Volume 8 Issue 4, April 2024

The on-target off-tumour toxicities of T-cell-engaging bispecific antibodies in patients can be captured in intestinal organoids derived from the patients’ biopsied tissue and supplemented with immune cells.

CRISPR–Cas12a was used to directly replace mouse antibody variable chain genes with human versions in primary B cells. The edited cells underwent affinity maturation in vivo, improving the potency of HIV-1 and SARS-CoV-2 neutralizing antibodies without loss of bioavailability. Affinity maturation of edited cells also enables new vaccine models and adaptive B cell therapies.

Many genetic therapies are limited by a lack of methods for delivering them to target cells in the body. We have developed technologies to engineer biological nanovesicles to load therapeutic proteins, target recipient immune cells and deliver Cas9 to knock out CXCR4 in primary human T cells.

Patient-derived intestinal organoids and tumouroids supplemented with immune cells can be used to predict and study the on-target off-tumour toxicities of T-cell-engaging bispecific antibodies and to capture inter-patient variabilities in the responses to the antibodies.

Mouse B cells can be reprogrammed via Cas12a to express human antibodies that when affinity-matured in recipient mice generate broader and more potent antibody variants.

Replacing the extracellular domains of heterodimeric cytokine receptors in chimeric antigen receptor T cells with two leucine zipper motifs leads to optimal JAK/STAT signalling and augments the effector function of the T cells.

Biologics can be specifically delivered to T cells by genetically engineering cells to secrete extracellular vesicles that actively load protein cargo and that display high-affinity T-cell-targeting domains and fusogenic glycoproteins.

The delivery of mRNAs into neurons at inflammatory sites in vivo can be enhanced by engineering leucocytes to produce extracellular vesicles incorporating mRNA-packaging retrovirus-like capsids.

The overexpression of eight immunomodulatory transgenes in mouse embryonic stem cells allows these immunologically ‘cloaked’ cells as well as tissues derived from them to escape rejection and to survive for months in immunocompetent allogeneic recipients.

Antigen-specific immunosuppression can be enhanced by genetically modifying mesenchymal stromal cells with chimaeric antigen receptors, as shown for the treatment of graft-versus-host disease in mice.

Antigen-restricted mature T cells can be generated from pluripotent stem cells edited to lack endogenous T cell receptors and class I major histocompatibility complexes by introducing the T cell selection components into the stromal microenvironment.

Metabolic rewiring during tachycardia promotes tissue hypoxia, elevated glucose utilization and the suppression of oxidative phosphorylation, driving contractile dysfunction.