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Cell Reports. Medicine Apr 2022John Maher has worked on CAR T cell immunotherapy with a primary focus on solid tumors for over 20 years. In this Q&A, Cell Reports Medicine interviewed him about his...
John Maher has worked on CAR T cell immunotherapy with a primary focus on solid tumors for over 20 years. In this Q&A, Cell Reports Medicine interviewed him about his journey in this arena and next steps.
Topics: Humans; Immunotherapy; Immunotherapy, Adoptive; Neoplasms
PubMed: 35522096
DOI: 10.1016/j.xcrm.2022.100595 -
Seminars in Hematology Jan 2023Hematopoietic stem cell transplantation (HSCT) has been used as a curative standard of care for moderate to severe primary immunodeficiency disorders as well as relapsed... (Review)
Review
Hematopoietic stem cell transplantation (HSCT) has been used as a curative standard of care for moderate to severe primary immunodeficiency disorders as well as relapsed hematologic malignancies for over 50 years [1,2]. However, chronic and refractory viral infections remain a leading cause of morbidity and mortality in the immune deficient period following HSCT, where use of available antiviral pharmacotherapies is limited by toxicity and emerging resistance [3]. Adoptive immunotherapy using virus-specific T cells (VSTs) has been explored for over 2 decades [4,5] in patients post-HSCT and has been shown prior phase I-II studies to be safe and effective for treatment or preventions of viral infections including cytomegalovirus, Epstein-Barr virus, BK virus, and adenovirus with minimal toxicity and low risk of graft vs host disease [6-9]. This review summarizes methodologies to generate VSTs the clinical results utilizing VST therapeutics and the challenges and future directions for the field.
Topics: Humans; T-Lymphocytes; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Neoplasm Recurrence, Local; Virus Diseases; Immunotherapy, Adoptive; Hematopoietic Stem Cell Transplantation
PubMed: 37080705
DOI: 10.1053/j.seminhematol.2022.12.002 -
Molecular Therapy : the Journal of the... Aug 2023Multiple clinical studies have treated mesothelin (MSLN)-positive solid tumors by administering MSLN-directed chimeric antigen receptor (CAR) T cells. Although these...
Multiple clinical studies have treated mesothelin (MSLN)-positive solid tumors by administering MSLN-directed chimeric antigen receptor (CAR) T cells. Although these products are generally safe, efficacy is limited. Therefore, we generated and characterized a potent, fully human anti-MSLN CAR. In a phase 1 dose-escalation study of patients with solid tumors, we observed two cases of severe pulmonary toxicity following intravenous infusion of this product in the high-dose cohort (1-3 × 10 T cells per m). Both patients demonstrated progressive hypoxemia within 48 h of infusion with clinical and laboratory findings consistent with cytokine release syndrome. One patient ultimately progressed to grade 5 respiratory failure. An autopsy revealed acute lung injury, extensive T cell infiltration, and accumulation of CAR T cells in the lungs. RNA and protein detection techniques confirmed low levels of MSLN expression by benign pulmonary epithelial cells in affected lung and lung samples obtained from other inflammatory or fibrotic conditions, indicating that pulmonary pneumocyte and not pleural expression of mesothelin may lead to dose-limiting toxicity. We suggest patient enrollment criteria and dosing regimens of MSLN-directed therapies consider the possibility of dynamic expression of mesothelin in benign lung with a special concern for patients with underlying inflammatory or fibrotic conditions.
Topics: Humans; Mesothelin; GPI-Linked Proteins; Immunotherapy, Adoptive; Neoplasms; T-Lymphocytes
PubMed: 37312454
DOI: 10.1016/j.ymthe.2023.06.006 -
Technology in Cancer Research &... 2023Adoptive cell immunotherapy (ACT) is an innovative promising treatment for tumors. ACT is characterized by the infusion of active anti-tumor immune cells (specific and... (Review)
Review
Adoptive cell immunotherapy (ACT) is an innovative promising treatment for tumors. ACT is characterized by the infusion of active anti-tumor immune cells (specific and non-specific) into patients to kill tumor cells either directly or indirectly by stimulating the body's immune system. The patient's (autologous) or a donor's (allogeneic) immune cells are used to improve immune function. Chimeric antigen receptor (CAR) T cells (CAR-T) is a type of ACT that has gained attention. T cells from the peripheral blood are genetically engineered to express CARs that rapidly proliferate and specifically recognize target antigens to exert its anti-tumor effects. Clinical application of CAR-T therapy for hematological tumors has shown good results, but adverse reactions and recurrence limit its applicability. Tumor infiltrating lymphocyte (TIL) therapy is effective for solid tumors. TIL therapy exhibits T cell receptor (TCR) clonality, superior tumor homing ability, and low targeted toxicity, but its successful application is limited to a number of tumors. Regardless, TIL and CAR-T therapies are effective for treating cancer. Additionally, CAR-natural killer (NK), CAR-macrophages (M), and TCR-T therapies are currently being researched. In this review, we highlight the current developments and limitations of several types of ACT.
