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The New England Journal of Medicine Mar 2021Large B-cell lymphomas, with an estimated 150,000 new cases annually worldwide, represent almost 30% of all cases of non-Hodgkin’s lymphoma. Patients typically present... (Review)
Review
Large B-cell lymphomas, with an estimated 150,000 new cases annually worldwide, represent almost 30% of all cases of non-Hodgkin’s lymphoma. Patients typically present with progressive lymphadenopathy, extranodal disease, or both and require therapy. Despite the advanced stage at presentation in the majority of patients, more than 60% can be cured with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) immunochemotherapy (Fig. 1A). Patients with treatment failure after R-CHOP often have a poor outcome — in particular, those with disease that is refractory to frontline or subsequent therapies — although some patients can have a durable remission and be cured after secondary therapies. Over the past two decades, improved insights into large B-cell lymphomas, in terms of epidemiology, prognostic factors, and biologic heterogeneity, have led to a refinement of disease classification and the development of new therapeutic approaches.
Topics: Algorithms; Antineoplastic Agents; Combined Modality Therapy; Humans; Immunotherapy, Adoptive; Lymphoma, Large B-Cell, Diffuse; Neoplasm Staging; Prognosis; Risk Factors; Stem Cell Transplantation; Transplantation, Autologous
PubMed: 33657296
DOI: 10.1056/NEJMra2027612 -
Cell Mar 2023Neutrophils accumulate in solid tumors, and their abundance correlates with poor prognosis. Neutrophils are not homogeneous, however, and could play different roles in...
Neutrophils accumulate in solid tumors, and their abundance correlates with poor prognosis. Neutrophils are not homogeneous, however, and could play different roles in cancer therapy. Here, we investigate the role of neutrophils in immunotherapy, leading to tumor control. We show that successful therapies acutely expanded tumor neutrophil numbers. This expansion could be attributed to a Sell state rather than to other neutrophils that accelerate tumor progression. Therapy-elicited neutrophils acquired an interferon gene signature, also seen in human patients, and appeared essential for successful therapy, as loss of the interferon-responsive transcription factor IRF1 in neutrophils led to failure of immunotherapy. The neutrophil response depended on key components of anti-tumor immunity, including BATF3-dependent DCs, IL-12, and IFNγ. In addition, we found that a therapy-elicited systemic neutrophil response positively correlated with disease outcome in lung cancer patients. Thus, we establish a crucial role of a neutrophil state in mediating effective cancer therapy.
Topics: Humans; Neutrophils; Lung Neoplasms; Signal Transduction; Immunotherapy; Interferons
PubMed: 37001504
DOI: 10.1016/j.cell.2023.02.032 -
Current Hematologic Malignancy Reports Apr 2023Chimeric antigen receptor (CAR) T cell therapy is an immunotherapy that has resulted in tremendous progress in the treatment of patients with B cell malignancies.... (Review)
Review
PURPOSE OF REVIEW
Chimeric antigen receptor (CAR) T cell therapy is an immunotherapy that has resulted in tremendous progress in the treatment of patients with B cell malignancies. However, the remarkable efficacy of therapy is not without significant safety concerns. Herein, we will review the unique and potentially life-threatening toxicities associated with CAR-T cell therapy and their association with treatment efficacy.
RECENT FINDINGS
Currently, CAR-T cell therapy is approved for the treatment of B cell relapsed or refractory leukemia and lymphoma, and most recently, multiple myeloma (MM). In these different diseases, it has led to excellent complete and overall response rates depending on the patient population and therapy. Despite promising efficacy, CAR-T cell therapy is associated with significant side effects; the two most notable toxicities are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The treatment of CAR-T-induced toxicity is supportive; however, as higher-grade adverse events occur, toxicity-directed therapy with tocilizumab, an IL-6 receptor antibody, and steroids is standard practice. Overall, a careful risk-benefit balance exists between the efficacy and toxicities of therapies. The challenge lies in the underlying pathophysiology of CAR-T-related toxicity which relies upon the activation of CAR-T cells. Some degree of toxicity is expected to achieve an effective response to therapy, and certain aspects of treatment are also associated with toxicity. As progress is made in the investigation and approval of new CARs, novel toxicity-directed therapies and toxicity-limited constructs will be the focus of attention.
Topics: Humans; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; Immunotherapy, Adoptive; Multiple Myeloma; Cell- and Tissue-Based Therapy
PubMed: 36763238
DOI: 10.1007/s11899-023-00687-7 -
European Journal of Physical and... Apr 2022Pain is the most common reason for physician consultations and the number one reason for missed work or school days is musculoskeletal pain. Pain management is utilized...
