Paving New Roads for CARs

CARs are a versatile platform to control T cell activation. Through advanced engineering, CAR signaling can be tuned to sculpt T cell responses and persistence in vivo. Combinations of CARs or SynNotch/CAR circuits can enhance the specificity of engineered T cells for tumors and tailor their therapeutic response. Tumor-localized production of immunomodulatory agents with CAR-T cells can relieve inhibition by the tumor microenvironment and improve efficacy. CRISPR-mediated targeted insertion of CARs at the TCR gene locus improves CAR-T cell therapy through more natural regulation of receptor expression. Synthetic biology approaches to CAR design and screening could rapidly identify new receptors optimized for particular disease contexts. Chimeric antigen receptor (CAR)-T cell therapy has had unprecedented impact in the treatment of hematological malignancies with few therapeutic options. However, it is clear that new strategies to enhance CAR-T cell function in solid tumors are needed to make these living drugs widely applicable. The roadblock in solid tumors has led to a surge in the development of strategies to enhance CAR-T cells through advanced receptor design, new tumor sensing mechanisms, coexpression of genes that improve T cell function or stimulate tumor immunity, and precise genome editing. Here we provide an overview of the current state of the art in CAR-T cell engineering and a framework for the development of next-generation immune cell therapies with synthetic biology. Chimeric antigen receptor (CAR)-T cell therapy has had unprecedented impact in the treatment of hematological malignancies with few therapeutic options. However, it is clear that new strategies to enhance CAR-T cell function in solid tumors are needed to make these living drugs widely applicable. The roadblock in solid tumors has led to a surge in the development of strategies to enhance CAR-T cells through advanced receptor design, new tumor sensing mechanisms, coexpression of genes that improve T cell function or stimulate tumor immunity, and precise genome editing. Here we provide an overview of the current state of the art in CAR-T cell engineering and a framework for the development of next-generation immune cell therapies with synthetic biology. apoptosis that is driven by repeated stimulation of T cells. This process is important for immune response resolution and for maintaining peripheral immune tolerance. the administration of tumor-reactive lymphocytes, such as ex vivo expanded tumor-infiltrating T cells or CAR-T cells. peptide or structural epitopes recognized by the variable regions of antibodies or TCRs. bispecific antibody platform comprising two separate scFvs fused via a peptide linker. One scFv often targets CD3, the other a tumor-associated antigen, thereby working as an adaptor for T cells to recognize tumor cells. type of cancer antibody-based therapy that targets immune checkpoints (e.g., PD-1, PD-L1, CTLA4) as a way to activate the endogenous immune response against tumor cells. artificial TCR designed to bind a specified disease-related target (often a cell-surface protein) through an extracellular scFv/nanobody/natural ligand–receptor portion and convert antigen binding to T cell activation through intracellular signaling domains. cytoplastic signaling domain derived from T cell co-stimulatory receptors that facilitate T cell expansion on antigen stimulation. These domains are often unstructured. component of many immunoglobulin-like receptors. They comprise a conserved amino acid sequence (YxxL/I-x6–8-YxxL/I), which is biphosphorylated at the two tyrosine residues. ITAM phosphorylation is a critical primary signaling event in a wide range of immune cells. cell-surface protein complex that binds and presents peptide antigens to TCRs. single-domain variable fragments derived from heavy chain-only antibodies (originally discovered among camelids) able to bind target antigens. analogs with diminished mTOR inhibitory function that retain their ability to chemically induce heterodimerization of mTOR/FRAP-derived domains. short linear stretches of amino acids in proteins. They are often found in the cytoplasmic tails of receptors and are sites of post-translational modification or binding sites for various classes of signaling proteins. synthetic version of the antigen-recognizing portion of a monoclonal antibody, comprising the variable regions of the heavy and light chains connected via a peptide linker. a synthetic version of the Notch receptor engineered with a user-determined ligand-binding domain and tethered transcription factor. The receptors can recognize disease or tissue-related antigens and directly initiate custom transcriptional programs in cells. ability of antigen-experienced T cells to persist in vivo. Increased T cell persistence is often associated with a less differentiated memory phenotype. receptor able to activate T cell recognition and binding of cognate peptides presented by MHCs. background receptor signaling in the absence of antigen. the heterogeneous tissue surrounding tumor cells, comprising infiltrating and resident immune cells, stromal cells, secreted factors, and extracellular matrix proteins.