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Nature Communications Nov 2023Chimeric Antigen Receptor (CAR) T cells directed to B cell maturation antigen (BCMA) mediate profound responses in patients with multiple myeloma, but most patients do...
Chimeric Antigen Receptor (CAR) T cells directed to B cell maturation antigen (BCMA) mediate profound responses in patients with multiple myeloma, but most patients do not achieve long-term complete remissions. In addition, recent evidence suggests that high-affinity binding to BCMA can result in on-target, off-tumor activity in the basal ganglia and can lead to fatal Parkinsonian-like disease. Here we develop CAR T cells against multiple myeloma using a binder to targeting transmembrane activator and CAML interactor (TACI) in mono and dual-specific formats with anti-BCMA. These CARs have robust, antigen-specific activity in vitro and in vivo. We also show that TACI RNA expression is limited in the basal ganglia, which may circumvent some of the toxicities recently reported with BCMA CARs. Thus, single-targeting TACI CARs may have a safer toxicity profile, whereas dual-specific BCMA-TACI CAR T cells have potential to avoid the antigen escape that can occur with single-antigen targeting.
Topics: Humans; Multiple Myeloma; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; B-Cell Maturation Antigen; T-Lymphocytes
PubMed: 37980341
DOI: 10.1038/s41467-023-43416-7 -
Viruses Jul 2023This review is focused on the use of hyperimmune globulin therapy to treat some infectious diseases of viral or bacterial origin. Despite the introduction of antibiotics... (Review)
Review
This review is focused on the use of hyperimmune globulin therapy to treat some infectious diseases of viral or bacterial origin. Despite the introduction of antibiotics and vaccines, plasma immunoglobulin therapy from whole blood donation can still play a key role. These treatments provide passive transfer of high-titer antibodies that either reduces the risk or the severity of the infection and offer immediate but short-term protection against specific diseases. Antibody preparations derived from immunized human donors are commonly used for the prophylaxis and treatment of rabies, hepatitis A and B viruses, varicella-zoster virus, and pneumonia caused by respiratory syncytial virus, , . The use of hyperimmune globulin therapy is a promising challenge, especially for the treatment of emerging viral infections for which there are no specific therapies or licensed vaccines.
Topics: Humans; Immunoglobulins; Globulins; Immunization, Passive; Vaccines; Communicable Diseases; Antibodies, Viral
PubMed: 37515229
DOI: 10.3390/v15071543 -
Blood Advances Dec 2023Survival of patients with acute myeloid leukemia (AML) can be improved by allogeneic hematopoietic stem cell transplantation (allo-HSCT) because of the antileukemic...
Survival of patients with acute myeloid leukemia (AML) can be improved by allogeneic hematopoietic stem cell transplantation (allo-HSCT) because of the antileukemic activity of T and natural killer cells from the donor. However, the use of allo-HSCT is limited by donor availability, recipient age, and potential severe side effects. Similarly, the efficacy of immunotherapies directing autologous T cells against tumor cells, including T-cell recruiting antibodies, chimeric antigen receptor T-cell therapy, and immune checkpoint inhibitors are limited in AML because of multiple mechanisms of leukemia immune escape. This has prompted a search for novel immunostimulatory approaches. Here, we show that activation of adenosine 5'-monophosphate-activated protein kinase (AMPK), a master regulator of cellular energy balance, by the small molecule GSK621 induces calreticulin (CALR) membrane exposure in murine and human AML cells. When CALR is exposed on the cell surface, it serves as a damage-associated molecular pattern that stimulates immune responses. We found that GSK621-treated murine leukemia cells promote the activation and maturation of bone marrow-derived dendritic cells. Moreover, vaccination with GSK621-treated leukemia cells had a protective effect in syngeneic immunocompetent recipients bearing transplanted AMLs. This effect was lost in recipients depleted of CD4/CD8 T cells. Together, these results demonstrate that AMPK activation by GSK621 elicits traits of immunogenic cell death and promotes a robust immune response against leukemia. Pharmacologic AMPK activation thus represents a new potential target for improving the activity of immunotherapy in AML.
Topics: Animals; Humans; Mice; AMP-Activated Protein Kinases; Immunogenic Cell Death; Immunotherapy; Immunotherapy, Adoptive; Leukemia, Myeloid, Acute
PubMed: 37903311
DOI: 10.1182/bloodadvances.2022009444 -
Clinical Lymphoma, Myeloma & Leukemia Oct 2023Secondary antibody deficiency (SAD) is a subtype of secondary immunodeficiency characterized by low serum antibody concentrations (hypogammaglobulinemia) or poor... (Review)
Review
Secondary antibody deficiency (SAD) is a subtype of secondary immunodeficiency characterized by low serum antibody concentrations (hypogammaglobulinemia) or poor antibody function. SAD is common in patients with multiple myeloma (MM) due to underlying disease pathophysiology and treatment-related immune system effects. Patients with SAD are more susceptible to infections and infection-related morbidity and mortality. With therapeutic advancements improving MM disease control and survival, it is increasingly important to recognize and treat the often-overlooked concurrent immunodeficiency present in patients with MM. The aims of this review are to define SAD and its consequences in MM, increase SAD awareness, and provide recommendations for SAD management. Based on expert panel discussions at a standalone meeting and supportive literature, several recommendations were made. Firstly, all patients with MM should be suspected to have SAD regardless of serum antibody concentrations. Patients should be evaluated for immunodeficiency at MM diagnosis and stratified into management categories based on their individualized risk of SAD and infection. Infection-prevention strategy education, early infection reporting, and anti-infective prophylaxis are key. We recommend prophylactic antibiotics or immunoglobulin replacement therapy (IgRT) should be considered in patients with severe hypogammaglobulinemia associated with a recurrent or persistent infection. To ensure an individualized and efficient treatment approach is utilized, patient's immunoglobin G concentration and infection burden should be closely monitored throughout treatment. Patient choice regarding route and IgRT treatment is also key in reducing treatment burden. Together, these recommendations and proposed management algorithms can be used to aid physician decision-making to improve patient outcomes.
