Bauer, Marie Semana, Bhargavi Jayaraman, Sandro Vivona, Scott McCauley, Romina Riener, Rene De Waal Malefyt, Paul-Joseph Aspuria, Deepti Rokkam, Patrick Lupardus, Rob Kastelein, Martin Oft. STK-012, an alpha/beta selective IL-2 mutein for the activation of the antigen-activated T cells in solid tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1744.

Crop damage by Asian elephant (Elephas maximus) in Ekgaloya and Dewalahinda areas in Ampara District, Eastern province, Sri Lanka

Crop damage by Asian elephant (Elephas maximus) in Ekgaloya and Dewalahinda areas in Ampara District, Eastern province, Sri Lanka

Suitability of the high performance organization framework for Egyptian ICT companies: a replication study

PurposeThe purpose of this paper is to answer the research question “Is the high-performance organization (HPO) Framework suitable for non-governmental private sector organizations, specifically the affiliates of international companies operating in the ICT sector in Egypt?”Design/methodology/approachThe research concerns a replication study in which the HPO Questionnaire was used to collect data, and factor analysis was applied to evaluate the reliability and consistency of the HPO Framework. The research approach was the same as applied by de Waal et al. (2016), but this time the research population consisted of affiliates of international ICT companies, instead of local ICT companies as in the de Waal et al. (2016) study.FindingsData gathered by means of the HPO Questionnaire from managers of these affiliates were used to evaluate the reliability and internal consistency of the HPO Framework. The confirmatory factor analysis was done twice, once for the original 35-characteristic HPO Framework and once for the 26-characteristic HPO Framework as proposed by de Waal et al. (2016) for Egyptian local ICT companies. The study results clearly show the applicability of the original 35-characteristic HPO Framework for measuring the organizational strength and identifying performance-gaps of ICT companies that are affiliates of international organizations operating in Egypt.Originality/valueThis study adds to the growing HPO literature on developing countries and helps Egyptian ICT companies to adopt high-performance practices to be able to contribute more to the economic development of Egypt.

Pacifist utopias: humanitarianism, tragedy and complicity in the Second World War

Pacifist utopias: humanitarianism, tragedy and complicity in the Second World War

