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Nature Reviews. Cancer Jan 2024The discovery of both cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) as negative regulators of antitumour immunity led to... (Review)
Review
The discovery of both cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) as negative regulators of antitumour immunity led to the development of numerous immunomodulatory antibodies as cancer treatments. Preclinical studies have demonstrated that the efficacy of immunoglobulin G (IgG)-based therapies depends not only on their ability to block or engage their targets but also on the antibody's constant region (Fc) and its interactions with Fcγ receptors (FcγRs). Fc-FcγR interactions are essential for the activity of tumour-targeting antibodies, such as rituximab, trastuzumab and cetuximab, where the killing of tumour cells occurs at least in part due to these mechanisms. However, our understanding of these interactions in the context of immunomodulatory antibodies designed to boost antitumour immunity remains less explored. In this Review, we discuss our current understanding of the contribution of FcγRs to the in vivo activity of immunomodulatory antibodies and the challenges of translating results from preclinical models into the clinic. In addition, we review the impact of genetic variability of human FcγRs on the activity of therapeutic antibodies and how antibody engineering is being utilized to develop the next generation of cancer immunotherapies.
Topics: Humans; Receptors, IgG; Immunoglobulin G; Immunomodulation; Immunotherapy; Neoplasms
PubMed: 38062252
DOI: 10.1038/s41568-023-00637-8 -
Cells Aug 2023In recent years, there has been a surge of interest in tumor microenvironment-associated cancer vaccine therapies. These innovative treatments aim to activate and... (Review)
Review
In recent years, there has been a surge of interest in tumor microenvironment-associated cancer vaccine therapies. These innovative treatments aim to activate and enhance the body's natural immune response against cancer cells by utilizing specific antigens present in the tumor microenvironment. The goal is to achieve a complete clinical response, where all measurable cancer cells are either eliminated or greatly reduced in size. With their potential to revolutionize cancer treatment, these therapies represent a promising avenue for researchers and clinicians alike. Despite over 100 years of research, the success of therapeutic cancer vaccines has been variable, particularly in advanced cancer patients, with various limitations, including the heterogeneity of the tumor microenvironment, the presence of immunosuppressive cells, and the potential for tumor escape mechanisms. Additionally, the effectiveness of these therapies may be limited by the variability of the patient's immune system response and the difficulty in identifying appropriate antigens for each patient. Despite these challenges, tumor microenvironment-targeted vaccine cancer therapies have shown promising results in preclinical and clinical studies and have the potential to become a valuable addition to current cancer treatment and "curative" options. While chemotherapeutic and monoclonal antibody treatments remain popular, ongoing research is needed to optimize the design and delivery of these therapies and to identify biomarkers that can predict response and guide patient selection. This comprehensive review explores the mechanisms of cancer vaccines, various delivery methods, and the role of adjuvants in improving treatment outcomes. It also discusses the historical background of cancer vaccine research and examines the current state of major cancer vaccination immunotherapies. Furthermore, the limitations and effectiveness of each vaccine type are analyzed, providing insights into the future of cancer vaccine development.
Topics: Humans; Cancer Vaccines; Immunotherapy; Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Antibodies, Monoclonal; Neoplasms
PubMed: 37681891
DOI: 10.3390/cells12172159 -
Hematology. American Society of... Dec 2023Patients with relapsed and refractory (R/R) aggressive B-cell non-Hodgkin lymphomas have historically poor survival outcomes, with chimeric antigen receptor T-cell... (Review)
Review
Patients with relapsed and refractory (R/R) aggressive B-cell non-Hodgkin lymphomas have historically poor survival outcomes, with chimeric antigen receptor T-cell (CAR-T) therapy now presenting a curative option for a subset of those patients. However, with the approval of several novel bispecific monoclonal antibody (BsAb) therapies with considerable activity in R/R aggressive large B-cell lymphomas (LBCL), patients and oncologists will be faced with decisions regarding how to sequence CAR-T and BsAb therapies based on patient- and disease-related factors. In this review, we compare CAR-T and BsAb therapies for R/R LBCL, highlighting data on the efficacy and toxicity of each treatment paradigm, and provide a roadmap for sequencing these highly effective therapies.
