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Nature Jul 2023Engineering a patient's own T cells to selectively target and eliminate tumour cells has cured patients with untreatable haematologic cancers. These results have... (Review)
Review
Engineering a patient's own T cells to selectively target and eliminate tumour cells has cured patients with untreatable haematologic cancers. These results have energized the field to apply chimaeric antigen receptor (CAR) T therapy throughout oncology. However, evidence from clinical and preclinical studies underscores the potential of CAR T therapy beyond oncology in treating autoimmunity, chronic infections, cardiac fibrosis, senescence-associated disease and other conditions. Concurrently, the deployment of new technologies and platforms provides further opportunity for the application of CAR T therapy to noncancerous pathologies. Here we review the rationale behind CAR T therapy, current challenges faced in oncology, a synopsis of preliminary reports in noncancerous diseases, and a discussion of relevant emerging technologies. We examine potential applications for this therapy in a wide range of contexts. Last, we highlight concerns regarding specificity and safety and outline the path forward for CAR T therapy beyond cancer.
Topics: Humans; Hematologic Neoplasms; Immunotherapy, Adoptive; Neoplasms; Receptors, Chimeric Antigen; T-Lymphocytes; Autoimmune Diseases; Infections; Fibrosis; Aging; Heart Diseases
PubMed: 37495877
DOI: 10.1038/s41586-023-06243-w -
Frontiers in Immunology 2023Immunotherapy has ushered in a new era in cancer treatment, and cancer immunotherapy continues to be rejuvenated. The clinical goal of cancer immunotherapy is to prime... (Review)
Review
Immunotherapy has ushered in a new era in cancer treatment, and cancer immunotherapy continues to be rejuvenated. The clinical goal of cancer immunotherapy is to prime host immune system to provide passive or active immunity against malignant tumors. Tumor infiltrating leukocytes (TILs) play an immunomodulatory role in tumor microenvironment (TME) which is closely related to immune escape of tumor cells, thus influence tumor progress. Several cancer immunotherapies, include immune checkpoint inhibitors (ICIs), cancer vaccine, adoptive cell transfer (ACT), have shown great efficacy and promise. In this review, we will summarize the recent research advances in tumor immunotherapy, including the molecular mechanisms and clinical effects as well as limitations of immunotherapy.
Topics: Immunotherapy; Immunomodulation; Immunity, Active; Immunotherapy, Adoptive; Adoptive Transfer; Neoplasms
PubMed: 37691932
DOI: 10.3389/fimmu.2023.1212476 -
The New England Journal of Medicine Jul 2023In an analysis of the primary outcome of this phase 3 trial, patients with early relapsed or refractory large B-cell lymphoma who received axicabtagene ciloleucel... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In an analysis of the primary outcome of this phase 3 trial, patients with early relapsed or refractory large B-cell lymphoma who received axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor T-cell therapy, as second-line treatment had significantly longer event-free survival than those who received standard care. Data were needed on longer-term outcomes.
METHODS
In this trial, we randomly assigned patients with early relapsed or refractory large B-cell lymphoma in a 1:1 ratio to receive either axi-cel or standard care (two to three cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation in patients who had a response). The primary outcome was event-free survival, and key secondary outcomes were response and overall survival. Here, we report the results of the prespecified overall survival analysis at 5 years after the first patient underwent randomization.
RESULTS
A total of 359 patients underwent randomization to receive axi-cel (180 patients) or standard care (179 patients). At a median follow-up of 47.2 months, death had been reported in 82 patients in the axi-cel group and in 95 patients in the standard-care group. The median overall survival was not reached in the axi-cel group and was 31.1 months in the standard-care group; the estimated 4-year overall survival was 54.6% and 46.0%, respectively (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.54 to 0.98; P = 0.03 by stratified two-sided log-rank test). This increased survival with axi-cel was observed in the intention-to-treat population, which included 74% of patients with primary refractory disease and other high-risk features. The median investigator-assessed progression-free survival was 14.7 months in the axi-cel group and 3.7 months in the standard-care group, with estimated 4-year percentages of 41.8% and 24.4%, respectively (hazard ratio, 0.51; 95% CI, 0.38 to 0.67). No new treatment-related deaths had occurred since the primary analysis of event-free survival.