The Origins of Behavioural Public Policy

The Origins of Behavioural Public Policy

Are We Smart Enough to Know How Smart Animals Are? by Frans de Waal

Reviewed by: Are We Smart Enough to Know How Smart Animals Are? by Frans de Waal John Skalko Are We Smart Enough to Know How Smart Animals Are? by Frans de Waal (New York: W. W. Norton, 2016), 340 pp. Frans de Waal's 2016 Are We Smart Enough to Know How Smart Animals Are? is an exciting read into the baffling and brilliant world of what goes on inside non-human animal heads. Given the sheer number of studies published in the late twentieth century on animal cognition, de Waal does an amazing job presenting many of them in a highly readable fashion with just enough detail to understand the importance and rigorous facets of the research (or in some cases not so rigorous), but without making the detail overwhelming. The extensive bibliography at the end of the book provides ample material for any curious reader interested in further research regarding any of the scientific studies. Much of what is presented in the book would present a big challenge for any contemporary Cartesians who may hold, as Descartes did, that animals are mere automata. If non-human animals are self-moving machines devoid of cognition, then how do chimpanzees learn to stack boxes high enough to reach objects overhead? De Waal tells the famous story of Sultan the chimpanzee who accomplished such a feat without any prior training or teaching (65). Further, if non-human animals have no emotions, then what of the two bottlenose dolphins who came to the rescue of a third after the explosion of a stick of dynamite (133)? De Waal's book presents many challenges for the Cartesian mechanistic view of animals. Most people today, however, need not be persuaded that that the Cartesian view is wrong. On a popular level the overwhelming view is that there is no significant difference in kind between the cognition of non-human [End Page 309] animals and that of man. It is this view that de Waal himself espouses throughout the book, and for which he provides much evidence, although at times his phrasing sounds a bit like dogmatic worship of Darwin. Nevertheless, if Darwin is right, he is right. And given the contemporary biological and psychological courses of study, Darwin appears to be the most reasonable view. But an older, middle view, between the extremes of Cartesian automata and Darwinian cognitivism has been forgotten by many scholars. This is the view of the Aristotelian tradition. Aristotle held a more nuanced view of animal cognition: animals are not mere machines devoid of cognitive states, but neither do they possess all of the same kind of mental faculties that man has—"In all animals other than man there is no thinking or calculation but only imagination."1 In the footsteps of Aristotle, Avicenna and Aquinas also did much to develop a rich account of animal cognition. De Waal seems to be completely unaware of the middle ground of the Aristotelians concerning animal cognition. Most of the case studies de Waal mentions remain perfectly compatible with the Aristotelian tradition (albeit, perhaps in its more developed forms): ravens have cognitive perspective-taking (147–48); apes imitate other apes (153–54); thrushes cognize ahead in gathering food for their young (205–6); rats remember in which part of a maze they encountered chocolate before (211); and wasps recognize the faces of other wasps (70–71). But various challenges remain for the Aristotelian. De Waal provides various cases of what he takes to be reasoning in non-human animals. Many of these cases are not reasoning in the Aristotelian sense: reasoning (for the Aristotelian) is coming to know another proposition from two prior propositions that are known. De Waal mentions Sadie, a chimpanzee who could cognize when a box had a fruit in it and when another box did not: [The experimenters] placed an apple in one [box] and a banana in another. After a few minutes of distraction, Sadie saw one of the experimenters munching on either an apple or a banana. This experimenter then left, and Sadie was released to inspect the boxes. She faced an interesting dilemma, since she had not seen how the experimenter had gotten...

Mama’s Last Hug: Animal Emotions and What They Tell Us about Ourselves by Frans de Waal

Book Review| January 01 2021 Mama’s Last Hug: Animal Emotions and What They Tell Us about Ourselves by Frans de Waal de Waal, Frans, Mama’s Last Hug: Animal Emotions and What They Tell Us about Ourselves (London: Granta Books, 2019), 326 pp. Thibault De Meyer Thibault De Meyer Search for other works by this author on: This Site Google Common Knowledge (2021) 27 (1): 109. https://doi.org/10.1215/0961754X-8723129 Cite Icon Cite Share Icon Share Twitter Permissions Search Site Citation Thibault De Meyer; Mama’s Last Hug: Animal Emotions and What They Tell Us about Ourselves by Frans de Waal. Common Knowledge 1 January 2021; 27 (1): 109. doi: https://doi.org/10.1215/0961754X-8723129 Download citation file: Zotero Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu nav search search input Search input auto suggest search filter Books & JournalsAll JournalsCommon Knowledge Search Advanced Search The text of this article is only available as a PDF. Copyright © 2021 Duke University Press2021 Article PDF first page preview Close Modal Issue Section: LITTLE REVIEWS You do not currently have access to this content.

