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Maus 2048 Navigation menu VideoThe Highest Score and Tile in 2048 and The End of the Game
Grupp, David L. Porter, Carl H. Blood ; 17 : — T cells redirected to specific antigen targets with engineered chimeric antigen receptors CARs are emerging as powerful therapies in hematologic malignancies.
Various CAR designs, manufacturing processes, and study populations, among other variables, have been tested and reported in over 10 clinical trials.
Here, we review and compare the results of the reported clinical trials and discuss the progress and key emerging factors that may play a role in effecting tumor responses.
We also discuss the outlook for CAR T-cell therapies, including managing toxicities and expanding the availability of personalized cell therapy as a promising approach to all hematologic malignancies.
Many questions remain in the field of CAR T cells directed to hematologic malignancies, but the encouraging response rates pave a wide road for future investigation.
Immune-based therapies for cancer have the tantalizing possibility of effecting long-term durable remissions and perhaps even offering the possibility of a cure.
This is the basis for the US Food and Drug administration FDA approval of interleukin-2 IL-2 in melanoma; more recent immune therapies that are FDA-approved treatments for cancer involve checkpoint blockade, which is a form of releasing the brakes on tumor-specific T cells and allowing them to persist and expand in vivo, leading to control or regression of cancer.
Adoptive T-cell therapy also offers this possibility but has thus far been limited in application to those patients with melanoma who have adequate culture and expansion of isolated tumor-infiltrating lymphocytes.
Therapeutic approaches to overcome immune tolerance to tumors. Cytokines and vaccines can be used to augment natural T-cell responses to tumor.
Antibodies targeting negative regulatory molecules such as programmed death 1 PD-1 and cytotoxic T-cell lymphocyte-associated antigen 4 CTLA-4 can be infused to release the brakes on natural T cells responsive to tumor.
Chemotherapy can reduce immune suppressive cells such as Tregs and myeloid-derived suppressor cells MDSC in addition to its direct effect on the tumor cells.
The infusion of gene-modified T cells directed to specific target antigens offers the same possibilities of long-term disease control and has the added benefit of the rapid onset of action that is usually seen with cytotoxic chemotherapy or with targeted therapies.
In particular, T cells modified to express antibody-based chimeric antigen receptors circumvent both immune tolerance of the T-cell repertoire and MHC restriction.
Furthermore, advances in the culture process and molecular and virology techniques used to introduce novel genes into T cells have made the manufacturing of gene-modified peripheral blood—derived T cells relatively straightforward.
In the last 5 years, chimeric antigen receptor CAR -redirected T cells have emerged from the bench and made splashy headlines in the clinical setting at a number of academic institutions.
It is not surprising that CAR T cells directed to hematologic malignancies have been the first ones tested, given the extent of the known surface antigens expressed on hematologic cells, the relative ease of sampling tumor, and the natural preference of T-cell homing to hematologic organs such as the blood, bone marrow, and lymph nodes.
Here, we will introduce the various CAR designs that have been tested clinically, the results from a series of clinical trials testing CAR T cells, and an overview and comparison of the manufacturing processes used.
We will also discuss the emerging toxicity profiles and management strategies and future outlook of CAR T-cell therapies. We limit our discussion to CAR T cells in hematologic malignancies and will not cover CARs that have been tested in solid tumors or engineered T-cell receptors TCRs that have been tested in any setting.
CARs are synthetic, engineered receptors that can target surface molecules in their native conformation. CARs typically engage the target via a single-chain variable fragment scFv derived from an antibody, although natural ligands have also been used.
Preclinical data suggest that the spatial location of epitope binding has a bigger effect on CAR activity than variation in affinity.
The hinge and transmembrane domains are probably the least commented on aspect of CAR design, though they may make important contributions to the interaction with antigen, assembly of the immunologic synapse, and association of the CAR with other proteins necessary to transduce a robust activation signal.
Chimeric antigen receptors. CARs target surface antigens in an MHC-independent fashion and consist of an ectodomain, hinge domain, transmembrane domain, and endodomain.
The initial trials tested first-generation CARs that have a single cytoplasmic domain. Current trials are testing second- and third-generation CARs that have combinations of signaling domains.
Investigators in the field are using a variety of methods to introduce their CAR constructs into T cells.
Non—viral-based DNA transfection was initially used because of cost and the low risk of insertional mutagenesis. This method requires long-term culture and antibiotic selection due to the relative inefficiency of gene transfer.
The long-term culture may be detrimental to the activity and persistence of the infused cells, and the antibiotic-resistance gene products may render them immunogenic.