CONCLUSIONS
At a median follow-up of 47.2 months, axi-cel as second-line treatment for patients with early relapsed or refractory large B-cell lymphoma resulted in significantly longer overall survival than standard care. (Funded by Kite; ZUMA-7 ClinicalTrials.gov number, NCT03391466.).
Topics: Humans; Antigens, CD19; Antineoplastic Agents, Immunological; Biological Products; Immunotherapy, Adoptive; Lymphoma, Large B-Cell, Diffuse; Survival Analysis
PubMed: 37272527
DOI: 10.1056/NEJMoa2301665 -
Frontiers in Immunology 2023Gliomas are the most prevalent primary malignant brain tumors worldwide, with glioblastoma (GBM) being the most common and aggressive type. Despite two decades of... (Review)
Review
Gliomas are the most prevalent primary malignant brain tumors worldwide, with glioblastoma (GBM) being the most common and aggressive type. Despite two decades of relentless pursuit in exploring novel therapeutic approaches for GBM, there is limited progress in improving patients' survival outcomes. Numerous obstacles impede the effective treatment of GBM, including the immunosuppressive tumor microenvironment (TME), the blood-brain barrier, and extensive heterogeneity. Despite these challenges, immunotherapies are emerging as a promising avenue that may offer new hope for the treatment of gliomas. There are four main types of immunotherapies for gliomas, immune checkpoint blockades, chimeric antigen receptor T-cell therapies, vaccines, and oncolytic viruses. In addition, gene therapy, bispecific antibody therapy, and combine therapy are also briefly introduced in this review. The significant role of TME in the process of immunotherapies has been emphasized in many studies. Although immunotherapy is a promising treatment for gliomas, enormous effort is required to overcome the existing barriers to its success. Owing to the rapid development and increasing attention paid to immunotherapies for gliomas, this article aims to review the recent advances in immunotherapies for gliomas.
Topics: Humans; Immunotherapy; Glioma; Glioblastoma; Immunotherapy, Adoptive; Radioimmunotherapy; Tumor Microenvironment
PubMed: 37744349
DOI: 10.3389/fimmu.2023.1255611 -
Cell Jul 2023Chimeric antigen receptor (CAR) T cell therapy effectively treats human cancer, but the loss of the antigen recognized by the CAR poses a major obstacle. We found that...
Chimeric antigen receptor (CAR) T cell therapy effectively treats human cancer, but the loss of the antigen recognized by the CAR poses a major obstacle. We found that in vivo vaccine boosting of CAR T cells triggers the engagement of the endogenous immune system to circumvent antigen-negative tumor escape. Vaccine-boosted CAR T promoted dendritic cell (DC) recruitment to tumors, increased tumor antigen uptake by DCs, and elicited the priming of endogenous anti-tumor T cells. This process was accompanied by shifts in CAR T metabolism toward oxidative phosphorylation (OXPHOS) and was critically dependent on CAR-T-derived IFN-γ. Antigen spreading (AS) induced by vaccine-boosted CAR T enabled a proportion of complete responses even when the initial tumor was 50% CAR antigen negative, and heterogeneous tumor control was further enhanced by the genetic amplification of CAR T IFN-γ expression. Thus, CAR-T-cell-derived IFN-γ plays a critical role in promoting AS, and vaccine boosting provides a clinically translatable strategy to drive such responses against solid tumors.