Topics: Humans; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Lymphoma, Large B-Cell, Diffuse; Antibodies, Bispecific; Cell- and Tissue-Based Therapy
PubMed: 38066907
DOI: 10.1182/hematology.2023000438 -
Signal Transduction and Targeted Therapy Aug 2023The immune-cell origin of hematologic malignancies provides a unique avenue for the understanding of both the mechanisms of immune responsiveness and immune escape,... (Review)
Review
The immune-cell origin of hematologic malignancies provides a unique avenue for the understanding of both the mechanisms of immune responsiveness and immune escape, which has accelerated the progress of immunotherapy. Several categories of immunotherapies have been developed and are being further evaluated in clinical trials for the treatment of blood cancers, including stem cell transplantation, immune checkpoint inhibitors, antigen-targeted antibodies, antibody-drug conjugates, tumor vaccines, and adoptive cell therapies. These immunotherapies have shown the potential to induce long-term remission in refractory or relapsed patients and have led to a paradigm shift in cancer treatment with great clinical success. Different immunotherapeutic approaches have their advantages but also shortcomings that need to be addressed. To provide clinicians with timely information on these revolutionary therapeutic approaches, the comprehensive review provides historical perspectives on the applications and clinical considerations of the immunotherapy. Here, we first outline the recent advances that have been made in the understanding of the various categories of immunotherapies in the treatment of hematologic malignancies. We further discuss the specific mechanisms of action, summarize the clinical trials and outcomes of immunotherapies in hematologic malignancies, as well as the adverse effects and toxicity management and then provide novel insights into challenges and future directions.
Topics: Humans; Immunotherapy; Hematologic Neoplasms; Immunoconjugates; Cancer Vaccines; Cell- and Tissue-Based Therapy
PubMed: 37591844
DOI: 10.1038/s41392-023-01521-5 -
Lancet (London, England) Jul 2023A genetically engineered pig cardiac xenotransplantation was done on Jan 7, 2022, in a non-ambulatory male patient, aged 57 years, with end-stage heart failure, and on...
BACKGROUND
A genetically engineered pig cardiac xenotransplantation was done on Jan 7, 2022, in a non-ambulatory male patient, aged 57 years, with end-stage heart failure, and on veno-arterial extracorporeal membrane oxygenation support, who was ineligible for an allograft. This report details our current understanding of factors important to the xenotransplantation outcome.
METHODS
Physiological and biochemical parameters critical for the care of all heart transplant recipients were collected in extensive clinical monitoring in an intensive care unit. To ascertain the cause of xenograft dysfunction, we did extensive immunological and histopathological studies, including electron microscopy and quantification of porcine cytomegalovirus or porcine roseolovirus (PCMV/PRV) in the xenograft, recipient cells, and tissue by DNA PCR and RNA transcription. We performed intravenous immunoglobulin (IVIG) binding to donor cells and single-cell RNA sequencing of peripheral blood mononuclear cells.
FINDINGS
After successful xenotransplantation, the graft functioned well on echocardiography and sustained cardiovascular and other organ systems functions until postoperative day 47 when diastolic heart failure occurred. At postoperative day 50, the endomyocardial biopsy revealed damaged capillaries with interstitial oedema, red cell extravasation, rare thrombotic microangiopathy, and complement deposition. Increased anti-pig xenoantibodies, mainly IgG, were detected after IVIG administration for hypogammaglobulinaemia and during the first plasma exchange. Endomyocardial biopsy on postoperative day 56 showed fibrotic changes consistent with progressive myocardial stiffness. Microbial cell-free DNA testing indicated increasing titres of PCMV/PRV cell-free DNA. Post-mortem single-cell RNA sequencing showed overlapping causes.
INTERPRETATION
Hyperacute rejection was avoided. We identified potential mediators of the observed endothelial injury. First, widespread endothelial injury indicates antibody-mediated rejection. Second, IVIG bound strongly to donor endothelium, possibly causing immune activation. Finally, reactivation and replication of latent PCMV/PRV in the xenograft possibly initiated a damaging inflammatory response. The findings point to specific measures to improve xenotransplant outcomes in the future.
