-
Nature Medicine Jun 2022Despite success in hematologic malignancies, the treatment landscape of chimeric antigen receptor (CAR) T cell therapy for solid tumors remains limited. Claudin18.2...
Despite success in hematologic malignancies, the treatment landscape of chimeric antigen receptor (CAR) T cell therapy for solid tumors remains limited. Claudin18.2 (CLDN18.2)-redirected CAR T cells showed promising efficacy against gastric cancer (GC) in a preclinical study. Here we report the interim analysis results of an ongoing, open-label, single-arm, phase 1 clinical trial of CLDN18.2-targeted CAR T cells (CT041) in patients with previously treated, CLDN18.2-positive digestive system cancers ( NCT03874897 ). The primary objective was safety after CT041 infusion; secondary objectives included CT041 efficacy, pharmacokinetics and immunogenicity. We treated 37 patients with one of three CT041 doses: 2.5 × 10, 3.75 × 10 or 5.0 × 10 cells. All patients experienced a grade 3 or higher hematologic toxicity. Grade 1 or 2 cytokine release syndrome (CRS) occurred in 94.6% of patients. No grade 3 or higher CRS or neurotoxicities, treatment-related deaths or dose-limiting toxicities were reported. The overall response rate (ORR) and disease control rate (DCR) reached 48.6% and 73.0%, respectively. The 6-month duration of response rate was 44.8%. In patients with GC, the ORR and DCR reached 57.1% and 75.0%, respectively, and the 6-month overall survival rate was 81.2%. These initial results suggest that CT041 has promising efficacy with an acceptable safety profile in patients with heavily pretreated, CLDN18.2-positive digestive system cancers, particularly in those with GC.
Topics: Claudins; Cytokine Release Syndrome; Humans; Immunotherapy, Adoptive; Stomach Neoplasms; T-Lymphocytes
PubMed: 35534566
DOI: 10.1038/s41591-022-01800-8 -
Cancer Journal (Sudbury, Mass.)The successful application of chimeric antigen receptor (CAR) T cells for the treatment of relapsed and refractory B-cell malignancies has ushered in a new frontier for... (Review)
Review
The successful application of chimeric antigen receptor (CAR) T cells for the treatment of relapsed and refractory B-cell malignancies has ushered in a new frontier for the immunotherapy of cancer. Despite its successes, CAR T-cell therapy presents several challenges. Cytokine release syndrome (CRS) triggered by robust and exponential CAR T-cell expansion is the most common adverse effect and may be severe or life-threatening. Although modulation of the interleukin 6 axis was appreciated early on as a means to manage CRS, the exact underlying mechanisms leading to severe CRS remain to be elucidated. What is clear is that severe CRS involves recruitment of the broader immune system into a hyperinflammatory and unregulated state. Myeloid-derived cells appear to play a critical role in this regard and are at the center of active investigation. In this article, we will focus on important elements of CRS, the clinical manifestations, underlying biology, and management strategies including grading, supportive care, and treatment via immunosuppression.
Topics: Animals; COVID-19; Cytokine Release Syndrome; Disease Models, Animal; Humans; Immunotherapy, Adoptive; Mice; Myeloid Cells
PubMed: 33750071
DOI: 10.1097/PPO.0000000000000515 -
Science Advances Feb 2023T cell engineering has changed the landscape of cancer immunotherapy. Chimeric antigen receptor T cells have demonstrated a remarkable efficacy in the treatment of B... (Review)
Review
T cell engineering has changed the landscape of cancer immunotherapy. Chimeric antigen receptor T cells have demonstrated a remarkable efficacy in the treatment of B cell malignancies in hematology. However, their clinical impact on solid tumors has been modest so far. T cells expressing an engineered T cell receptor (TCR-T cells) represent a promising therapeutic alternative. The target repertoire is not limited to membrane proteins, and intrinsic features of TCRs such as high antigen sensitivity and near-to-physiological signaling may improve tumor cell detection and killing while improving T cell persistence. In this review, we present the clinical results obtained with TCR-T cells targeting different tumor antigen families. We detail the different methods that have been developed to identify and optimize a TCR candidate. We also discuss the challenges of TCR-T cell therapies, including toxicity assessment and resistance mechanisms. Last, we share some perspectives and highlight future directions in the field.