Grief Lit

Grief Lit Siân Roberts (bio) Vidui David Slavitt Livingston Press https://www.spdbooks.org/Products/9781604892314/vidui.aspx 130 Pages; Print, $15.95 In 2018, the British artist Edmund de Waal was tasked with judging a new category for the Hay Literary Festival. The focus of this new prize was a burgeoning genre of literature: writing which focused on the end-of-life, grief, bereavement, and memorial. After spending nine months reading and judging fiction of this nature, de Waal wrote a short essay, titled “Breaking the silence: are we getting better at talking about death?” reflecting on the way that modern life is saturated with death: the news brings us a constant stream of strangers’ deaths and grief memoirs fill our shelves. But despite this heightened exposure to death, he argued that the language of loss remains “so impoverished, so mired in cliche and euphemism, that deep metaphors of ‘passing’ become thinned to nothing, to sentimentality.” In particular, he criticized the way that the language of mourning is frequently reduced to metaphors of “courage,” “being strong,” and finally “losing the battle.” This type of language asks the bereaved to play a certain role and leave no space for emotions other than endurance, resilience or strength. No doubt fiction has played its part in our inability to speak in novel or honest ways about grief and dying. For a theme as old as literature itself, representations of death in fiction are remarkable in their sameness. Fictional deaths are often heroic or symbolic. Where are the cowardly deaths, or the ones marked by confusion or anger? Is it possible to write about death in a non-cliché way? David Slavitt’s Vidui is a rare example of a more original approach to the literature of dying. Vidui is voiced by a man named Vernon who narrates from his deathbed. Vernon tells us from the offset that he is “no longer trying to impress anyone or to be pleasing” and begins a meandering journey through his dying thoughts. There is little in the way of plot and with the exception of a few brief interjections from Slavitt as the author, we stay in Vernon’s consciousness for the entirety of the novel. At first, this intimacy with a dying man’s thoughts might sound like a sombre premise. However, Vidui is far from mournful. Instead, Vernon tells us that “silliness is a way of fending off stillness”: Slavitt’s approach is eccentric, playful, and humorous. A sense of pleasure comes from getting lost in Vernon’s thoughts: his intelligence and imagination are vivacious even as his physical strength fades away. Allusive patterns of thought spiral through every page, as the text jumps from Kermit the frog to Milton all in the space of a few paragraphs. There is also delight in wordplay, puns both mono and bilingual and the strange music words make when they are placed against one and other. This intertextuality and performance of language is not just postmodern play. We are also left with the strong sense it is Vernon’s escape into his mind that allows him to retain a sense of dignity, even as he is infantilized by his unnamed illness. Reading through Vidui leaves the reader with a strange sense of circling further and further away from the real world and into abstraction. This deep sense of introspection has echoes of Samuel Beckett’s Malone Dies (1951), another experimental representation of a man’s thoughts on his deathbed. Slavitt tells us that Vidui more directly pays homage to Tolstoy’s Death of Ivan Ilyich (1886), another pensive, metaphysical exploration of a man’s final days. But in opposition to the grief-stricken introspection narrator of Tolstoy’s novel, who ruminates over a life he believes that he has lived and wasted, Slavitt’s speaker prefers to remain on the surface of things, stating that “the brevity of my attention span is a carefully developed defence mechanism, an evasive stratagem that allows me that has served me well. It avoids the unpleasantness and keeps me from dwelling too long anywhere, with anyone, on anything.” And while Ivan Ilyich expresses a deep sense of regret, it...

New Pandemics, Old Politics: Two Hundred Years of War on Disease and Its Alternatives, Alex de Waal (Cambridge, U.K.: Polity, 2021), 284 pp., cloth $64.95, paperback $22.95, eBook $14.00.

New Pandemics, Old Politics: Two Hundred Years of War on Disease and Its Alternatives, Alex de Waal (Cambridge, U.K.: Polity, 2021), 284 pp., cloth $64.95, paperback $22.95, eBook $14.00.

Between Artist and Curator: On the ‘Laws of Attraction’ in Edmund De Waal’s “Elective Affinities” Exhibition

BETWEEN ARTIST AND CURATOR: ON THE ‘LAWS OF ATTRACTION’ IN EDMUND DE WAAL’S “ELECTIVE AFFINITIES” EXHIBITION

OrthoCARs: Engineered human IL-2/IL-2Rb orthogonal pairs selectively enhance CAR T cell antitumorefficacy