FUNDING
The University of Maryland School of Medicine, and the University of Maryland Medical Center.
Topics: Humans; Male; Transplantation, Heterologous; Compassionate Use Trials; Leukocytes, Mononuclear; Immunoglobulins, Intravenous; Heart; Graft Rejection
PubMed: 37393920
DOI: 10.1016/S0140-6736(23)00775-4 -
Human Vaccines & Immunotherapeutics Aug 2023Guillain - Barré syndrome (GBS) is an immune-mediated neuropathy, the pathology of which is not clear. Both cellular and humoral immunity are involved in the occurrence... (Review)
Review
Guillain - Barré syndrome (GBS) is an immune-mediated neuropathy, the pathology of which is not clear. Both cellular and humoral immunity are involved in the occurrence of the disease, and molecular mimicry is currently the most widely recognized pathogenesis. Intravenous immunoglobulin (IVIg) and plasma exchange (PE) have been proven to be effective in improving the prognosis of patients with GBS, but there has been no progress in the treatment of the disease or strategies to improve the prognosis. New treatment strategies for GBS are mostly immunotherapies, including treatment against antibodies, complement pathways, immune cells and cytokines. Some of the new strategies are being investigated in clinical trials, but none of them have been approved for the treatment of GBS. Here, we summarized the current therapies for GBS, and new immunotherapies for GBS according to pathogenesis.
Topics: Humans; Guillain-Barre Syndrome; Immunoglobulins, Intravenous; Prognosis; Immunotherapy; Cytokines; Plasma Exchange
PubMed: 37278272
DOI: 10.1080/21645515.2023.2215153 -
Frontiers in Immunology 2023Muscle-specific kinase (MuSK) Myasthenia Gravis (MG) represents a prototypical antibody-mediated disease characterized by predominantly focal muscle weakness (neck,... (Review)
Review
Muscle-specific kinase (MuSK) Myasthenia Gravis (MG) represents a prototypical antibody-mediated disease characterized by predominantly focal muscle weakness (neck, facial, and bulbar muscles) and fatigability. The pathogenic antibodies mostly belong to the immunoglobulin subclass (Ig)G4, a feature which attributes them their specific properties and pathogenic profile. On the other hand, acetylcholine receptor (AChR) MG, the most prevalent form of MG, is characterized by immunoglobulin (Ig)G1 and IgG3 antibodies to the AChR. IgG4 class autoantibodies are impotent to fix complement and only weakly bind Fc-receptors expressed on immune cells and exert their pathogenicity interfering with the interaction between their targets and binding partners (e.g. between MuSK and LRP4). Cardinal differences between AChR and MuSK-MG are the thymus involvement (not prominent in MuSK-MG), the distinct HLA alleles, and core immunopathological patterns of pathology in neuromuscular junction, structure, and function. In MuSK-MG, classical treatment options are usually less effective (e.g. IVIG) with the need for prolonged and high doses of steroids difficult to be tapered to control symptoms. Exceptional clinical response to plasmapheresis and rituximab has been particularly observed in these patients. Reduction of antibody titers follows the clinical efficacy of anti-CD20 therapies, a feature implying the role of short-lived plasma cells (SLPB) in autoantibody production. Novel therapeutic monoclonal against B cells at different stages of their maturation (like plasmablasts), or against molecules involved in B cell activation, represent promising therapeutic targets. A revolution in autoantibody-mediated diseases is pharmacological interference with the neonatal Fc receptor, leading to a rapid reduction of circulating IgGs (including autoantibodies), an approach already suitable for AChR-MG and promising for MuSK-MG. New precision medicine approaches involve Chimeric autoantibody receptor T (CAAR-T) cells that are engineered to target antigen-specific B cells in MuSK-MG and represent a milestone in the development of targeted immunotherapies. This review aims to provide a detailed update on the pathomechanisms involved in MuSK-MG (cellular and humoral aberrations), fostering the understanding of the latest indications regarding the efficacy of different treatment strategies.
