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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. Silberstein, Laurence Jay ed. Mapping Jewish Identities.
New York University Press. Comic Books: How the Industry Works. University of Nebraska Press. In Ndalianis, Angela ed. The Contemporary Comic Book Superhero.
Adult Comics: An Introduction. In Royal, Derek Parker ed. Purdue University Press. Chute, Hillary ed. Viking Press.
Oxford University Press. Northwestern University Press. NBM Publishing. Princeton University Press. Da Capo Press. Walch Publishing. In Rüsen, Jörn ed.
Meaning and Representation in History. Berghahn Books. Arnold, Andrew D. September 7, Retrieved February 19, Stephen October The Comics Journal.
Fantagraphics Books. Bibcode : Natur. Oral History Review. Oral History Association Spring : 91— Twentieth Century Literature.
Frahm, Ole May Geis ed. Retrieved January 30, Retrieved February 1, Fantagraphics Books : February Groth, Gary ed.
Fantagraphics Books Retrieved March 1, Pekar, Harvey December Fantagraphics Books : 54— Fantagraphics Books : 36— Lingua Franca.
Retrieved May 15, University of Florida. Archived from the original on November 29, Retrieved April 16, Wizard Entertainment Couvreur, Daniel March 5, Le Soir in French.
Archived from the original on November 2, 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.
The severity of CRS does appear to be related to the tumor burden. If engagement of the innate immune system contributes to the mechanism of action, this could bode well for the use of CAR T cells in solid tumors, where T cells may not preferentially home to and persist at the sites of tumors as efficiently as they do in hematologic malignancies.
Several patients in CDCAR trials across institutions have experienced obtundation, seizures, aphasia, and mental status changes, which have all been reversible.
Some of these may be related to CRS, but whether this results from systemic cytokines crossing the blood-brain barrier and engaging cytokine receptors in the brain or from direct cytokine production in the central nervous system CNS is not clear.
Blinatumomab, a type of bispecific T-cell—engaging antibody BiTE that is a fusion protein between an anti-CD19 scFv and an anti-CD3 scFv, also has neurologic toxicity and seizures as its dose-limiting toxicity, even though it does not appear to control CNS disease.
It is interesting that blinatumomab has also been shown to cause MAS. B-cell aplasia is an expected on-target result of CDdirected therapies and has served as useful surrogate to determine the persistence and effectiveness of CDdirected CAR T cells.
Persistent B-cell aplasia could also result in an increased risk of infection even with replacement therapy. In an ideal setting, the CAR T cells would persist long enough to mediate definitive control of disease but then allow for recovery of normal B-cell and plasma cell recovery such that patients could be revaccinated.
As more patients are treated with CAR T cells directed to CD19, clinician investigators will need to establish straightforward algorithms for management of toxicities, including the optimal timing and dose of administration of cytokine blockade, corticosteroids, and immunoglobulin replacement.
However, suicide systems are still difficult to implement in all CAR T-cell trials, because many of the suicide systems are immunogenic eg, herpes simplex virus thymidine kinase or require intravenous administration of the suicide-inducing prodrug.
All investigators involved in CAR T-cell trials are acutely aware of the technical, regulatory, and financial challenges in manufacturing single-patient product lots.
One potential solution is to generate universal T-cell products from allogeneic donors, based on knockdown of the HLA genes coupled with enforced expression of nonclassical HLA molecules to avoid natural killer NK cell—mediated recognition and lysis.
One mandate of the guidance is for sponsors to attempt to define the active ingredient in the cell or gene therapy product.
For gene-modified T cells, there are multiple factors that contribute to the definition of the active ingredient: optimal vector, culture conditions, CAR design, cell type, and dose of that cell type.
However, the precise type of cell that is transduced may be important in defining the active ingredient as well. Most investigators have focused on peripheral blood—derived T cells and subsets of these such as virus-specific T cells, central memory T cells, or cord blood—derived T cells.
Aside from defining the optimal cell product, there are 2 main hurdles in broadening the use of CAR-directed T cells beyond B-cell malignancies: target discovery and manufacturing on a wide scale.
Baylor has 2 open clinical trials targeting CD30 in Hodgkin disease, and the University of Cologne plans to treat patients with mycosis fungoides with CD30 CAR T cells encoding a CD28 domain with a deleted lck binding moiety, based on preclinical data that this reduces Tregs in the tumor microenvironment.
In the case of CDdirected CAR T cells, multisite trials are in the planning stages for several groups and now include involvement of the pharmaceutical and biotechnology industries as well as cooperative group networks.
This is an exciting time in the treatment strategies for all hematologic malignancies; a decade ago, few would have predicted that the promises of gene-modified cell therapies would be delivered by CAR T cells directed to aggressive hematologic malignancies such as adult and pediatric B-cell ALL.
Contribution: M. Conflict-of-interest disclosure: M. All authors have sponsored research grant support from Novartis.
Sign In or Create an Account. Sign In. Skip Nav Destination Content Menu. Close Abstract. Review of clinical data with CAR T cells in hematologic malignancies.
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