CAR T cell therapy has demonstrated remarkable clinical efficacy against relapsed and refractory hematological malignancies, such as B cell non-Hodgkin lymphoma (NHL) and acute lymphoblastic leukemia (ALL) (Neelapu et al. NEJM, 2017; Schuster et al. NEJM, 2018; Turtle et al. Sci Trans Med, 2016). Despite these advances, prominent barriers including poor T cell effector function, lack of proliferation, and limited CAR T cell persistence prevent CAR T cell therapies from reaching their full curative potential (Srivastava and Riddell, Journal of Immunology, 2019). Interleukin-2 (IL-2) is a potent stimulator of CD4 and CD8 T cell proliferation, survival, and cytotoxic function, thereby making it an attractive molecule to support CAR T cell therapy. However, therapeutic use of IL-2 is limited by systemic toxicity due its promiscuous activation of undesired immune cell populations, including non-tumor reactive T cells and NK cells (Rosenberg et al. Journal of Immunology, 2014). To facilitate selective ex vivo and in vivo expansion of engineered T cells we have developed a human orthogonal (ortho) ligand/receptor system consisting of a pegylated, IL-2 mutein (STK- 009) that does not significantly activate the wild type receptor and a mutated IL-2 Receptor Beta (orthoIL-2Rβ) that does not significantly respond to its native ligand, wild type IL-2. This system enables in vivo IL-2 signaling in engineered cells that express the orthoIL-2Rβ while avoiding signaling in bystander T cells and NK cells. Here, we demonstrate the ability of the STK-009/orthoIL-2Rb ligand/receptor pair to selectively potentiate human orthoIL-2Rb (hoRb) expressing CD19 CAR T cells (CD19 orthoCAR T cells) in vitro and in vivo. We also demonstrate that STK-009 is selective for the orthogonal IL-2Rb and in a non-human primate model does not potentiate wild type T or NK cells and shows no evidence of toxicity. The STK-009/CD19 orthoCAR T platform was evaluated in a disseminated Raji mouse model of aggressive lymphoma. Subcutaneous administration of STK-009 dramatically expanded the CD19 orthoCAR T cells possessing a clinically favorable TSCM and TEMRA immunophenotype and significant antitumor efficacy was observed even at doses of CAR T cells typically regarded as sub-efficacious. When STK-009 dosing was stopped after complete tumor responses, CD19 orthoCAR T cells contracted as expected. Subsequent redosing of STK-009 in these tumor free mice re-expanded CD19 orthoCAR T cell levels demonstrating the on-demand control of the STK-009/orthoCAR T cell platform. Given the deep and durable responses we observed in the disseminated Raji model, we subsequently invested investigated the efficacy of the STK-009/orthoCAR T cell platform in a subcutaneous Raji model of lymphoma characteristically resistant to CAR T cell therapy. No significant anti-tumor effect was observed in mice treated with either CAR T cells alone or the combination of high dose wild-type IL-2 and CAR T cells. The subcutaneous administration of STK-009 in combination with a sub-efficacious dose of CD19 orthoCAR T cells demonstrated significant expansion of the CD19 orthoCAR T cells with the clinically favorable TSCM and TEMRA immunophenotype and potent anti-tumor efficacy in this subcutaneous lymphoma model, demonstrating the selective potentiation of the CD19 orthoCAR T cells in response to STK-009. The toxicity of STK-009 was evaluated in a non-human primate dose-escalation study. Subcutaneous administration STK-009 at anticipated therapeutic doses showed no evidence of toxicity or biological effect on immune cells expressing the wild-type IL-2 receptor. Pharmacokinetic analysis of STK-009 in this study showed stable exposure with minimal clearance, demonstrating the selectivity of STK-009. These findings validate an orthogonal platform that selectively drives potent T cell effector functions of engineered cells without the toxicities mediated by NK cells or non-tumor specific T cells associated with high dose IL-2 therapy. These results demonstrate the ability of this orthogonal platform to improve the efficacy and durability of CAR T cell therapies. Disclosures Aspuria: Synthekine: Current Employment. Bauer:Synthekine: Current Employment. vivona:Synthekine: Current Employment. de Waal Malefyt:Synthekine: Current Employment. Kastelein:Synthekine: Current Employment. Oft:Synthekine: Current Employment. Emmerich:Synthekine: Current Employment. Rokkam:Synthekine: Current Employment. Kauder:Synthekine: Current Employment. McCauley:Synthekine: Current Employment. Riener:Synthekine: Current Employment. Verma:Synthekine: Current Employment.