Transposon-based systems can integrate transgenes more efficiently than plasmids that do not contain an integrating element. Use of specific promoters in combination with lentiviral transduction has enabled sustained surface expression of CARs on transduced T cells; this likely extends the survival of functional CAR T cells in vivo.
The methods and duration of T-cell culture used in the manufacturing of CAR T cells may also be an important variable in the composition of the final CAR T-cell product.
Generally, the options have involved combinations of TCR stimulation through antibodies and supportive cytokines or artificial antigen-presenting cells that are either cell based or bead based.
There are 14 publications reporting clinical trials of CAR T cells in hematologic malignancies. The CAR design, manufacturing process, and results are summarized in Table 1.
Each group has designed slightly different protocols, and they vary with regard to design of the CAR, expression of the CAR on the T cells, T-cell culture conditions, lymphodepleting strategy, cytokine support for the infused T cells, disease targeted, and timing of CAR T-cell infusion with regard to standard therapy such as bone marrow transplantation.
Not surprisingly, the most effective CAR T-cell products are also associated with on-target toxicity. The results of these clinical trials point to several key factors that may have an impact on the efficacy of CAR-modified T cells in hematologic malignancies.
At the level of product characterization, the relative importance of the CD4:CD8 ratio or the proportion of regulatory T cells Tregs in the final product is not clear, and it is not known if the T-cell product can be improved upon by selection or graft engineering.
Characterization of the tumor microenvironment, and in particular the inhibitory factors that may affect or abrogate CAR T-cell lytic functions, will be even more complex to sort out.
Several investigators have also aimed to address the question of whether or which lymphodepletion strategy to use and whether supporting the infused T cells with systemically administered cytokines will improve their expansion or persistence; although both strategies appear to be improve T-cell engraftment, they may confound interpretation of efficacy and toxicity, and neither appears to be universally required for CAR T-cell—mediated responses.
At least a few key characteristics of efficacious CAR T-cell products have emerged. One is that expression of the CAR at the cell surface seems to be required for efficacy; another is that in vivo detection of the CAR T-cell product in the blood is a sign of adequate engraftment and that engraftment is required for responses.
Detection of the CAR transgene by polymerase chain reaction does not inform about the surface expression of the CAR, which is the only form that matters for efficacy.
Thus, the availability of reagents to specifically detect CARs at the cell surface by flow cytometry is crucial to understand the activity and engraftment of CAR T cells.
In addition, it is not yet clear if there is a relationship between the dose of CAR T cells administered and the level of engraftment that is achieved, ie, the in vivo dose.
Some degree of persistent engraftment is also required, although the length of this persistence has not been established.
We hypothesize that for CAR T cells to be able to replace allogeneic transplantation as definitive therapy, persistence for at least several months will probably be required based on the kinetics of tumor clearance that we have observed.
The question of whether CAR T cells are on par with the efficacy of transplant would best be answered in randomized trials.
However, short of this, we also anticipate many recipients of CAR T cells will not eligible for transplant or have comorbidities or only suboptimal donors available such that the transplant is impractical.
Long-term follow up of these patients will provide critical information about the durability of CAR T-cell—induced remissions.
Alternatively, the answer may come from patients who have relapsed after an allogeneic transplant, for whom a second transplant may not be possible or efficacious; these patients may benefit from CAR T-cell products that potentially offer durable remissions.
The use of CAR-modified donor T cells to treat relapsed ALL is being tested by our group and will hopefully be studied in a multisite trial.
In addition, multisite trials are underway in collaboration with Novartis, and a dual-center grant-funded trial between MSKCC and the University of Pennsylvania involves a competitive repopulation study design where T cells transduced with Penn vector and MSKCC vector are infused simultaneously into each patient.
Given the finding that, in most cases, cytokine release syndrome CRS seems to correlate with antitumor activity, one question that has emerged is the degree to which the innate immune system contributes to antitumor efficacy.
It is possible that the IL-6 is produced by the dying B cells, dying tumor cells, or activated macrophages that are recruited to digest lysed tumor cells.
Does interruption of the cytokine cascade lead to interruption of the antitumor effect? This remains an unanswered question and has direct clinical impact for patients and physicians deciding on when to abort the CRS.
Furthermore, although, in our experience, most responding patients have some degree of CRS, it is not yet clear whether the severity of CRS or macrophage activation syndrome MAS is related to antitumor efficacy.
Spiegelman took advantage of the way Nazi propaganda films depicted Jews as vermin,  though he was first struck by the metaphor after attending a presentation where Ken Jacobs showed films of minstrel shows along with early American animated films, abundant with racial caricatures.