Topics: Humans; Autoantibodies; Immunoglobulin G; Immunotherapy; Myasthenia Gravis; Receptor Protein-Tyrosine Kinases; Receptors, Cholinergic
PubMed: 37564637
DOI: 10.3389/fimmu.2023.1212757 -
ESMO Open Aug 2023The current treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC) has been greatly impacted in the past decade... (Review)
Review
The current treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC) has been greatly impacted in the past decade by the introduction of antibody-drug conjugates (ADCs), which represent a relatively novel therapeutic class with the peculiar ability to deliver otherwise overtly toxic chemotherapeutics to tumor sites by exploiting the specificities of monoclonal antibodies. Indeed, drug engineering refinements in ADC design, such as through the introduction of cleavable linkers and hydrophobic payloads, resulted in improved patient outcomes in recent years. Two different ADCs, namely trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), have already entered clinical practice for the treatment of HER2-positive ABC. In this scenario, T-DXd has shown to portend better survival outcomes compared to T-DM1, while leaving a large unsought area of unmet medical need upon T-DXd failure. Treatment decision and benefit of cancer drugs following T-DXd still represent an area of clinical controversy, where a preclinical investigation and clinical development should be prioritized. As the pace of innovation is currently accelerating, and with novel ADC formulations advancing in early-phase clinical trials, the whole BC field is changing at an unprecedented rate, with potential broadenings of therapeutic indications. In this review, we present the clinical landscape of HER2-positive advanced BC and discuss our vision on how to tackle T-DXd resistance, providing a perspective on the priority areas of the cancer research in this setting.
Topics: Humans; Female; Breast Neoplasms; Antibodies, Monoclonal, Humanized; Trastuzumab; Ado-Trastuzumab Emtansine; Immunoconjugates
PubMed: 37467660
DOI: 10.1016/j.esmoop.2023.101608 -
Vaccine Nov 2023The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variant BA.2.86 has over 30 mutations in spike compared with BA.2 and XBB.1.5, which raised the...
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variant BA.2.86 has over 30 mutations in spike compared with BA.2 and XBB.1.5, which raised the possibility that BA.2.86 might evade neutralizing antibodies (NAbs) induced by vaccination or infection. In this study, we show that NAb titers are substantially lower to BA.2.86 compared with BA.2 but are similar or slightly higher than to other current circulating variants, including XBB.1.5, EG.5.1, and FL.1.5.1. Moreover, NAb titers against all these variants were higher in vaccinated individuals with a history of XBB.1.5 infection compared with vaccinated individuals with no history of XBB.1.5 infection, suggesting the potential utility of the monovalent XBB.1.5 mRNA boosters.
Topics: Humans; COVID-19; SARS-CoV-2; Antibodies, Neutralizing; Immunization, Secondary; Antibodies, Viral
PubMed: 37872011
DOI: 10.1016/j.vaccine.2023.10.051 -
Life Sciences Jun 2024Antibody-drug conjugates (ADCs) are immunoconjugates that combine the specificity of monoclonal antibodies with a cytotoxic agent. The most appealing aspects of ADCs... (Review)
Review
Antibody-drug conjugates (ADCs) are immunoconjugates that combine the specificity of monoclonal antibodies with a cytotoxic agent. The most appealing aspects of ADCs include their potential additive or synergistic effects of the innate backbone antibody and cytotoxic effects of the payload on tumors without the severe toxic side effects often associated with traditional chemotherapy. Recent advances in identifying new targets with tumor-specific expression, along with improved bioactive payloads and novel linkers, have significantly expanded the scope and optimism for ADCs in cancer therapeutics. In this paper, we will first provide a brief overview of antibody specificity and the structure of ADCs. Next, we will discuss the mechanisms of action and the development of resistance to ADCs. Finally, we will explore opportunities for enhancing ADC efficacy, overcoming drug resistance, and offer future perspectives on leveraging ADCs to improve the outcome of ADC therapy for cancer treatment.
Topics: Humans; Immunoconjugates; Neoplasms; Animals; Antibodies, Monoclonal; Antineoplastic Agents; Drug Resistance, Neoplasm; Antibody Specificity
PubMed: 38688384
DOI: 10.1016/j.lfs.2024.122676