Topics: Humans; Immunotherapy, Adoptive; Neoplasms; Receptors, Antigen, T-Cell; Antigens, Neoplasm; Cell- and Tissue-Based Therapy
PubMed: 36791198
DOI: 10.1126/sciadv.adf3700 -
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 -
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 -
Frontiers in Immunology 2020Adoptive cell therapy (ACT) is a kind of immunotherapy in which T cells are genetically modified to express a chimeric antigen receptor (CAR) or T cell receptor (TCR),... (Review)
Review
Adoptive cell therapy (ACT) is a kind of immunotherapy in which T cells are genetically modified to express a chimeric antigen receptor (CAR) or T cell receptor (TCR), and ACT has made a great difference in treating multiple types of tumors. ACT is not perfect, and it can be followed by severe side effects, which hampers the application of ACT in clinical trials. One of the most promising methods to minimize side effects is to endow adoptive T cells with the ability to target neoantigens, which are specific to tumor cells. With the development of antigen screening technologies, more methods can be applied to discover neoantigens in cancer cells, such as whole-exome sequencing combined with mass spectrometry, neoantigen screening through an inventory-shared neoantigen peptide library, and neoantigen discovery via trogocytosis. In this review, we focus on the side effects of existing antigens and their solutions, illustrate the strategies of finding neoantigens in CAR-T and TCR-T therapies through methods reported by other researchers, and summarize the clinical behavior of these neoantigens.
Topics: Animals; Antigens, Neoplasm; Cell- and Tissue-Based Therapy; Disease Models, Animal; Humans; Immunotherapy, Adoptive; Lymphocytes, Tumor-Infiltrating; Mass Spectrometry; Mice; Neoplasms; Receptors, Chimeric Antigen; Exome Sequencing
PubMed: 32194541
DOI: 10.3389/fimmu.2020.00176 -
Frontiers in Immunology 2022Adoptive cell therapy with T cells reprogrammed to express chimeric antigen receptors (CAR-T cells) has been highly successful in patients with hematological neoplasms.... (Review)
Review
Adoptive cell therapy with T cells reprogrammed to express chimeric antigen receptors (CAR-T cells) has been highly successful in patients with hematological neoplasms. However, its therapeutic benefits have been limited in solid tumor cases. Even those patients who respond to this immunotherapy remain at risk of relapse due to the short-term persistence or non-expansion of CAR-T cells; moreover, the hostile tumor microenvironment (TME) leads to the dysfunction of these cells after reinfusion. Some research has shown that, in adoptive T-cell therapies, the presence of less differentiated T-cell subsets within the infusion product is associated with better clinical outcomes. Naive and memory T cells persist longer and exhibit greater antitumor activity than effector T cells. Therefore, new methods are being studied to overcome the limitations of this therapy to generate CAR-T cells with these ideal phenotypes. In this paper, we review the characteristics of T-cell subsets and their implications in the clinical outcomes of adoptive therapy with CAR-T cells. In addition, we describe some strategies developed to overcome the reduced persistence of CAR T-cells and alternatives to improve this therapy by increasing the expansion ability and longevity of modified T cells. These methods include cell culture optimization, incorporating homeostatic cytokines during the expansion phase of manufacturing, modulation of CAR-T cell metabolism, manipulating signaling pathways involved in T-cell differentiation, and strategies related to CAR construct designs.
Topics: Humans; Immunotherapy, Adoptive; Lymphocyte Activation; Neoplasm Recurrence, Local; Receptors, Chimeric Antigen; Tumor Microenvironment
PubMed: 35572525
DOI: 10.3389/fimmu.2022.878209 -
International Journal of Hematology Nov 2021Over the past few years, cellular immunotherapy has emerged as a novel treatment option for certain forms of hematologic malignancies with multiple CAR-T therapies now... (Review)
Review
Over the past few years, cellular immunotherapy has emerged as a novel treatment option for certain forms of hematologic malignancies with multiple CAR-T therapies now routinely administered in the clinic. The limitations of generating an autologous cell product and the challenges of toxicity with CAR-T cells underscore the need to develop novel cell therapy products that are universal, safe, and potent. Natural killer (NK) cells are part of the innate immune system with unique advantages, including the potential for off-the-shelf therapy. A recent first-in-human trial of CD19-CAR-NK infusion in patients with relapsed/refractory lymphoid malignancies proved safe with promising clinical activity. Building on these encouraging clinical responses, research is now actively exploring ways to further enhance CAR-NK cell potency by prolonging in vivo persistence and overcoming mechanisms of functional exhaustion. Besides these strategies to modulate CAR-NK cell intrinsic properties, there are increasing efforts to translate the successes seen in hematologic malignancies to the solid tumor space. This review will provide an overview on current trends and evolving concepts to genetically engineer the next generation of CAR-NK therapies. Emphasis will be placed on innovative multiplexed engineering approaches including CRISPR/Cas9 to overcome CAR-NK functional exhaustion and reprogram immune cell metabolism for enhanced potency.
