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The New England Journal of Medicine Feb 2024Treatment for autoimmune diseases such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis often involves long-term immune...
BACKGROUND
Treatment for autoimmune diseases such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis often involves long-term immune suppression. Resetting aberrant autoimmunity in these diseases through deep depletion of B cells is a potential strategy for achieving sustained drug-free remission.
METHODS
We evaluated 15 patients with severe SLE (8 patients), idiopathic inflammatory myositis (3 patients), or systemic sclerosis (4 patients) who received a single infusion of CD19 chimeric antigen receptor (CAR) T cells after preconditioning with fludarabine and cyclophosphamide. Efficacy up to 2 years after CAR T-cell infusion was assessed by means of Definition of Remission in SLE (DORIS) remission criteria, American College of Rheumatology-European League against Rheumatism (ACR-EULAR) major clinical response, and the score on the European Scleroderma Trials and Research Group (EUSTAR) activity index (with higher scores indicating greater disease activity), among others. Safety variables, including cytokine release syndrome and infections, were recorded.
RESULTS
The median follow-up was 15 months (range, 4 to 29). The mean (±SD) duration of B-cell aplasia was 112±47 days. All the patients with SLE had DORIS remission, all the patients with idiopathic inflammatory myositis had an ACR-EULAR major clinical response, and all the patients with systemic sclerosis had a decrease in the score on the EUSTAR activity index. Immunosuppressive therapy was completely stopped in all the patients. Grade 1 cytokine release syndrome occurred in 10 patients. One patient each had grade 2 cytokine release syndrome, grade 1 immune effector cell-associated neurotoxicity syndrome, and pneumonia that resulted in hospitalization.
CONCLUSIONS
In this case series, CD19 CAR T-cell transfer appeared to be feasible, safe, and efficacious in three different autoimmune diseases, providing rationale for further controlled clinical trials. (Funded by Deutsche Forschungsgemeinschaft and others.).
Topics: Humans; Antigens, CD19; Cytokine Release Syndrome; Follow-Up Studies; Immunotherapy, Adoptive; Lupus Erythematosus, Systemic; Myositis; Scleroderma, Systemic; Myeloablative Agonists; Cyclophosphamide; Infections; Treatment Outcome
PubMed: 38381673
DOI: 10.1056/NEJMoa2308917 -
Journal For Immunotherapy of Cancer Feb 2024Adoptive cell therapy with autologous, ex vivo-expanded, tumor-infiltrating lymphocytes (TILs) is being investigated for treatment of solid tumors and has shown robust... (Review)
Review
Adoptive cell therapy with autologous, ex vivo-expanded, tumor-infiltrating lymphocytes (TILs) is being investigated for treatment of solid tumors and has shown robust responses in clinical trials. Based on the encouraging efficacy, tolerable safety profile, and advancements in a central manufacturing process, lifileucel is now the first US Food and Drug Administration (FDA)-approved TIL cell therapy product. To this end, treatment management and delivery practice guidance is needed to ensure successful integration of this modality into clinical care. This review includes clinical and toxicity management guidelines pertaining to the TIL cell therapy regimen prepared by the TIL Working Group, composed of internationally recognized hematologists and oncologists with expertize in TIL cell therapy, and relates to patient care and operational aspects. Expert consensus recommendations for patient management, including patient eligibility, screening tests, and clinical and toxicity management with TIL cell therapy, including tumor tissue procurement surgery, non-myeloablative lymphodepletion, TIL infusion, and IL-2 administration, are discussed in the context of potential standard of care TIL use. These recommendations provide practical guidelines for optimal clinical management during administration of the TIL cell therapy regimen, and recognition of subsequent management of toxicities. These guidelines are focused on multidisciplinary teams of physicians, nurses, and stakeholders involved in the care of these patients.
Topics: United States; Humans; Immunotherapy, Adoptive; Lymphocytes, Tumor-Infiltrating; Melanoma; Combined Modality Therapy; Cell- and Tissue-Based Therapy
PubMed: 38423748
DOI: 10.1136/jitc-2023-008735 -
Continuum (Minneapolis, Minn.) Dec 2023This article reviews the clinical presentation, diagnostic workup, staging, and treatment of primary central nervous system (CNS) lymphoma and common manifestations of... (Review)
Review
OBJECTIVE
This article reviews the clinical presentation, diagnostic workup, staging, and treatment of primary central nervous system (CNS) lymphoma and common manifestations of secondary CNS lymphoma.
LATEST DEVELOPMENTS
Lymphoma can arise in the CNS de novo (primary CNS lymphoma) or as the result of systemic disease (secondary CNS lymphoma). Symptoms may include focal neurologic deficits related to the disease site, cognitive decline, and symptoms of increased intracranial pressure. Standard treatment may differ based on lymphoma subtype and location. A majority of CNS lymphoma is diffuse large B-cell subtype and exhibits aggressive behavior. First-line treatment is generally methotrexate-based polychemotherapy. Response rates to treatment are high, approximately 80% to 90% for primary CNS lymphoma, but relapse is common. