-
Cell Reports. Medicine Feb 2024Chimeric antigen receptor (CAR)-T therapy has shown superior efficacy against hematopoietic malignancies. However, many patients failed to achieve sustainable tumor...
Chimeric antigen receptor (CAR)-T therapy has shown superior efficacy against hematopoietic malignancies. However, many patients failed to achieve sustainable tumor control partially due to CAR-T cell exhaustion and limited persistence. In this study, by performing single-cell multi-omics data analysis on patient-derived CAR-T cells, we identify CD38 as a potential hallmark of exhausted CAR-T cells, which is positively correlated with exhaustion-related transcription factors and further confirmed with in vitro exhaustion models. Moreover, inhibiting CD38 activity reverses tonic signaling- or tumor antigen-induced exhaustion independent of single-chain variable fragment design or costimulatory domain, resulting in improved CAR-T cell cytotoxicity and antitumor response. Mechanistically, CD38 inhibition synergizes the downregulation of CD38-cADPR -Ca signaling and activation of the CD38-NAD-SIRT1 axis to suppress glycolysis. Collectively, our findings shed light on the role of CD38 in CAR-T cell exhaustion and suggest potential clinical applications of CD38 inhibition in enhancing the efficacy and persistence of CAR-T cell therapy.
Topics: Humans; T-Lymphocytes; Immunotherapy, Adoptive; Neoplasms; Antigens, Neoplasm; Single-Chain Antibodies
PubMed: 38307031
DOI: 10.1016/j.xcrm.2024.101400 -
The New England Journal of Medicine Sep 2023
Topics: Humans; Antigens, CD19; Immunotherapy, Adoptive; Lymphoma, B-Cell
PubMed: 37733322
DOI: 10.1056/NEJMc2309399 -
The New England Journal of Medicine Sep 2023
Topics: Humans; Immunotherapy, Adoptive; T-Lymphocytes; Cell- and Tissue-Based Therapy; Cell Engineering
PubMed: 37672700
DOI: 10.1056/NEJMe2304744 -
Human Vaccines & Immunotherapeutics Dec 2023New technologies for the prevention of infectious diseases are emerging to address unmet medical needs, in particular, the use of long-acting monoclonal antibodies (mAb)...
New technologies for the prevention of infectious diseases are emerging to address unmet medical needs, in particular, the use of long-acting monoclonal antibodies (mAb) to prevent Respiratory Syncytial Virus (RSV) lower respiratory tract disease in infants during their first RSV season. The lack of precedent for mAbs for broad population protection creates challenges in the assessment of upcoming prophylactic long-acting mAbs for RSV, with associated consequences in legislative and registration categorization, as well as in recommendation, funding, and implementation pathways. We suggest that the legislative and regulatory categorization of preventative solutions should be decided by the effect of the product in terms of its impact on the population and health-care systems rather than by the technology used or its mechanism of action. Immunization can be passive and active, both having the same objective of prevention of infectious diseases. Long-acting prophylactic mAbs work as passive immunization, as such, their recommendations for use should fall under the remit of National Immunization Technical Advisory Groups or other relevant recommending bodies for inclusion into National Immunization Programs. Current regulations, policy, and legislative frameworks need to evolve to embrace such innovative preventative technologies and acknowledge them as one of key immunization and public health tools.
Topics: Infant; Humans; Respiratory Syncytial Virus Infections; Immunization; Vaccination; Respiratory Syncytial Virus, Human; Antibodies, Monoclonal; Immunization, Passive; Communicable Diseases
PubMed: 37193673
DOI: 10.1080/21645515.2023.2209000 -
Nature Medicine Apr 2024Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to...
Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan. Secondary objectives included overall survival, disease response, cytokine dynamics and tumor immune contexture biomarkers. This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process. Locoregional CAR-T cell administration was feasible and well tolerated, and as there were no dose-limiting toxicities across all arms, a maximum tolerated dose was not determined. Probable treatment-related grade 3+ toxicities were one grade 3 encephalopathy and one grade 3 ataxia. A clinical maximum feasible dose of 200 × 10 CAR-T cells per infusion cycle was achieved for arm 5; however, other arms either did not test or achieve this dose due to manufacturing feasibility. A recommended phase 2 dose will be refined in future studies based on data from this trial. Stable disease or better was achieved in 50% (29/58) of patients, with two partial responses, one complete response and a second complete response after additional CAR-T cycles off protocol. For rGBM, median overall survival for all patients was 7.7 months and for arm 5 was 10.2 months. Central nervous system increases in inflammatory cytokines, including IFNγ, CXCL9 and CXCL10, were associated with CAR-T cell administration and bioactivity. Pretreatment intratumoral CD3 T cell levels were positively associated with survival. These findings demonstrate that locoregional IL-13Rα2-targeted CAR-T therapy is safe with promising clinical activity in a subset of patients. ClinicalTrials.gov Identifier: NCT02208362 .