Topics: Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; T-Lymphocytes; Receptors, Antigen, T-Cell; Neoplasms; Immunotherapy
PubMed: 38037341
DOI: 10.1177/15330338231204198 -
Trends in Pharmacological Sciences Jun 2023Immunotherapies modulate the body's defense system to treat cancer. While these therapies have shown efficacy against multiple types of cancer, patient response rates... (Review)
Review
Immunotherapies modulate the body's defense system to treat cancer. While these therapies have shown efficacy against multiple types of cancer, patient response rates are limited, and the off-target effects can be severe. Typical approaches in developing immunotherapies tend to focus on antigen targeting and molecular signaling, while overlooking biophysical and mechanobiological effects. Immune cells and tumor cells are both responsive to biophysical cues, which are prominent in the tumor microenvironment. Recent studies have shown that mechanosensing - including through Piezo1, adhesions, and Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) - influences tumor-immune interactions and immunotherapeutic efficacy. Furthermore, biophysical methods such as fluidic systems and mechanoactivation schemes can improve the controllability and manufacturing of engineered T cells, with potential for increasing therapeutic efficacy and specificity. This review focuses on leveraging advances in immune biophysics and mechanobiology toward improving chimeric antigen receptor (CAR) T-cell and anti-programmed cell death protein 1 (anti-PD-1) therapies.
Topics: Humans; T-Lymphocytes; Immunotherapy; Neoplasms; Transcription Factors; Biophysics; Immunotherapy, Adoptive; Tumor Microenvironment; Ion Channels
PubMed: 37172572
DOI: 10.1016/j.tips.2023.03.007 -
Hematology/oncology Clinics of North... Oct 2019Cell therapies have become an important part of clinical hematology and oncology. Cell therapy laboratories were first established in academic health centers to process... (Review)
Review
Cell therapies have become an important part of clinical hematology and oncology. Cell therapy laboratories were first established in academic health centers to process ABO-incompatible marrow grafts. These laboratories now produce a wide variety of cell and gene therapies. Some of the most widely used and clinically important cell therapies are T-cell immunotherapies. These therapies include donor lymphocyte infusions, tumor-infiltrating lymphocytes, T-cell receptor-engineered T cells, chimeric antigen receptor T cells, and virus-specific T cells. The clinical application and methods used to manufacture these adoptive cell therapies are reviewed.
Topics: Cell- and Tissue-Based Therapy; Disease Management; Genetic Engineering; Genetic Therapy; Humans; Immunotherapy, Adoptive; Lymphocytes, Tumor-Infiltrating; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Cell Antigen Receptor Specificity; T-Lymphocyte Subsets; T-Lymphocytes; Tissue Donors
PubMed: 31466607
DOI: 10.1016/j.hoc.2019.05.006 -
International Journal of Molecular... Aug 2020Hematological malignancies define a highly heterogeneous set of blood-, bone marrow-, and organ-associated diseases with highly variable prognoses that constantly...
Hematological malignancies define a highly heterogeneous set of blood-, bone marrow-, and organ-associated diseases with highly variable prognoses that constantly relapse upon treatment [...].
Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Drug Resistance, Neoplasm; Drug Therapy, Combination; Hematologic Neoplasms; Humans; Immunotherapy; Immunotherapy, Adoptive; Molecular Targeted Therapy
PubMed: 32847013
DOI: 10.3390/ijms21176091 -
Current Problems in Cancer Feb 2022Approaches to immunologic therapies in myelodysplastic syndromes (MDS) have generally fallen into 2 categories: therapies that target immune effector cells and enhance... (Review)
Review
Approaches to immunologic therapies in myelodysplastic syndromes (MDS) have generally fallen into 2 categories: therapies that target immune effector cells and enhance or direct an antileukemic effect, and therapies which target immunological markers on MDS progenitors themselves. Examples of the former include immune checkpoint inhibitors, immunomodulatory therapies, and vaccines, among others, while examples of the latter include antibody-drug conjugate therapies and naked antibodies; while bispecific antibodies and modified T-cells (such as CAR-T therapies) bridge both therapeutic modalities. In this review, we will discuss the rationale for the above therapies, clinical results to date, and potential future directions for investigation.
Topics: Humans; Immunotherapy; Immunotherapy, Adoptive; Medical Oncology; Myelodysplastic Syndromes; Neoplasms
PubMed: 34980485
DOI: 10.1016/j.currproblcancer.2021.100824 -
Med (New York, N.Y.) Jun 2024Med discusses the future of CAR T cell therapy for autoimmune diseases with Dr. Fabian Müller, Senior Attending Physician and Head of the CAR T Cell Unit, Department...
Med discusses the future of CAR T cell therapy for autoimmune diseases with Dr. Fabian Müller, Senior Attending Physician and Head of the CAR T Cell Unit, Department of Medicine 5 (Hematology and Oncology), University Hospital Erlangen, Germany.
Topics: Humans; Autoimmune Diseases; Immunotherapy, Adoptive; Germany; Receptors, Chimeric Antigen
PubMed: 38878762
DOI: 10.1016/j.medj.2024.04.004 -
European Journal of Immunology Mar 2023Adoptive cell transfer (ACT) therapies have gained renewed interest in the field of immunotherapy following the advent of chimeric antigen receptor (CAR) technology.... (Review)
Review
Adoptive cell transfer (ACT) therapies have gained renewed interest in the field of immunotherapy following the advent of chimeric antigen receptor (CAR) technology. This immunological breakthrough requires immune cell engineering with an artificial surface protein receptor for antigen-specific recognition coupled to an intracellular protein domain for cell activating functions. CAR-based ACT has successfully solved some hematological malignancies, and it is expected that other tumors may soon benefit from this approach. However, the potential of CAR technology is such that other immune-mediated disorders are beginning to profit from it. This review will focus on CAR-based ACT therapeutic areas other than oncology such as infection, allergy, autoimmunity, transplantation, and fibrotic repair. Herein, we discuss the results and limitations of preclinical and clinical studies in that regard.
Topics: Humans; Receptors, Chimeric Antigen; T-Lymphocytes; Neoplasms; Immunotherapy, Adoptive; Hematologic Neoplasms
PubMed: 36649259
DOI: 10.1002/eji.202250184