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A synthetic biology approach to engineering circuits in immune cells

IMMUNOLOGICAL REVIEWS (2023)

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Summary: Cell adhesion molecules play a crucial role in various cellular processes, and their synthetic counterparts can be generated by combining extracellular interactions with intracellular domains. These synthetic molecules allow for customized cell-cell interactions with properties similar to native interactions. The intracellular domains determine the interface morphology and mechanics, while the extracellular interaction domains specify the connectivity between cells. This toolkit of synthetic cell adhesion molecules enables the assembly of multicellular architectures and the systematic remodeling of native tissues, providing insights into the evolution of different classes of cell-cell interfaces. Overall, these tools have significant implications for cell and tissue engineering and the study of multicellular organization.

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Article Oncology

CD4 CAR-T cells targeting CD19 play a key role in exacerbating cytokine release syndrome, while maintaining long-term responses

Camilla Bove et al.

Summary: This study investigated the role of CD4 and CD8 T cells in CD19 CAR-T cell responses and the development of cytokine release syndrome (CRS). CD4 CAR-T cells exhibited superior proliferation and activation potential compared to CD8 CAR-T cells. CD4 CAR-T cells were found to play a key role in the development of CRS, and CD4 CAR-T cells with embedded 4-1BB were associated with a safer profile. CD4 cells were crucial for maintaining long-term responses and the combination of CD4.BBz with CD8.28z CAR-T cells resulted in the lowest toxicity without compromising antitumor efficacy.

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Dual targeting of CD19 and CD22 with Bicistronic CAR-T cells in Patients with Relapsed/Refractory Large B Cell Lymphoma

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Louai Labanieh et al.

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Engineered skin bacteria induce antitumor T cell responses against melanoma

Y. Erin Chen et al.

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Review Oncology

Programming CAR T Cell Tumor Recognition: Tuned Antigen Sensing and Logic Gating

Mohamad Hamieh et al.

Summary: The success of CAR T cells in treating B-cell malignancies has opened up possibilities for treating solid tumors. However, challenges such as antigen escape and the lack of specific CAR targets need to be addressed. Recent advances in CAR T cell engineering offer potential solutions to these challenges by enhancing antigen sensitivity and enabling composite antigen recognition. These advancements have the potential to improve the clinical efficacy of CAR T cell therapies beyond B-cell malignancies.

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Chemokines expressed by engineered bacteria recruit and orchestrate antitumor immunity

Thomas M. Savage et al.

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Dana V. Foss et al.

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Decade-long leukaemia remissions with persistence of CD4(+) CAR T cells

J. Joseph Melenhorst et al.

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The evolution of synthetic receptor systems

Janvie Manhas et al.

Summary: Researchers have repurposed natural receptors to engineer synthetic receptors that enable cells to detect and respond to their environments. By improving and integrating protein-based receptors and signal-processing components, customized functions and programming can be achieved.

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Synthetic multistability in mammalian cells

Ronghui Zhu et al.

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Shuhang Wang et al.

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Theresa L. Murphy et al.

Summary: The clinical success of immune checkpoint therapy has led to a surge in tumor immunology research, with efforts aimed at enhancing ICT by identifying targets that synergize with existing therapies. Expanding principles through basic research may help broaden translational efforts. This review focuses on key aspects of dendritic cell biology, antigen processing, and helper cells that relate to ICT mechanisms and cell-mediated immunity.

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Mark L. Sandberg et al.

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Greg M. Allen et al.

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Multidimensional control of therapeutic human cell function with synthetic gene circuits

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Candice R. Gurbatri et al.

Summary: With the use of synthetic biology tools, researchers are repurposing bacteria as tumor-specific delivery systems, which can modulate the tumor microenvironment and enhance therapeutic efficacy and safety through their immunogenicity and local payload production.

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Katherine A. Freitas et al.

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Decoding CAR T cell phenotype using combinatorial signaling motif libraries and machine learning

Kyle G. Daniels et al.

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Pooled screening of CAR T cells identifies diverse immune signaling domains for next-generation immunotherapies

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CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) in Naïve/Memory T Cells for the Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma

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Jarrod Shilts et al.

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Mechanisms of CD40-dependent cDC1 licensing beyond costimulation

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RASA2 ablation in T cells boosts antigen sensitivity and long-term function

Julia Carnevale et al.

Summary: This study identifies RASA2 as a potential target gene that can enhance the efficacy of T cell therapies for cancer treatment. Ablation of RASA2 increases the activation and cytolytic activity of T cells, leading to improved cancer cell killing. Furthermore, RASA2-deficient CAR T cells have a competitive advantage in the bone marrow and extended the survival of mice in preclinical models. These findings highlight the importance of targeting RASA2 in enhancing T cell therapies for cancer treatment.

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Reversible ON- and OFF-switch chimeric antigen receptors controlled by lenalidomide

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Chimeric Antigen Receptor beyond CAR-T Cells

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Transcriptional regulatory network for the establishment of CD8+ T cell exhaustion

Wooseok Seo et al.

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EXPERIMENTAL AND MOLECULAR MEDICINE (2021)

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Andres Cubillos-Ruiz et al.

Summary: Cell-based therapeutics designed with synthetic biology is an emerging strategy in medicine, utilizing genetically engineered cells for precise therapeutic control and potential treatment of various diseases. Compared to traditional therapies, synthetic biology approaches offer greater flexibility, specificity, and predictability in combating human diseases.

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T cell circuits that sense antigen density with an ultrasensitive threshold

Rogelio A. Hernandez-Lopez et al.

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SCIENCE (2021)

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Jang Hwan Cho et al.

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Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling

Evan W. Weber et al.

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SynNotch CAR circuits enhance solid tumor recognition and promote persistent antitumor activity in mouse models

Axel Hyrenius-Wittsten et al.

Summary: The synthetic Notch (synNotch) CAR circuits improve the specificity and persistent antitumor activity of therapeutic T cells in solid tumors by preventing CAR-mediated tonic signaling, allowing T cells to maintain long-lived memory and non-exhausted phenotype. ALPPL2 is established as a clinically viable cell therapy target for multiple solid tumors, and synNotch CAR T cells demonstrate multifaceted therapeutic benefits.

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