Pain is the most common reason for physician consultations and the number one reason for missed work or school days is musculoskeletal pain. Pain management is utilized for easing the suffering and improving the Quality of Life of those living with chronic pain. Over the past several decades, physicians have become increasingly willing to prescribe opioids to manage pain. However, the opioid use can cause side effects as poor coordination, sedation, mood swings, depression, and anxiety combined with a dependence on the drugs. In the rehabilitation setting, patients benefit most when their health providers utilize a multimodal approach combining different types of therapies and when patients take on a significant role in optimal management of their own pain. The use of light as a therapeutic alternative form of medicine to manage pain and inflammation has been proposed to fill this void. Photobiomodulation therapy applied in the form of low-intensity Light Amplification by Stimulated Emission of Radiation (LASER) and light-emitting diode (LED) has been shown to reduce inflammation and swelling, promote healing, and reduce pain for an array of musculoskeletal conditions. There is evidence that photobiomodulation therapy reduces pain intensity in non-specific knee pain, osteoarthritis, pain post-total hip arthroplasty, fibromyalgia, temporomandibular diseases, neck pain, and low back pain. Therefore, the purpose of this paper was to present the up-to-dated evidence about the effects of low-intensity LASER and LED (photobiomodulation therapy) on pain control of the most common musculoskeletal conditions. We observed that the photobiomodulation therapy offers a non-invasive, safe, drug-free, and side-effect-free method for pain relief of both acute and chronic musculoskeletal conditions as well as fibromyalgia.
Topics: Chronic Pain; Fibromyalgia; Humans; Inflammation; Lasers; Low-Level Light Therapy; Musculoskeletal Pain; Pain Management; Quality of Life
PubMed: 34913330
DOI: 10.23736/S1973-9087.21.07236-1 -
Journal of Investigative Surgery : the... Dec 2023Pancreatic cancer is one of the leading causes for cancer-related deaths in the United States. Majority of patients present with unresectable or metastatic disease. For... (Review)
Review
Pancreatic cancer is one of the leading causes for cancer-related deaths in the United States. Majority of patients present with unresectable or metastatic disease. For those that present with localized disease, a multidisciplinary approach is necessary to maximize survival and optimize outcomes. The quality and safety of surgery for pancreatic cancer have improved in recent years with increasing adoption of minimally invasive techniques and surgical adjuncts. Systemic chemotherapy has also evolved to impact survival. It is now increasingly being utilized in the neoadjuvant setting, often with concomitant radiation. Increased utilization of genomic testing in metastatic pancreatic cancer has led to better understanding of their biology, thereby allowing clinicians to consider potential targeted therapies. Similarly, targeted agents such as PARP inhibitors and immune checkpoint- inhibitors have emerged with promising results. In summary, pancreatic cancer remains a disease with poor long-term survival. However, recent developments have led to improved outcomes and have changed practice in the past decade. This review summarizes current practices in pancreatic cancer treatment and the milestones that brought us to where we are today, along with emerging therapies.
Topics: Humans; United States; Pancreatic Neoplasms; Combined Modality Therapy; Neoadjuvant Therapy; Antineoplastic Agents
PubMed: 36191926
DOI: 10.1080/08941939.2022.2129884 -
Blood Feb 2023Interest in adoptive cell therapy for treating cancer is exploding owing to early clinical successes of autologous chimeric antigen receptor (CAR) T lymphocyte therapy.... (Review)
Review
Interest in adoptive cell therapy for treating cancer is exploding owing to early clinical successes of autologous chimeric antigen receptor (CAR) T lymphocyte therapy. However, limitations using T cells and autologous cell products are apparent as they (1) take weeks to generate, (2) utilize a 1:1 donor-to-patient model, (3) are expensive, and (4) are prone to heterogeneity and manufacturing failures. CAR T cells are also associated with significant toxicities, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and prolonged cytopenias. To overcome these issues, natural killer (NK) cells are being explored as an alternative cell source for allogeneic cell therapies. NK cells have an inherent ability to recognize cancers, mediate immune functions of killing and communication, and do not induce graft-versus-host disease, cytokine release syndrome, or immune effector cell-associated neurotoxicity syndrome. NK cells can be obtained from blood or cord blood or be derived from hematopoietic stem and progenitor cells or induced pluripotent stem cells, and can be expanded and cryopreserved for off-the-shelf availability. The first wave of point-of-care NK cell therapies led to the current allogeneic NK cell products being investigated in clinical trials with promising preliminary results. Basic advances in NK cell biology and cellular engineering have led to new translational strategies to block inhibition, enhance and broaden target cell recognition, optimize functional persistence, and provide stealth from patients' immunity. This review details NK cell biology, as well as NK cell product manufacturing, engineering, and combination therapies explored in the clinic leading to the next generation of potent, off-the-shelf cellular therapies for blood cancers.
