The functions of, and interactions between, the innate and adaptive immune systems are vital for anticancer immunity. Cytotoxic T cells expressing cell-surface CD8 are the most powerful effectors in the anticancer immune response and form the backbone of current successful cancer immunotherapies. Immune-checkpoint inhibitors are designed to target immune-inhibitory receptors that function to regulate the immune response, whereas adoptive cell-transfer therapies use CD8+ T cells with genetically modified receptors-chimaeric antigen receptors-to specify and enhance CD8+ T-cell functionality. New generations of cytotoxic T cells with genetically modified or synthetic receptors are being developed and evaluated in clinical trials. Furthermore, combinatory regimens might optimise treatment effects and reduce adverse events. This review summarises advances in research on the most prominent immune effectors in cancer and cancer immunotherapy, cytotoxic T cells, and discusses possible implications for future cancer treatment.

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Cytotoxic CD8 + T cells in cancer and cancer immunotherapy

This Review discusses the major advances and changes made over the past 3 years to our understanding of chimeric antigen receptor (CAR) T cell efficacy and safety. Recently, the field has gained insight into how various molecular modules of the CAR influence signalling and function. We report on mechanisms of toxicity and resistance as well as novel engineering and pharmaceutical interventions to overcome these challenges. Looking forward, we discuss new targets and indications for CAR T cell therapy expected to reach the clinic in the next 1–2 years. We also consider some new studies that have implications for the future of CAR T cell therapies, including changes to manufacturing, allogeneic products and drug-regulatable CAR T cells. 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.

Recent advances and discoveries in the mechanisms and functions of CAR T cells.

Immunotherapy with checkpoint blockade induces rapid and durable immune control of cancer in some patients and has driven a monumental shift in cancer treatment Neoantigen-specific CD8+ T cells are at the forefront of current immunotherapy strategies, and the majority of drug discovery and clinical trials revolve around further harnessing these immune effectors Yet the immune system contains a diverse range of antitumour effector cells, and these must function in a coordinated and synergistic manner to overcome the immune-evasion mechanisms used by tumours and achieve complete control with tumour eradication A key antitumour effector is the natural killer (NK) cells, cytotoxic innate lymphocytes present at high frequency in the circulatory system and identified by their exquisite ability to spontaneously detect and lyse transformed or stressed cells Emerging data show a role for intratumoural NK cells in driving immunotherapy response and, accordingly, there have been renewed efforts to further elucidate and target the pathways controlling NK cell antitumour function In this Review, we discuss recent clinical evidence that NK cells are a key immune constituent in the protective antitumour immune response and highlight the major stages of the cancer-NK cell immunity cycle We also perform a new analysis of publicly available transcriptomic data to provide an overview of the prognostic value of NK cell gene expression in 25 tumour types Furthermore, we discuss how the role of NK cells evolves with tumour progression, presenting new opportunities to target NK cell function to enhance cancer immunotherapy response rates across a more diverse range of cancers

The cancer–natural killer cell immunity cycle

The foundational adenine base editors (for example, ABE7.10) enable programmable A•T to G•C point mutations but editing efficiencies can be low at challenging loci in primary human cells. Here we further evolve ABE7.10 using a library of adenosine deaminase variants to create ABE8s. At NGG protospacer adjacent motif (PAM) sites, ABE8s result in ~1.5× higher editing at protospacer positions A5-A7 and ~3.2× higher editing at positions A3-A4 and A8-A10 compared with ABE7.10. Non-NGG PAM variants have a ~4.2-fold overall higher on-target editing efficiency than ABE7.10. In human CD34+ cells, ABE8 can recreate a natural allele at the promoter of the γ-globin genes HBG1 and HBG2 with up to 60% efficiency, causing persistence of fetal hemoglobin. In primary human T cells, ABE8s achieve 98-99% target modification, which is maintained when multiplexed across three loci. Delivered as messenger RNA, ABE8s induce no significant levels of single guide RNA (sgRNA)-independent off-target adenine deamination in genomic DNA and very low levels of adenine deamination in cellular mRNA.

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Directed evolution of adenine base editors with increased activity and therapeutic application.

CAR T Cell Therapy for Solid Tumors: Bright Future or Dark Reality?

Autologous chimeric antigen receptor (CAR) T cells have changed the therapeutic landscape in haematological malignancies. Nevertheless, the use of allogeneic CAR T cells from donors has many potential advantages over autologous approaches, such as the immediate availability of cryopreserved batches for patient treatment, possible standardization of the CAR-T cell product, time for multiple cell modifications, redosing or combination of CAR T cells directed against different targets, and decreased cost using an industrialized process. However, allogeneic CAR T cells may cause life-threatening graft-versus-host disease and may be rapidly eliminated by the host immune system. The development of next-generation allogeneic CAR T cells to address these issues is an active area of research. In this Review, we analyse the different sources of T cells for optimal allogeneic CAR-T cell therapy and describe the different technological approaches, mainly based on gene editing, to produce allogeneic CAR T cells with limited potential for graft-versus-host disease. These improved allogeneic CAR-T cell products will pave the way for further breakthroughs in the treatment of cancer. The use of allogeneic chimeric antigen receptor T cells from donors has many potential advantages over autologous approaches, such as immediate availability, standardization and the possibility of redosing or combination. This Review analyses the different sources of T cells and technological approaches to produce optimal allogeneic chimeric antigen receptor T cells with limited potential for graft-versus-host disease and increased persistence.

Philippe Duchateau

Papers

'Off-the-shelf' allogeneic CAR T cells: development and challenges.