Topics: Humans; Multiple Myeloma; Agammaglobulinemia; Immunologic Deficiency Syndromes; Immunization, Passive; Antibodies
PubMed: 37353432
DOI: 10.1016/j.clml.2023.05.008 -
Biomedicine & Pharmacotherapy =... Dec 2023The advent of chimeric antigen receptor T cells (CAR-T cells) has made a tremendous revolution in the era of cancer immunotherapy, so that since 2017 eight CAR-T cell... (Review)
Review
The advent of chimeric antigen receptor T cells (CAR-T cells) has made a tremendous revolution in the era of cancer immunotherapy, so that since 2017 eight CAR-T cell products have been granted marketing authorization. All of these approved products are generated from autologous sources, but this strategy faces several challenges such as time-consuming and expensive manufacturing process and reduced anti-tumor potency of patients' T cells due to the disease or previous therapies. The use of an allogeneic source can overcome these issues and provide an industrial, scalable, and standardized manufacturing process that reduces costs and provides faster treatment for patients. Nevertheless, for using allogeneic CAR-T cells, we are faced with the challenge of overcoming two formidable impediments: severe life-threatening graft-versus-host-disease (GvHD) caused by allogeneic CAR-T cells, and allorejection of allogeneic CAR-T cells by host immune cells which is called "host versus graft" (HvG). In this study, we reviewed recent registered clinical trials of allogeneic CAR-T cell therapy to analyze different approaches to achieve a safe and efficacious "off-the-shelf" source for chimeric antigen receptor (CAR) based immunotherapy.
Topics: Humans; Cell- and Tissue-Based Therapy; Immunotherapy, Adoptive; Neoplasms; Receptors, Chimeric Antigen; T-Lymphocytes; Clinical Trials as Topic
PubMed: 37979380
DOI: 10.1016/j.biopha.2023.115888 -
International Journal of Molecular... Oct 2023The landscape of therapeutic measures to treat multiple myeloma has undergone a seismic shift since the dawn of the current century. This has been driven largely by the... (Review)
Review
The landscape of therapeutic measures to treat multiple myeloma has undergone a seismic shift since the dawn of the current century. This has been driven largely by the introduction of new classes of small molecules, such as proteasome blockers (e.g., bortezomib) and immunomodulators (e.g., lenalidomide), as well as by immunotherapeutic agents starting with the anti-CD38 monoclonal antibody daratumumab in 2015. Recently, other immunotherapies have been added to the armamentarium of drugs available to fight this malignancy. These include the bispecifics teclistamab, talquetamab, and elranatamab, and the chimeric antigen receptor (CAR) T-cell products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). While the accumulated benefits of these newer agents have resulted in a more than doubling of the disease's five-year survival rate to nearly 60% and improved quality of life, the disease remains incurable, as patients become refractory to the drugs and experience relapse. This review covers the current scope of antimyeloma immunotherapeutic agents, both those in clinical use and in development. Included in the discussion are additional monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), bi- and multitargeted mAbs, and CAR T-cells and emerging natural killer (NK) cells, including products intended for "off-the-shelf" (allogeneic) applications. Emphasis is placed on the benefits of each along with the challenges that need to be surmounted if MM is to be cured.
Topics: Humans; Multiple Myeloma; Quality of Life; Immunotherapy; Lenalidomide; Bortezomib; Antibodies, Bispecific; Immunotherapy, Adoptive
PubMed: 37958658
DOI: 10.3390/ijms242115674 -
Frontiers in Immunology 2023Osteosarcoma, the most common bone malignancy in children and adolescents, poses considerable challenges in terms of prognosis, especially for patients with metastatic... (Review)
Review
Osteosarcoma, the most common bone malignancy in children and adolescents, poses considerable challenges in terms of prognosis, especially for patients with metastatic or recurrent disease. While surgical intervention and adjuvant chemotherapy have improved survival rates, limitations such as impractical tumor removal or chemotherapy resistance hinder the treatment outcomes. Chimeric antigen receptor (CAR)-T cell therapy, an innovative immunotherapy approach that involves targeting tumor antigens and releasing immune factors, has shown significant advancements in the treatment of hematological malignancies. However, its application in solid tumors, including osteosarcoma, is constrained by factors such as low antigen specificity, limited persistence, and the complex tumor microenvironment. Research on osteosarcoma is ongoing, and some targets have shown promising results in pre-clinical studies. This review summarizes the current status of research on CAR-T cell therapy for osteosarcoma by compiling recent literature. It also proposes future research directions to enhance the treatment of osteosarcoma.
