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Adoptive chimeric antigen receptor (CAR) T cell therapy has proved a remarkable breakthrough in cancer treatment, with six FDA-approved therapies to date. This progress has motivated research efforts to expand its application to more complex cancer targets, as well as other diseases marked by cellular dysfunction. Current conventional CAR designs are limited by their ability to target only one cancer-associated antigen and suffer from a lack of tunability that results in broad toxicities and has limited their scope. To overcome these limitations, we have developed two inducible universal CAR platforms: a split, universal, programmable (SUPRA) CAR design that uses leucine zippers to decouple the targeting modality from the engineered T cell receptor, and recently a switchable CAR antibody-binding (SCARAB) platform that uses off-the-shelf antibody adapters for antigen targeting. In both platforms, separating the antigen binding domain into an added adapter allows control over the activation levels of the CAR T cells in a dose-dependent manner, reducing the risk of off-tumor toxicity. Additionally, the adapters can be switched to target multiple antigens and tackle more complex tumor phenotypes. First, we demonstrate the feasibility of using a SUPRA “OR” gate against FLT3 and CD33 as a therapeutic approach to tackle acute myeloid leukemia (AML), a heterogeneous hematopoietic malignancy marked by poor prognosis. The split platform affords tunability over activation levels and multiplexed targeting that tackles the disease heterogeneity and allowed us to identify a therapeutic dose window that eliminates cancer cell lines while sparing healthy hematopoietic stem cells. Next, we introduce the SCARAB platform that uses off-the-shelf FITC or biotin-conjugated antibodies as the targeting modality in a universal CAR design. The modular nature of this system allowed us to independently interrogate the effect of varying antigen binder choices on CAR targeting performance. We demonstrate the utility of this platform as an antigen screening tool to evaluate target combinations against ovarian cancer cells using an AND gate logic approach. Lastly, we adapt this universal platform towards other therapeutic indications, such as eliminating alloreactive or autoreactive T cell clones in transplant rejection and autoimmune disease using FITC or biotin-conjugated peptide-MHC multimer adapters. We develop in vitro models of major histocompatibility complex (MHC) mismatch in rejection and reactive T-cell receptor (TCR) targeting in Type 1 Diabetes and demonstrate that our universal CAR system can selectively target mouse and human TCRs in a pMHC-adapter dependent manner. These applications demonstrate the expansive utility of next-generation CAR T cell designs in broadening our cell therapy applications and developing the next wave of therapeutic platforms.

In 1954, Allport wrote, “No corner of the world is free from group scorn. Being fettered to our respective cultures, we … are bundles of prejudice” (4). In so many ways, prejudice seems part of the nature of human beings and an inevitable cognitive process that we all fall into. It is basically because the human mind is naturally skilled at forming categories of related information. This categorization skill leads people to think of individuals on the basis of the social categories to which they belong rather than considering them in terms of their unique attributes and characteristics. These categories function as templates, and when they designate people of other social groups, these templates are typically referred to as stereotypes (Amodio and Devine 251). Stereotypes thus have their basis in the human mind’s attempt at simplifying information and trying to understand the complex social environment around us. But stereotypes often lead to prejudice and discrimination. This project focuses specifically on the stereotypes surrounding Muslim women. Many of these stereotypes are triggered by hijab or veil. Hijab is a marker through which a hijabi woman is instantly recognized as being a Muslim. As a result, hijabi Muslim women are easy targets for Islamophobic sentiments that take the shape of various prejudicial attitudes and discrimination and sometimes even hate crimes. A hijabi Muslim woman is instantly categorized as an “other,” and the hijab, this piece of clothing, becomes a saturated symbol: a Muslim woman is seen as either oppressed and needing to be saved, with the hijab as the sign of oppression, or as a threat and an accomplice to terrorism, with the hijab as a sign of danger. To redress the stereotypes surrounding Muslim women, this dissertation has developed pedagogical practices employing various prejudice-reducing techniques, which are demonstrated using two literary works written by and about Western Muslim women. The two novels; Randa Abdel-Fattah’s Does My Head Look Big in This? and Mohja Kahf’s The Girl in the Tangerine Scarf, were selected to be used with young adult or college students. They offer ample opportunities to engage students in cognitive activities that have been found to reduce stereotyping and prejudice. The pedagogy developed here consists of questions, writing assignments, and discussion prompts that can be used in and outside the classroom to engage students in these prejudice-reducing cognitive activities and challenge stereotypical representations of Muslim women. One prejudice-reducing technique is to provide diverse representative exemplars that individually and collectively challenge and undermine stereotypical representations of Muslim women. These exemplars include the protagonists of the two books, Amal and Khadra, along with other Muslim women in their circles and communities. In Does My Head Look Big in This?, the main exemplar is the protagonist Amal, a 16-year-old Palestinian-Australian teenager who decides during winter break that she is ready to wear hijab full time. As a result, she faces various prejudicial attitudes inside and outside the posh private school that she goes to. Following her journey of faith and self-discovery, students are tuned through various questions and activities to pay attention to commonalities between themselves and Amal as a teenager. They are also guided to closely examine traits in Amal that challenge the assumption that Muslim women are oppressed and lack agency. Amal is strong-willed, and she independently decides to wear hijab, even though her parents are worried and not sure if she is ready to deal with the inevitable prejudice that comes with such a decision. Other female characters, such as Amal’s friend Leila, further demonstrate the strength, agency, and ambition of Muslim women and challenge the stereotypes of the weak ,submissive, or oppressed Muslim woman. The narrative also has numerous other influential exemplars of Muslim women. There is Amal’s mother Jamila, who is open-minded and supportive of her daughter, works as a dentist, and wears a headscarf. There is also Cassandra, a white blonde who is originally from England. She converted to Islam and married a Pakistani and often wears a beanie as a hijab and volunteers in a Christian-affiliated