Topics: Humans; Receptors, Chimeric Antigen; Neoplasms; T-Lymphocytes; Immunotherapy, Adoptive; Cancer Vaccines; Receptors, Antigen, T-Cell
PubMed: 37413990
DOI: 10.1016/j.cell.2023.06.002 -
Blood Sep 2023Hematological toxicity is the most common adverse event after chimeric antigen receptor (CAR) T-cell therapy. Cytopenias can be profound and long-lasting and can... (Review)
Review
Hematological toxicity is the most common adverse event after chimeric antigen receptor (CAR) T-cell therapy. Cytopenias can be profound and long-lasting and can predispose for severe infectious complications. In a recent worldwide survey, we demonstrated that there remains considerable heterogeneity in regard to current practice patterns. Here, we sought to build consensus on the grading and management of immune effector cell-associated hematotoxicity (ICAHT) after CAR T-cell therapy. For this purpose, a joint effort between the European Society for Blood and Marrow Transplantation (EBMT) and the European Hematology Association (EHA) involved an international panel of 36 CAR T-cell experts who met in a series of virtual conferences, culminating in a 2-day meeting in Lille, France. On the basis of these deliberations, best practice recommendations were developed. For the grading of ICAHT, a classification system based on depth and duration of neutropenia was developed for early (day 0-30) and late (after day +30) cytopenia. Detailed recommendations on risk factors, available preinfusion scoring systems (eg, CAR-HEMATOTOX score), and diagnostic workup are provided. A further section focuses on identifying hemophagocytosis in the context of severe hematotoxicity. Finally, we review current evidence and provide consensus recommendations for the management of ICAHT, including growth factor support, anti-infectious prophylaxis, transfusions, autologous hematopoietic stem cell boost, and allogeneic hematopoietic cell transplantation. In conclusion, we propose ICAHT as a novel toxicity category after immune effector cell therapy, provide a framework for its grading, review literature on risk factors, and outline expert recommendations for the diagnostic workup and short- and long-term management.
Topics: Consensus; Hematopoietic Stem Cell Transplantation; Immunotherapy, Adoptive; Immunologic Factors; Hematology
PubMed: 37300386
DOI: 10.1182/blood.2023020578 -
RMD Open Nov 2023Autoimmune disorders occur when immune cells go wrong and attack the body's own tissues. Currently, autoimmune disorders are largely treated by broad immunosuppressive... (Review)
Review
Autoimmune disorders occur when immune cells go wrong and attack the body's own tissues. Currently, autoimmune disorders are largely treated by broad immunosuppressive agents and blocking antibodies, which can manage the diseases but often are not curative. Thus, there is an urgent need for advanced therapies for patients suffering from severe and refractory autoimmune diseases, and researchers have considered cell therapy as potentially curative approach for several decades. In the wake of its success in cancer therapy, adoptive transfer of engineered T cells modified with chimeric antigen receptors (CAR) for target recognition could now become a therapeutic option for some autoimmune diseases. Here, we review the ongoing developments with CAR T cells in the field of autoimmune disorders. We will cover first clinical results of applying anti-CD19 and anti-B cell maturation antigen CAR T cells for B cell elimination in systemic lupus erythematosus, refractory antisynthetase syndrome and myasthenia gravis, respectively. Furthermore, in preclinical models, researchers have also developed chimeric autoantibody receptor T cells that can eliminate individual B cell clones producing specific autoantibodies, and regulatory CAR T cells that do not eliminate autoreactive immune cells but dampen their wrong activation. Finally, we will address safety and manufacturing aspects for CAR T cells and discuss mRNA technologies and automation concepts for ensuring the future availability of safe and efficient CAR T cell products.
Topics: Humans; Immunotherapy, Adoptive; T-Lymphocytes; Receptors, Chimeric Antigen; Autoimmune Diseases
PubMed: 37996128
DOI: 10.1136/rmdopen-2022-002907 -
MMWR. Morbidity and Mortality Weekly... Aug 2023Respiratory syncytial virus (RSV) is the leading cause of hospitalization among U.S. infants. In July 2023, the Food and Drug Administration approved nirsevimab, a...
Use of Nirsevimab for the Prevention of Respiratory Syncytial Virus Disease Among Infants and Young Children: Recommendations of the Advisory Committee on Immunization Practices - United States, 2023.