Topics: Humans; Immunotherapy, Adoptive; Cytokine Release Syndrome; Killer Cells, Natural; Neoplasms; Hematopoietic Stem Cell Transplantation
PubMed: 36416736
DOI: 10.1182/blood.2022016200 -
Parkinsonism & Related Disorders Apr 2020Progressive supranuclear palsy (PSP) is a complex clinicopathologic disease with no current cure or disease modulating therapies that can only be definitively confirmed... (Review)
Review
Progressive supranuclear palsy (PSP) is a complex clinicopathologic disease with no current cure or disease modulating therapies that can only be definitively confirmed at autopsy. Growing understanding of the phenotypic diversity of PSP has led to expanded clinical criteria and new insights into etiopathogenesis that coupled with improved in vivo biomarkers makes increased access to current clinical trials possible. Current standard-of-care treatment of PSP is multidisciplinary, supportive and symptomatic, and several trials of potentially disease modulating agents have already been completed with disappointing results. Current ongoing clinical trials target the abnormal aggregation of tau through a variety of mechanisms including immunotherapy and gene therapy offer a more direct method of treatment. Here we review PSP clinicopathologic correlations, in vivo biomarkers including MRI, PET, and CSF biomarkers. We additionally review current pharmacologic and non-pharmacologic methods of treatment, prior and ongoing clinical trials in PSP. Newly expanded clinical criteria and improved specific biomarkers will aid in identifying patients with PSP earlier and more accurately and expand access to these potentially beneficial clinical trials.
Topics: Drug Therapy; Genetic Therapy; Humans; Immunotherapy; Supranuclear Palsy, Progressive
PubMed: 32487421
DOI: 10.1016/j.parkreldis.2020.04.014 -
Cell Metabolism Apr 2018RNA-targeted therapies represent a platform for drug discovery involving chemically modified oligonucleotides, a wide range of cellular RNAs, and a novel target-binding... (Review)
Review
RNA-targeted therapies represent a platform for drug discovery involving chemically modified oligonucleotides, a wide range of cellular RNAs, and a novel target-binding motif, Watson-Crick base pairing. Numerous hurdles considered by many to be impassable have been overcome. Today, four RNA-targeted therapies are approved for commercial use for indications as diverse as Spinal Muscular Atrophy (SMA) and reduction of low-density lipoprotein cholesterol (LDL-C) and by routes of administration including subcutaneous, intravitreal, and intrathecal delivery. The technology is efficient and supports approaching "undruggable" targets. Three additional agents are progressing through registration, and more are in clinical development, representing several chemical and structural classes. Moreover, progress in understanding the molecular mechanisms by which these drugs work has led to steadily better clinical performance and a wide range of mechanisms that may be exploited for therapeutic purposes. Here we summarize the progress, future challenges, and opportunities for this drug discovery platform.
Topics: Animals; Drug Discovery; Genetic Therapy; Humans; Molecular Targeted Therapy; Muscular Atrophy, Spinal; Oligoribonucleotides, Antisense; RNA, Small Interfering
PubMed: 29617640
DOI: 10.1016/j.cmet.2018.03.004 -
Signal Transduction and Targeted Therapy Feb 2021Throughout its 40-year history, the field of gene therapy has been marked by many transitions. It has seen great strides in combating human disease, has given hope to... (Review)
Review
Throughout its 40-year history, the field of gene therapy has been marked by many transitions. It has seen great strides in combating human disease, has given hope to patients and families with limited treatment options, but has also been subject to many setbacks. Treatment of patients with this class of investigational drugs has resulted in severe adverse effects and, even in rare cases, death. At the heart of this dichotomous field are the viral-based vectors, the delivery vehicles that have allowed researchers and clinicians to develop powerful drug platforms, and have radically changed the face of medicine. Within the past 5 years, the gene therapy field has seen a wave of drugs based on viral vectors that have gained regulatory approval that come in a variety of designs and purposes. These modalities range from vector-based cancer therapies, to treating monogenic diseases with life-altering outcomes. At present, the three key vector strategies are based on adenoviruses, adeno-associated viruses, and lentiviruses. They have led the way in preclinical and clinical successes in the past two decades. However, despite these successes, many challenges still limit these approaches from attaining their full potential. To review the viral vector-based gene therapy landscape, we focus on these three highly regarded vector platforms and describe mechanisms of action and their roles in treating human disease.
Topics: Dependovirus; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Lentivirus
PubMed: 33558455
DOI: 10.1038/s41392-021-00487-6 -
Nature Reviews. Drug Discovery Jan 2022Atopic dermatitis (AD) is a common chronic inflammatory skin disease with a complex pathophysiology that underlies a wide spectrum of clinical phenotypes. AD remains... (Review)
Review
Atopic dermatitis (AD) is a common chronic inflammatory skin disease with a complex pathophysiology that underlies a wide spectrum of clinical phenotypes. AD remains challenging to treat owing to the limited response to available therapies. However, recent advances in understanding of disease mechanisms have led to the discovery of novel potential therapeutic targets and drug candidates. In addition to regulatory approval for the IL-4Ra inhibitor dupilumab, the anti-IL-13 inhibitor tralokinumab and the JAK1/2 inhibitor baricitinib in Europe, there are now more than 70 new compounds in development. This Review assesses the various strategies and novel agents currently being investigated for AD and highlights the potential for a precision medicine approach to enable prevention and more effective long-term control of this complex disease.
Topics: Animals; Dermatitis, Atopic; Humans; Pharmaceutical Preparations; Precision Medicine
PubMed: 34417579
DOI: 10.1038/s41573-021-00266-6