hospital. The pedagogy developed here includes activities that guide students to attend to and reflect on the diverse characteristics of these Muslim women characters and thus problematize the monolithic view of Muslim women as homogeneous and indistinguishable from each other. In The Girl in the Tangerine Scarf, Khadra is the most prominent exemplar of Muslim women. As students are led through various activities to follow her coming-of-age story closely, they will find similarities between themselves and Khadra in the various stages of development. They will also find, through close analysis and other activities, that Khadra’s Islamic upbringing does not stifle her agency and autonomy. On the contrary, through the various stages of her life, students will be able to observe her strength and agency in standing up for herself and not allowing anyone, including her parents, to stop her from doing what she deems right. Khadra is grounded in her religion and educated, which make her able to make well-informed decisions. Other Muslim women in the novel, such as Khadra’s mother and her Teta, reinforce the strength and agency of Muslim women and challenge the stereotypes of the submissive, oppressed, and uneducated Muslim woman. The pedagogy includes numerous activities that use these exemplars in the narrative to lead students to examine and note the diversity of Muslim women--diversity of ethnicities and backgrounds, of the careers they choose. and even of the ways they approach and interpret veiling or hijab. As students encounter these various exemplars of Muslim women and as they respond to the questions and engage in the other activities, they will internalize these varied representations of Muslim women and they will no longer have one single monolithic image for what a Muslim woman is. Another pedagogical approach to redressing and undermining stereotypes is through the use of empathy-evoking techniques. Empathy can be evoked through memory-based techniques, in which students are led to empathize by remembering a similar experience that they have had, and through perspective-taking, in which students are encouraged to imagine what it would feel like to be in another person’s situation. The two novels treated in this study offer situations that can easily be employed to evoke empathy in the readers. Most notably the protagonists are faced with prejudice and bullying incidents that can be effectively used to lead students either to remember bullying incidents in their own lives or to imagine themselves in the protagonists’ shoes through perspective-taking. In Does My Head Look Big in This?, various questions are posed to lead students to closely examine these incidents of prejudice and bullying. Amal, for instance, is faced with prejudiced attitudes from her school principal and is also constantly bullied by the school bully, Tia Tamo. Questions regarding these incidents are used to engage students in either remembering or imagining going through similar situations and then ask students to reflect on the empathetic feelings that such experiences evoke in them. For The Girl in the Tangerine Scarf, numerous questions and activities have been designed to lead students to adopt Khadra’s perspective and imagine her pain and terror as she experiences bullying. or to remember situations where they experienced similar feelings. For instance, during the Iranian hostage crisis, Khadra finds herself constantly subjected to bullying, which culminates in an incident where she is called raghead and two boys try to take off her scarf. Perhaps one of the strongest elements in the narrative that can be used to trigger empathy towards the plight of Muslim women is Zuhura’s murder by Klan members. Leading students to adopt Zuhura’s perspective, or her mother’s, or even Khadra’s, will trigger strong empathetic feelings as they experience the intensity of such a traumatic tragedy. The pedagogy developed here also employs various indirect contact techniques to redress prejudice towards Muslim women and to encourage future contact with them, so that students can truly experience the positive effects of actual contact. The two portray numerous relationships between ingroup and outgroup members, and these relationships can be effectively used to implement the various indirect contact cognitive techniques. Indirect contact techniques include vicarious contact, which entails observing in-group members having successful cross-group contact, and imagined contact, which entails imagining interaction with an outgroup member. Indirect contact techniques enact the safe haven hypothesis, which proposes that narrative fiction can provide a safe haven from the threats and anxiety entailed by direct contact.Indirect contact techniques can be enacted in Does My Head Look Big in This? by leading students through carefully designed activities and questions to observe, for instance, the interactions that Amal has with her circle of friends. Amal’s circle of friends includes Leila Okulgen, a Turkish seventeen-year-old Muslim girl; Yasmeen Khan, an Australian Muslim girl of Pakistani and British descent; and Eileen Tanaka, a sixteen-year-old Japanese girl. Each one of these girls can be an outgroup member to the other, and yet they choose to become fast friends, overcome their differences, and support each other at every turn. Students are prompted to observe the dynamics of these multiple relationships that Amal has, or to imagine having such relationships themselves. The narrative offers a “safe haven” for those who reject and fear direct contact with outgroup members, and so engaging in vicarious or imagined contact can lessen cross-group anxiety and encourage future interactions. In the Girl in the Tangerine Scarf, indirect contact techniques can be employed through questions that lead students to observe and learn behavioral scripts from the different friendships that Khadra has over the years. Her friends include Livvy Morton, a white Christian American, and Blu Froehlig, a Jewish American. There is also the blooming friendship that Ebtehja, Khadra’s mother, has with her American neighbor Norma. The pedagogy developed here employs various questions and prompts to lead students to observe the dynamics of these relationships and learn from them positive behavior scripts that can be emulated, as well as scripts that should be avoided. Additionally, the various cross-group relationships are also used as possible scripts to apply imagined-contact techniques, in which students imagine having interactions with a Muslim friend or neighbor. The pedagogy presented here works to repeatedly engage students in three basic prejudice-reducing cognitive activities: encountering multiple, diverse, counter-stereotypical exemplars of Muslim women; experiencing empathy for female Muslim characters; and engaging in indirect contact, both vicarious and imagined, with female Muslim characters. These activities promise to counteract students’ false and harmful stereotypes of Muslim women and help them recognize that beneath the hijab and other apparent differences, Muslim women are a heterogeneous group with whom the students share many qualities, including a common humanity.