Topics: Animals; Clinical Trials as Topic; Combined Modality Therapy; Disease Management; Disease Susceptibility; Gene Editing; Genetic Engineering; Genetic Therapy; Hematologic Neoplasms; Humans; Immunotherapy, Adoptive; Killer Cells, Natural; Receptors, Chimeric Antigen; Translational Research, Biomedical; Treatment Outcome
PubMed: 34453686
DOI: 10.1007/s12185-021-03209-4 -
The Lancet. Oncology Mar 2020The recent clinical successes of immunotherapy, as a result of a broader and more profound understanding of cancer immunobiology, and the leverage of this knowledge to... (Review)
Review
The recent clinical successes of immunotherapy, as a result of a broader and more profound understanding of cancer immunobiology, and the leverage of this knowledge to effectively eradicate malignant cells, has revolutionised the field of cancer therapeutics. Immunotherapy is now considered the fifth pillar of cancer care, alongside surgery, chemotherapy, radiotherapy, and targeted therapy. Recently, the success of genetically modified T cells that express chimeric antigen receptors (CAR T cells) has generated considerable excitement. CAR T-cell therapy research and development has built on experience generated by laboratory research and clinical investigation of lymphokine-activated killer cells, tumour-infiltrating lymphocytes, and allogeneic haemopoietic stem-cell transplantation for cancer treatment. This Review aims to provide a background on the field of adoptive T-cell therapy and the development of genetically modified T cells, most notably CAR T-cell therapy. Many challenges exist to optimise efficacy, minimise toxicity, and broaden the application of immunotherapies based on T cells.
Topics: Animals; Diffusion of Innovation; Forecasting; Humans; Immunotherapy, Adoptive; Neoplasms; Receptors, Chimeric Antigen; T-Lymphocytes; Treatment Outcome; Tumor Microenvironment
PubMed: 32135120
DOI: 10.1016/S1470-2045(19)30823-X -
Journal of Clinical Oncology : Official... Sep 2023Historically, the outcomes for individuals with triple-class refractory and penta-drug refractory multiple myeloma (MM) have been poor because of a dearth of effective... (Review)
Review
Historically, the outcomes for individuals with triple-class refractory and penta-drug refractory multiple myeloma (MM) have been poor because of a dearth of effective treatment options. However, the advent of chimeric antigen receptor (CAR) T-cell and T-cell redirecting bispecific antibody (BsAb) therapies has led to unprecedented response rates and durations of response in heavily relapsed/refractory (R/R) populations. Currently, two B-cell maturation antigen (BCMA)-directed CAR T-cell therapies (idecabtagene vicleucel and ciltacabtagene autoleucel) as well as one BCMA/CD3 BsAb (teclistamab) have been approved for late-line (greater than four previous lines) R/R MM in the United States. The purpose of this review is to analyze the recent data for these approved therapies as well as provide an overview of other related CAR T-cell and BsAb therapies under development, including non-BCMA-targeting agents. We review efficacy and safety considerations, with particular focus on cytokine release syndrome, neurotoxicity, and infection risk. The relative merits and limitations of each class of therapy are discussed, as well as the areas of unmet need with respect to optimal sequencing and supportive care measures. We examine the factors that challenge equitable access to these novel therapies across minoritized racial, ethnic, and socioeconomic populations. Although it is evident that CAR T-cell and BsAb therapies will transform treatment paradigms in MM for years to come, significant work remains to identify the optimal utilization of these novel therapies and ensure equitable access.
Topics: Humans; Multiple Myeloma; Receptors, Chimeric Antigen; T-Lymphocytes; Immunotherapy, Adoptive; Treatment Outcome; Antibodies, Bispecific
PubMed: 37471687
DOI: 10.1200/JCO.23.00512