Healthy emotions tell every independent young man and every honorable youth that the dirty and filth-covered vermin, the greatest bacteria carrier in the animal kingdom, cannot be the ideal type of animal Away with Jewish brutalization of the people!
Down with Mickey Mouse! Wear the Swastika Cross! Jewish characters try to pass themselves off as ethnic Poles by tying pig masks to their faces, with the strings showing at the back.
Spiegelman shows this Jewishness by having her tail hang out of her disguise. According to art historian Andrea Liss , this may paradoxically enable the reader to identify with the characters as human, preventing the reader from observing racial characteristics based on facial traits, while reminding readers that racist classification is ever present.
In making people of each ethnicity look alike, Spiegelman hoped to show the absurdity of dividing people along such lines.
Spiegelman has stated that "these metaphors When asked what animal he would make Israeli Jews , Spiegelman suggests porcupines.
In every respect other than their heads and tails, they act and speak as ordinary humans. To Marianne Hirsch , Spiegelman's life is "dominated by memories that are not his own".
This describes the relation of the children of survivors with the survivors themselves. While these children have not had their parents' experiences, they grow up with their parents' memories—the memory of another's memory—until the stories become so powerful that for these children they become memories in their own right.
The children's proximity creates a "deep personal connection" with the memory, though separated from it by "generational distance". Art tried to keep his father's story chronological, because otherwise he would "never keep it straight".
Hirsch sees Maus in part as an attempt to reconstruct her memory. Vladek keeps her memory alive with the pictures on his desk, "like a shrine", according to Mala.
Spiegelman displays his sense of guilt in many ways. He suffers anguish over his dead brother, Richieu, who perished in the Holocaust, and whom he feels he can never live up to.
When she berates him, a victim of antisemitism, for his attitude, he replies, "It's not even to compare, the schwartsers and the Jews! The Germans are depicted with little difference between them, but there is great variety among the Poles and Jews who dominate the story.
Spiegelman shows numerous instances of Poles who risked themselves to aid Jews, and also shows antisemitism as being rife among them.
The kapos who run the camps are Poles, and Anja and Vladek are tricked by Polish smugglers into the hands of the Nazis.
Anja and Vladek hear stories that Poles continue to drive off and even kill returning Jews after the war. Vladek's English is broken in contrast with that of Art's more fluent therapist, Paul Pavel, who is also an immigrant and Holocaust survivor.
He also uses it to befriend a Frenchman, and continues to correspond with him in English after the war. His recounting of the Holocaust, first to American soldiers, then to his son, is never in his mother tongue,  and English becomes his daily language when he moves to America.
I was very religious, and it wasn't else to do". This unidiomatic expression was used as the subtitle of the second volume.
The German word Maus is cognate to the English word "mouse",  and also reminiscent of the German verb mauscheln , which means "to speak like a Jew"  and refers to the way Jews from Eastern Europe spoke German  —a word not etymologically related to Maus , but distantly to Moses.
Spiegelman's perceived audacity in using the Holocaust as his subject was compounded by his telling the story in comics. The prevailing view in the English-speaking world held comics as inherently trivial,  thus degrading Spiegelman's subject matter, especially as he used animal heads in place of recognizably human ones.
Ostensibly about the Holocaust, the story entwines with the frame tale of Art interviewing and interacting with his father.
Art's "Prisoner on the Hell Planet" is also encompassed by the frame, and stands in visual and thematical contrast with the rest of the book as the characters are in human form  in a surreal , German Expressionist woodcut style inspired by Lynd Ward.
Spiegelman blurs the line between the frame and the world, such as when neurotically trying to deal with what Maus is becoming for him, he says to his wife, "In real life you'd never have let me talk this long without interrupting.
Spiegelman started taking down his interviews with Vladek on paper, but quickly switched to a tape recorder,  face-to-face or over the phone.
Spiegelman worried about the effect that his organizing of Vladek's story would have on its authenticity.
In the end, he eschewed a Joycean approach and settled on a linear narrative he thought would be better at "getting things across".
The story is text-driven, with few wordless panels  in its 1, black-and-white panels. There is little gray in the shading.
Spiegelman rendered the original three-page "Maus" and "Prisoner on the Hell Planet" in highly detailed, expressive styles. Spiegelman planned to draw Maus in such a manner, but after initial sketches he decided to use a pared-down style, one little removed from his pencil sketches, which he found more direct and immediate.
