CAR-based therapies: opportunities for immuno-medicine beyond cancer

Aghajanian, Haig; Rurik, Joel G.; Epstein, Jonathan A.

doi:10.1038/s42255-022-00537-5

Cited by 63 publications

(52 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This information could be important in the field of finding therapeutic candidates for renal fibrosis. We noted a large cluster of FAP-positive fibroblasts in diseased human kidneys (44)(45)(46). FAP targeted cellular and RNA therapies have been developed and shown to have efficacy animal models of cardiac fibrosis (44)(45)(46).…”

Section: Discussionmentioning

confidence: 89%

Spatially resolved human kidney multi-omics single cell atlas highlights the key role of the fibrotic microenvironment in kidney disease progression

Abedini

Frederick

et al. 2022

Preprint

View full text Add to dashboard Cite

Kidneys have one of the most complex three-dimensional cellular organizations in the body, but the spatial molecular principles of kidney health and disease are poorly understood. Here we generate high-quality single cell (sc), single nuclear (sn), spatial (sp) RNA expression and sn open chromatin datasets for 73 samples, capturing half a million cells from healthy, diabetic, and hypertensive diseased human kidneys. Combining the sn/sc and sp RNA information, we identify > 100 cell types and states and successfully map them back to their spatial locations. Computational deconvolution of spRNA-seq identifies glomerular/vascular, tubular, immune, and fibrotic spatial microenvironments (FMEs). Although injured proximal tubule cells appear to be the nidus of fibrosis, we reveal the complex, heterogenous cellular and spatial organization of human FMEs, including the highly intricate and organized immune environment. We demonstrate the clinical utility of the FME spatial gene signature for the classification of a large number of human kidneys for disease severity and prognosis. We provide a comprehensive spatially-resolved molecular roadmap for the human kidney and the fibrotic process and demonstrate the clinical utility of spatial transcriptomics.

show abstract

Section: Discussionmentioning

confidence: 89%

Spatially resolved human kidney multi-omics single cell atlas highlights the key role of the fibrotic microenvironment in kidney disease progression

Abedini

Frederick

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…T cells engineered to express chimeric antigen receptors are considered a revolution in cell and gene therapy owing to their success in the treatment of lymphocytic leukemia and promissory to treat solid tumors. The redirection of cytotoxic T cells using CAR technology to target proteins, carbohydrates, lipids, and other molecules has opened new applications of CAR technology beyond cancer [ 6 ]. Although this therapy has proven to be potent in targeting several types of epitopes, the rationale for CAR design must be considered when applied to a new ligand.…”

Section: Discussionmentioning

confidence: 99%

“…In 2017, the US Food and Drug Administration approved the first CAR T-cell product manufactured to target B-cell lymphoma [ 5 ]. Major successes in oncology have led to many possibilities of using CARs to redirect immune cells to treat autoimmune diseases [ 6 ] and infections caused by viruses or fungi [ 7 ]. The importance of T cells and natural killer (NK) cells in antifungal immunity is well established [ 8 , 9 ], and previous studies have demonstrated the capacity of CAR-modified cells to target invasive forms of Aspergillus fumigatus and Cryptococcus spp.…”

Section: Introductionmentioning

confidence: 99%

Modification of Hinge/Transmembrane and Signal Transduction Domains Improves the Expression and Signaling Threshold of GXMR-CAR Specific to Cryptococcus spp.

Santos

Machado

Kumaresan

et al. 2022

Cells

View full text Add to dashboard Cite

Chimeric antigen receptors (CARs) redirect T cells to recognize a specific target. CAR components play a pivotal role in antigen specificity, structure stability, expression on cell surface, and induction of cellular activation, which together determine the success of CAR T-cell therapy. CAR products targeting B-cell lymphoma encouraged the development of new CAR applications beyond cancer. For example, our group developed a CAR to specifically target glucuronoxylomannan (GXM) in the capsule of Cryptococcus species, called GXMR-CAR or GXMR-IgG4-28ζ. Cryptococcus are fungi that cause the life-threatening disease cryptococcosis, and GXMR-IgG4-28ζ redirected T cells to target yeast and titan cell forms of Cryptococcus spp. Here, we replaced the IgG4-hinge and CD28-transmembrane domains from GXMR-CAR with a CD8α molecule as the hinge/transmembrane and used CD28 or 4-1BB molecules as co-stimulatory domains, creating GXMR-8-28ζ and GXMR-8-BBζ, respectively. Jurkat cells expressing GXMR-CAR containing CD8α as the hinge/transmembrane improved the CAR expression and induced a tonic signaling. GXMR-8-28ζ and GXMR-8-BBζ induced high levels of IL-2 and up-regulation of CD69 expression in the presence of reference strains of C. neoformans and C. gattii. Moreover, GXMR-8-28ζ and GXMR-8-BBζ showed increased strength in response to incubation with clinical isolates of Cryptococcuss spp., and 4-1BB co-stimulatory domain triggered a more pronounced cellular activation. Dasatinib, a tyrosine kinase inhibitor, attenuated the GXMR-CAR signaling cascade’s engagement in the presence or absence of its ligand. This study optimized novel second-generation GXMR-CARs containing the CD8-hinge/transmembrane domain that improved CAR expression, antigen recognition, and signal strength in T-cell activation.

show abstract

“…Recently, a group of investigators showed the feasibility to produce in vivo engineered T cells, by injecting T cell-targeted lipid nanoparticles with modified mRNA to ameliorate cardiac fibrosis in mice ( Rurik et al., 2022 ). A growing body of preclinical data supports the use of these combinatorial approaches to treat pathologies beyond cancer, including autoimmune, metabolic and infectious diseases ( Aghajanian et al, 2022 ). Thus, we envision that coupling of these technologies holds tremendous promise in harnessing the next generation of T cell-based immunomodulatory pharmacotherapies to treat an expanding population of patients with severe Gram-negative pneumonia.…”

Section: Discussionmentioning

confidence: 99%

Gearing up for battle: Harnessing adaptive T cell immunity against gram-negative pneumonia

Gao

Morales‐Nebreda

Pickens

2022

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Pneumonia is one of the leading causes of morbidity and mortality worldwide and Gram-negative bacteria are a major cause of severe pneumonia. Despite advances in diagnosis and treatment, the rise of multidrug-resistant organisms and hypervirulent strains demonstrates that there will continue to be challenges with traditional treatment strategies using antibiotics. Hence, an alternative approach is to focus on the disease tolerance components that mediate immune resistance and enhance tissue resilience. Adaptive immunity plays a pivotal role in modulating these processes, thus affecting the incidence and severity of pneumonia. In this review, we focus on the adaptive T cell responses to pneumonia induced by Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. We highlight key factors in these responses that have potential for therapeutic targeting, as well as the gaps in current knowledge to be focused on in future work.

show abstract

CAR-based therapies: opportunities for immuno-medicine beyond cancer

Cited by 63 publications

References 71 publications

Spatially resolved human kidney multi-omics single cell atlas highlights the key role of the fibrotic microenvironment in kidney disease progression

Spatially resolved human kidney multi-omics single cell atlas highlights the key role of the fibrotic microenvironment in kidney disease progression

Modification of Hinge/Transmembrane and Signal Transduction Domains Improves the Expression and Signaling Threshold of GXMR-CAR Specific to Cryptococcus spp.

Gearing up for battle: Harnessing adaptive T cell immunity against gram-negative pneumonia

Contact Info

Product

Resources

About