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In vivo loss-of-function CRISPR screens were performed to identify genes influencing CAR T cell persistence and function in human multiple myeloma, highlighting CDKN1B as a promising target.

Promising clinical activity of Claudin (CLDN) 18.2-directed CAR-T cell therapy in patients with gastric cancer has been recently reported, however gastrointestinal toxicities have also been described. Here the authors recapitulate the on-target off-tumor toxicity of CLDN18.2-directed CAR-T cells due to gastric mucosa damage in preclinical models, suggesting an AND-gate strategy targeting CLDN18.2 and mesothelin to overcome CAR-T cell toxicity

Components of the glycocalyx have been shown to impair immune cell functions, including of CAR-T cells. Here the authors show that CAR-T cell mediated cytotoxicity in pancreatic cancer models can be enhanced by incorporating non-signalling binding domains that target the glycocalyx.

CAR-T therapy is a promising treatment modality for B-cell malignancies, yet many patients relapse. Using an in vivo genomewide screen in a model of B cell leukemia, we identify an unexpected mechanism of CAR-T resistance in which interferon gamma from the in vivo tumor microenvironment induces an adaptive T-cell resistance program in tumor cells.

Patients with myeloma multiple treated with BCMA CAR T cells often relapse with BCMA-negative disease or antigen escape. Here the authors describe the design of TACI-directed single and dual CAR T cells with in vitro and in vivo activity against multiple myeloma, overcoming BCMA antigen loss.

Single-cell transcriptomics analyses of pretreatment and post-treatment peripheral blood mononuclear cells from patients treated with CD19 chimeric antigen receptor (CAR)-T products reveal a role for CAR-T regulatory cells in treatment relapse.

This is a post hoc 18-month follow-up analysis of the CRB-401 trial, testing idecabtagene vicleucel (ide-cel, bb2121) in relapsed and refractory multiple myeloma, and reports sustained safety and clinical efficacy, which correlates with T cell phenotypes.

The T cells of the immune system can be engineered to target a tumour, but why some people respond better than others to such therapy is unclear. One patient’s striking response to treatment now offers some clues.

Genomics analyses reveal that in vitro culture of CAR T cells can lead to reactivation of a latent herpesvirus, which might be involved in complications in patients receiving associated cell therapies.

Cytokines released after T cell activation improve the efficacy of T cell therapies in mice.

Immune cells known as T cells can destroy tumour cells, but their clinical use requires complex preparation and the cells can lose effectiveness over time. A new approach might improve the efficiency of T-cell therapy. See Letter p.113

Infections account for the highest number of non-relapse-related deaths after CAR T cell therapy, underscoring the necessity for clinical risk-mitigating strategies and a deeper understanding of CAR T cell-related cytopenia.

BiTE-secreting CAR-T cells overcome antigen escape from EGFRvIII-targeted therapy for glioblastoma.

Supraphysiological T cell activation by chimeric antigen receptor (CAR) contributes to T cell exhaustion and adverse events in CAR T cell therapies. Here the authors engineer a synthetic antigen receptor that integrates into the endogenous TCR complex, preserving natural regulatory circuits and achieving improved performance in mouse tumor models.

Loss-of-function CRISPR-based screens have identified several genes associated with cancer resistance to T cell-induced cytotoxicity. Here the authors perform a genome-scale, gain-of-function CRISPR screen and identify candidate genes, including the poly-N-acetyllactosamine synthase B3GNT2, whose overexpression confers tumor cell resistance to T cell cytotoxicity

Shortages of CAR T cells should be alleviated by distributed manufacturing, according to Elsallab and Maus.

The composition of the intestinal microbiome may predict clinical outcomes of CAR-T cell therapy for lymphoma, which could inform microbiota-based intervention strategies.

A genome-wide CRISPR knockout screen in a model of glioblastoma shows that killing by chimeric antigen receptor T cells requires interferon-γ receptor-dependent adhesion to tumour cells, but cytotoxicity of liquid tumours does not rely on this pathway.

Structure-guided protein engineering of Cas12a yields variants that have increased activity and that can edit sites with previously inaccessible PAMs.

T-cell-binding nanoparticles bypass the complexities of in vitro gene transfer to deliver genes to T cells within the host.

Two of the first patients with cancer treated with chimeric antigen receptor-modified (CAR) T cells have been cancer free for a decade. A new study uses single-cell sequencing technologies to provide a window into the evolution of their CAR T cells over the course of the ten-year remission period.

Prime editors are delivered as ribonucleoproteins to zebrafish embryos and human primary cells.

CAR T cells targeting PSMA and engineered to be resistant to immunosuppressive TGFβ signaling exhibit dose-dependent toxicity and expansion following infusion, with some transient antitumor activity, in patients with metastatic castration-resistant prostate cancer

Reports of T cell malignancies after CAR-T cell therapy should be investigated, but existing data from follow-up studies suggest a low risk compared with other cancer treatments.

Bailey and Maus discuss cutting-edge developments in engineering immune cells towards expanding the reach and efficacy of adoptive cell therapies in cancer and beyond.

Plasma cell-free DNA analysis has emerged as a powerful liquid biopsy assay to assess circulating tumour DNA in response to cancer treatments. A new study shows that cell-free DNA can also inform on expansion kinetics and tumour-infiltration patterns in patients receiving chimeric antigen receptor T cells and, together with circulating tumour DNA, provides vivid prognostic insights into intratumoural dynamics.

CAR T cells have transformed the treatment of some haematological cancers. This Perspective explores how insights into T cell receptor signalling have enabled the engineering of CAR formats that can outcompete currently approved CARs in preclinical models and clinical trials.

This Review outlines the major advances that have been made to the efficacy and safety of chimeric antigen receptor (CAR) T cell therapies over the past 3 years and looks to new findings that will have consequences for the future of this immunotherapy.

This Review discusses current research strategies to overcome resistance to CAR-T cell therapy in blood cancers, including optimization of CAR design, improvement of T cell function and persistence, modulation of the immunosuppressive tumour microenvironment and synergistic combination strategies.

This Review discusses the manufacturing of cell products for clinically advanced cell therapies, and highlights potential manufacturing bottlenecks and solutions towards the cost-effective commercialization of the therapies.