Topics: Humans; Receptors, Chimeric Antigen; Neoplasm Recurrence, Local; Glioma; T-Lymphocytes; Glioblastoma; Immunotherapy, Adoptive
PubMed: 38454126
DOI: 10.1038/s41591-024-02875-1 -
Journal of Hematology & Oncology Oct 2023T cell differentiation is a highly regulated, multi-step process necessary for the progressive establishment of effector functions, immunological memory, and long-term... (Review)
Review
T cell differentiation is a highly regulated, multi-step process necessary for the progressive establishment of effector functions, immunological memory, and long-term control of pathogens. In response to strong stimulation, as seen in severe or chronic infections or cancer, T cells acquire a state of hypo-responsiveness known as exhaustion, limiting their effector function. Recent advances in autologous chimeric antigen receptor (CAR)-T cell therapies have revolutionized the treatment of hematologic malignancies by taking advantage of the basic principles of T cell biology to engineer products that promote long-lasting T cell response. However, many patients' malignancies remain unresponsive to treatment or are prone to recur. Discoveries in T cell biology, including the identification of key regulators of differentiation and exhaustion, offer novel opportunities to have a durable impact on the fate of CAR-T cells after infusion. Such next-generation CAR-T cell therapies and their clinical implementation may result in the next leap forward in cancer treatment for selected patients. In this context, this review summarizes the foundational principles of T cell differentiation and exhaustion and describes how they can be utilized and targeted to further improve the design and efficacy of CAR-T cell therapies.
Topics: Humans; Receptors, Chimeric Antigen; Cell Differentiation; Hematologic Neoplasms; Immunologic Memory; Immunotherapy, Adoptive; Cell- and Tissue-Based Therapy
PubMed: 37880715
DOI: 10.1186/s13045-023-01504-7 -
Pathology, Research and Practice Aug 2023Neoplasms are a worldwide recognized non-contagious disease which has the most mortality rate after cardiovascular diseases. For decades, there has been a vast amount of... (Review)
Review
Neoplasms are a worldwide recognized non-contagious disease which has the most mortality rate after cardiovascular diseases. For decades, there has been a vast amount of study on treatment methods of cancer which has led to conventional therapies such as chemotherapy, radiation therapy, surgery and so on. Clinicians and researchers believed that there is an urgent need, considering the high rate of incidence and prevalence, for an alternative treatment option which is more efficacious and has less adverse effects than the above-mentioned treatments. Immunotherapy has emerged as a potential treatment alternative in a few years and became one of the fastest developing therapeutic approaches. Different kinds of immunotherapies are FDA approved and available for treatment of various cancer types. In this review, we have summarized the major immunotherapy methods including checkpoint inhibitors, CAR T cell therapies and cancer vaccines. Furthermore, application of combination therapy, precision medicine, biomarker discovery, overcoming resistance and reduction of adverse effects are discussed in this study.
Topics: Immunotherapy; Humans; Neoplasms; Immune Checkpoint Inhibitors; Immunotherapy, Adoptive; Cancer Vaccines; Precision Medicine
PubMed: 37480597
DOI: 10.1016/j.prp.2023.154632 -
Annals of the Rheumatic Diseases Mar 2024
Topics: Humans; Scleroderma, Systemic; Antigens, CD19; Immunotherapy, Adoptive; T-Lymphocytes
PubMed: 38135464
DOI: 10.1136/ard-2023-225174 -
Trends in Biotechnology Oct 2023Cell therapy offers the potential for curative treatment of cancers. Although T cells have been the predominantly used cell type, natural killer (NK) cells have... (Review)
Review
Cell therapy offers the potential for curative treatment of cancers. Although T cells have been the predominantly used cell type, natural killer (NK) cells have attracted great attention owing to their ability to kill cancer cells and because they are naturally suitable for allogeneic applications. Upon stimulation by cytokines or activation by a target cell, NK cells proliferate and expand their population. These cytotoxic NK cells can be cryopreserved and used as an off-the-shelf medicine. The production process for NK cells thus differs from that of autologous cell therapies. We briefly outline key biological features of NK cells, review the manufacturing technologies for protein biologics, and discuss their adaptation for developing robust NK cell biomanufacturing processes.
Topics: Humans; Immunotherapy, Adoptive; Killer Cells, Natural; Immunotherapy; Neoplasms; T-Lymphocytes
PubMed: 37142447
DOI: 10.1016/j.tibtech.2023.03.018 -
Cancer Cell Nov 2023Chimeric antigen receptor (CAR) T cell therapies are limited by antigen escape and on-target/off-tumor toxicity. In addressing these challenges, Haubner et al. develop...
Chimeric antigen receptor (CAR) T cell therapies are limited by antigen escape and on-target/off-tumor toxicity. In addressing these challenges, Haubner et al. develop an "IF-BETTER" strategy. Their combinatorial chimeric co-stimulatory receptor with an attenuated CAR enhances acute myeloid leukemia (AML) killing while protecting healthy progenitors, highlighting the potential to leverage cooperative CAR designs.
Topics: Humans; Leukemia, Myeloid, Acute; Immunotherapy, Adoptive
PubMed: 37832553
DOI: 10.1016/j.ccell.2023.09.015