Since the first clinical approval in 2017, chimeric antigen receptor (CAR) T cell therapy has emerged as one of the most powerful modalities for redirecting the immune response against cancer. Building on decades of foun...Since the first clinical approval in 2017, chimeric antigen receptor (CAR) T cell therapy has emerged as one of the most powerful modalities for redirecting the immune response against cancer. Building on decades of foundational discoveries in T cell biology and synthetic immunoengineering, CAR T cell therapy has transformed the treatment of B cell malignancies, resulting in durable remissions in patients with B cell leukaemias, lymphomas and multiple myeloma. Next-generation CAR designs are now expanding the reach of this approach into autoimmune disease and solid tumours. Innovations in gene editing, allogeneic manufacturing and in vivo delivery are improving the scalability, safety and accessibility of CAR T cell therapies, although challenges persist in overcoming antigen heterogeneity and tumour microenvironmental barriers and in promoting the long-term persistence of CAR T cells. In this Review, we summarize the key discoveries that laid the foundations for CAR T cell therapies and provide a broad overview of the current principles of CAR design, their clinical development and emerging strategies aimed at enhancing efficacy, broadening indications and achieving durable immune control across disease types.
Macrophages are essential components of the innate immune system and have crucial roles in host defence, tissue homeostasis and inflammation. Embryonic macrophages are specialized populations of macrophages that arise ea...Macrophages are essential components of the innate immune system and have crucial roles in host defence, tissue homeostasis and inflammation. Embryonic macrophages are specialized populations of macrophages that arise early during development and contribute to tissue organization, immune system development and homeostasis. These cells originate from yolk sac and fetal liver progenitors and colonize various tissues during embryogenesis, becoming long-lived tissue-resident macrophages. In the embryo, macrophages are involved in a wide range of developmental processes, including the clearance of apoptotic cells, regulation of organogenesis and establishment of tissue integrity. They are also pivotal in the early establishment of immune tolerance and in the development of the fetal haematopoietic and immune systems. Plenty of literature covers the role of yolk sac-derived macrophages in adult tissues, whereas less is known about their functions in the embryo itself. This Review highlights our emerging understanding of embryonic macrophages, their origin and their roles in organogenesis and development in mice and humans.
T cell engagers (TCEs) are antibody-based, bispecific or multi-specific constructs that can reprogramme T cells to eliminate target cells expressing a defined surface antigen. Originally developed for cancer therapy, TCE...T cell engagers (TCEs) are antibody-based, bispecific or multi-specific constructs that can reprogramme T cells to eliminate target cells expressing a defined surface antigen. Originally developed for cancer therapy, TCEs are now being investigated for the treatment of autoimmune diseases, with promising initial results. The interest in using TCEs for autoimmune diseases is rapidly growing given their comparable potency with cellular therapies, combined with the advantages of biologics, including ease of manufacturing, off-the-shelf availability, better safety and more convenient delivery. Here we review the history of TCEs, focus on distinct aspects of the mechanism of action of TCEs and explain design principles. We also discuss key challenges for future TCE development in autoimmunity, including enhanced safety, high convenience and complete target cell elimination. Finally, we provide an overview of the preclinical and clinical development landscape and give an outlook on next-generation TCEs that are optimized to treat a wide variety of autoimmune diseases.
Messenger RNA (mRNA) vaccines are a transformative platform for inducing antigen-specific T cell and B cell responses that are now being trialled in oncology. Here we propose an immunological framework that reconciles fo...Messenger RNA (mRNA) vaccines are a transformative platform for inducing antigen-specific T cell and B cell responses that are now being trialled in oncology. Here we propose an immunological framework that reconciles four axes controlling the efficacy of mRNA cancer vaccines: adjuvanticity versus immunopathology, antigen immunogenicity versus tolerance, adaptive immune memory versus exhaustion, and beneficial versus maladaptive trained immunity. We argue that mRNA vaccines should be viewed as programmable constructs in which nucleoside chemistry, delivery platforms and dosing schedules can be manipulated to tune these four axes by modulating antigen identity and decay, costimulation, cytokine tone and innate stimulation. By fitting recent mechanistic and translational insights into this framework, we outline design principles for positioning mRNA cancer vaccines within an optimal window of immune activation that supports durable, tumour-specific immunity while minimizing T cell exhaustion, tolerance and systemic toxicity.
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Current therapies for relapsing MS primarily target the peripheral immune system but have consistently failed to address mech...Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Current therapies for relapsing MS primarily target the peripheral immune system but have consistently failed to address mechanisms underlying disease progression, which are thought to involve CNS-resident glial cells such as astrocytes, microglia and oligodendrocytes. Recent technological advances have revealed the functional heterogeneity of these glial cells, highlighting their crucial roles in inflammation, demyelination, remyelination and neurodegeneration. In this Review, we summarize emerging insights into the diversity, function and regulation of glial cells in MS and inflammation in general, highlight their interactions with immune cells and non-immune cells in the CNS, and discuss potential strategies for their therapeutic modulation.
Cancer immunotherapies have shown promise and success in a number of different types of tumours, yet many solid epithelial tumours remain recalcitrant. Somatic mutations in tumour cells can lead to the expression of neoa...Cancer immunotherapies have shown promise and success in a number of different types of tumours, yet many solid epithelial tumours remain recalcitrant. Somatic mutations in tumour cells can lead to the expression of neoantigens, which are potent targets of the human antitumour immune response. These can be targeted through adoptive cell transfer (ACT) of neoantigen-specific T cells, including tumour-infiltrating lymphocytes (TILs) or T cell receptor (TCR)-engineered T cells (TCR-T cells), an approach that has been shown to achieve tumour regression in patients with different types of metastatic solid tumours including melanoma, breast and gastrointestinal cancer. Immunogenomics, systems immunology and genome editing now provide multidisciplinary tools to design cell therapies against solid cancer. Here, we review historical efforts and our current conceptual understanding of ACT using TILs or TCR-T cells. Moreover, we highlight emerging correlates of response to ACT and novel strategies that integrate tumour immunology, cancer genomics, computational biology and T cell engineering for the development of next-generation cellular immunotherapies.