Respiratory syncytial virus (RSV) is the leading cause of hospitalization among U.S. infants. In July 2023, the Food and Drug Administration approved nirsevimab, a long-acting monoclonal antibody, for passive immunization to prevent RSV-associated lower respiratory tract infection among infants and young children. Since October 2021, the Advisory Committee on Immunization Practices (ACIP) Maternal and Pediatric RSV Work Group has reviewed evidence on the safety and efficacy of nirsevimab among infants and young children. On August 3, 2023, ACIP recommended nirsevimab for all infants aged <8 months who are born during or entering their first RSV season and for infants and children aged 8-19 months who are at increased risk for severe RSV disease and are entering their second RSV season. On the basis of pre-COVID-19 pandemic patterns, nirsevimab could be administered in most of the continental United States from October through the end of March. Nirsevimab can prevent severe RSV disease among infants and young children at increased risk for severe RSV disease.
Topics: Humans; Infant; Advisory Committees; Communicable Diseases; COVID-19; Immunization; Pandemics; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human; United States
PubMed: 37616235
DOI: 10.15585/mmwr.mm7234a4 -
Biomedicine & Pharmacotherapy =... Sep 2023Adoptive cell therapies (ACT) based on chimeric antigen receptor (CAR)-modified immune cells have made great progress with six CAR-T cell products approved by the U.S.... (Review)
Review
Adoptive cell therapies (ACT) based on chimeric antigen receptor (CAR)-modified immune cells have made great progress with six CAR-T cell products approved by the U.S. FDA for hematological malignancies. Compared with CAR-T cells, CAR-NK cells have attracted increasing attention owing to their multiple killing mechanisms, higher safety profile, and broad sources. Induced pluripotent stem cell (iPSC)-derived NK (iPSC-NK) cells possess a mature phenotype and potent cytolytic activity, and can provide a homogeneous population of CAR-NK cells that can be expanded to clinical scale. Thus, iPSC-derived CAR-NK (CAR-iNK) cells could be used as a standardized and "off-the-shelf" product for cancer immunotherapy. In this review, we summarize the current status of the manufacturing techniques, genetic modification strategies, preclinical and clinical evidence of CAR-iNK cells, and discuss the challenges and future prospects of CAR-iNK cell therapy as a novel cellular immunotherapy in cancer.
Topics: Humans; Receptors, Chimeric Antigen; Induced Pluripotent Stem Cells; Killer Cells, Natural; Immunotherapy, Adoptive; Immunotherapy; Neoplasms
PubMed: 37406511
DOI: 10.1016/j.biopha.2023.115123 -
Journal of Hematology & Oncology Aug 2023Adoptive cell therapies (ACTs) have existed for decades. From the initial infusion of tumor-infiltrating lymphocytes to the subsequent specific enhanced T cell receptor... (Review)
Review
Adoptive cell therapies (ACTs) have existed for decades. From the initial infusion of tumor-infiltrating lymphocytes to the subsequent specific enhanced T cell receptor (TCR)-T and chimeric antigen receptor (CAR)-T cell therapies, many novel strategies for cancer treatment have been developed. Owing to its promising outcomes, CAR-T cell therapy has revolutionized the field of ACTs, particularly for hematologic malignancies. Despite these advances, CAR-T cell therapy still has limitations in both autologous and allogeneic settings, including practicality and toxicity issues. To overcome these challenges, researchers have focused on the application of CAR engineering technology to other types of immune cell engineering. Consequently, several new cell therapies based on CAR technology have been developed, including CAR-NK, CAR-macrophage, CAR-γδT, and CAR-NKT. In this review, we describe the development, advantages, and possible challenges of the aforementioned ACTs and discuss current strategies aimed at maximizing the therapeutic potential of ACTs. We also provide an overview of the various gene transduction strategies employed in immunotherapy given their importance in immune cell engineering. Furthermore, we discuss the possibility that strategies capable of creating a positive feedback immune circuit, as healthy immune systems do, could address the flaw of a single type of ACT, and thus serve as key players in future cancer immunotherapy.
Topics: Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Immunotherapy; Cell Engineering; Hematologic Neoplasms
PubMed: 37596653
DOI: 10.1186/s13045-023-01492-8