Characters are rendered in a minimalist way: animal heads with dots for eyes and slashes for eyebrows and mouths, sitting on humanoid bodies. Spiegelman wanted the artwork to have a diary feel to it, and so drew the pages on stationery with a fountain pen and typewriter correction fluid.
It was reproduced at the same size it was drawn, unlike his other work, which was usually drawn larger and shrunk down, which hides defects in the art.
Spiegelman has published articles promoting a greater knowledge of his medium's history. Spiegelman stated, "without Binky Brown , there would be no Maus ".
Spiegelman's work as cartoonist and editor had long been known and respected in the comics community, but the media attention after the first volume's publication in was unexpected.
Maus proved difficult to classify to a genre,  and has been called biography, fiction, autobiography, history, and memoir. An editor responded, "Let's go out to Spiegelman's house and if a giant mouse answers the door, we'll move it to the nonfiction side of the list!
Maus ranked highly on comics and literature lists. The Comics Journal called it the fourth greatest comics work of the 20th century,  and Wizard placed it first on their list of Greatest Graphic Novels.
Early installments of Maus that appeared in Raw inspired the young Chris Ware to "try to do comics that had a 'serious' tone to them".
In , cartoonist Ted Rall had an article published in The Village Voice criticizing Spiegelman's prominence and influence in the New York cartooning community.
Hellman followed up by posting fake responses from New York magazine editors and art directors. A cottage industry of academic research has built up around Maus ,  and schools have frequently used it as course material in a range of fields: history, dysfunctional family psychology,  language arts, and social studies.
Few approached Maus who were familiar with comics, largely because of the lack of an academic comics tradition— Maus tended to be approached as Holocaust history or from a film or literary perspective.
According to writer Arie Kaplan, some Holocaust survivors objected to Spiegelman making a comic book out of their tragedy. Harvey argued that Spiegelman's animal metaphor threatened "to erode [ Maus ' s] moral underpinnings",  and played "directly into [the Nazis'] racist vision".
Commentators such as Peter Obst and Lawrence Weschler expressed concern over the Poles' depiction as pigs,  which reviewer Marek Kohn saw as an ethnic slur  and The Norton Anthology of American Literature called "a calculated insult".
Literary critic Walter Ben Michaels found Spiegelman's racial divisions "counterfactual". To Michaels, Maus seems to gloss over the racial inequality that has plagued the history of the U.
Other critics, such as Bart Beaty, objected to what they saw as the work's fatalism. Scholar Paul Buhle asserted, "More than a few readers have described [ Maus ] as the most compelling of any [Holocaust] depiction, perhaps because only the caricatured quality of comic art is equal to the seeming unreality of an experience beyond all reason.
The book reproduced every page and line of dialogue from the French translation of Maus. Spiegelman's French publisher, Flammarion , had the Belgian publisher destroy all copies under charges of copyright violation.
Moss, Joshua Louis University of Texas Press. From Wikipedia, the free encyclopedia. This article is about the graphic novel.
For other uses, see Maus disambiguation. This spelling was chosen for Maus as it was deemed the easiest spelling for English speakers to pronounce correctly.
The German version of his name was "Wilhelm" or "Wolf" for short , and he became William when he moved to the U.
Her name became Anna when she and Vladek arrived in the U. Abell, Catharine Documentary Graphic Novels and Social Realism. Peter Lang.
Continuum International Publishing Group. Picturing the Beast: Animals, Identity, and Representation. Manchester University Press. The Listener : Ball, David M.
University Press of Mississippi. After the End: Representations of Post-Apocalypse. University of Minnesota Press.
Columbia University Press. The Power of Comics. Comic Book Collections for Libraries. In Witek, Joseph ed. Art Spiegelman: Conversations.
Walter de Gruyter. Alternative Comics: An Emerging Literature. Yale University Press. Family Frames: Photography, Narrative, and Postmemory.
Harvard University Press. In Shatzky, Joel; Taub, Michael eds. Greenwood Publishing Group. University of Chicago Press. In Baetens, Jan ed.
The Graphic Novel. Leuven University Press. Masters of the Comic Book Universe Revealed! Chicago Review Press. Jewish Publication Society.
The Norton Anthology of American Literature. History and Memory After Auschwitz. Cornell University Press. Stanford University Press.
In Williams, Paul; Lyons, James eds. University of Virginia Press. Camden House Publishing. Monnin, Katie Maupin House Publishing, Inc.
In Klaehn, Jeffery ed. Inside the World of Comic Books. Black Rose Books. The information in this document applies to the following:. Microsoft Windows 10 19H1 Version To resolve this issue, perform the following procedures:.
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