Topics: Adolescent; Child; Humans; Receptors, Chimeric Antigen; Osteosarcoma; Immunotherapy, Adoptive; Bone Neoplasms; Cell- and Tissue-Based Therapy; Tumor Microenvironment
PubMed: 38187386
DOI: 10.3389/fimmu.2023.1290762 -
Journal of Translational Medicine Aug 2023Despite being an integral part of the immune response in the tumor microenvironment (TME), few studies have mechanistically elucidated eosinophil functions in cancer... (Review)
Review
Despite being an integral part of the immune response in the tumor microenvironment (TME), few studies have mechanistically elucidated eosinophil functions in cancer outcomes. Eosinophils are a minor population of granulocytes that are mostly explored in asthma and allergic disorders. Their influence on primary and metastatic tumors, however, has recently come to light. Eosinophils' diverse armamentarium of mediators and receptors allows them to participate in innate and adaptive immunity, such as type 1 and type 2 immunity, and shape TME and tumor outcomes. Based on TME cells and cytokines, activated eosinophils drive other immune cells to ultimately promote or suppress tumor growth. Discovering exactly what conditions determine the pro-tumorigenic or anti-tumorigenic role of eosinophils allows us to take advantage of these signals and devise novel strategies to target cancer cells. Here, we first revisit eosinophil biology and differentiation as recognizing eosinophil mediators is crucial to their function in homeostatic and pathological conditions as well as tumor outcome. The bulk of our paper discusses eosinophil interactions with tumor cells, immune cells-including T cells, plasma cells, natural killer (NK) cells-and gut microbiota. Eosinophil mediators, such as IL-5, IL-33, granulocyte-macrophage colony-stimulating factor (GM-CSF), thymic stromal lymphopoietin (TSLP), and CCL11 also determine eosinophil behavior toward tumor cells. We then examine the implications of these findings for cancer immunotherapy approaches, including immune checkpoint blockade (ICB) therapy using immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T cell therapy. Eosinophils synergize with CAR T cells and ICB therapy to augment immunotherapies.
Topics: Humans; Eosinophils; Neoplasms; Immunotherapy; Carcinogenesis; Immunotherapy, Adoptive; Cytokines; Tumor Microenvironment
PubMed: 37587450
DOI: 10.1186/s12967-023-04418-7 -
Oncoimmunology 2023Immunotherapeutic innovation is crucial for limited operability tumors. CAR T-cell therapy displayed reduced efficiency against glioblastoma (GBM), likely due to...
BACKGROUND
Immunotherapeutic innovation is crucial for limited operability tumors. CAR T-cell therapy displayed reduced efficiency against glioblastoma (GBM), likely due to mutations underlying disease progression. Natural Killer cells (NKs) detect cancer cells despite said mutations - demonstrating increased tumor elimination potential. We developed an NK differentiation system using human pluripotent stem cells (hPSCs). Via this system, genetic modifications targeting cancer treatment challenges can be introduced during pluripotency - enabling unlimited production of modified "off-the-shelf" hPSC-NKs.
METHODS
hPSCs were differentiated into hematopoietic progenitor cells (HPCs) and NKs using our novel organoid system. These cells were characterized using flow cytometric and bioinformatic analyses. HPC engraftment potential was assessed using NSG mice. NK cytotoxicity was validated using and K562 assays and further corroborated on lymphoma, diffuse intrinsic pontine glioma (DIPG), and GBM cell lines .
RESULTS
HPCs demonstrated engraftment in peripheral blood samples, and hPSC-NKs showcased morphology and functionality akin to same donor peripheral blood NKs (PB-NKs). The hPSC-NKs also displayed potential advantages regarding checkpoint inhibitor and metabolic gene expression, and demonstrated and cytotoxicity against various cancers.
CONCLUSIONS
Our organoid system, designed to replicate cellular organization (including signaling gradients and shear stress conditions), offers a suitable environment for HPC and NK generation. The engraftable nature of HPCs and potent NK cytotoxicity against leukemia, lymphoma, DIPG, and GBM highlight the potential of this innovative system to serve as a valuable tool that will benefit cancer treatment and research - improving patient survival and quality of life.
Topics: Humans; Animals; Mice; Quality of Life; Immunotherapy; Cell Differentiation; Immunotherapy, Adoptive; Glioblastoma
PubMed: 37720687
DOI: 10.1080/2162402X.2023.2240670 -
Nature Communications Dec 2023To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and...
To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1-11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely.
Topics: Humans; Follow-Up Studies; Cytokines; COVID-19; COVID-19 Serotherapy; Brain Injuries; Autoantibodies; Inflammation Mediators; Biomarkers; Glial Fibrillary Acidic Protein
PubMed: 38135686
DOI: 10.1038/s41467-023-42320-4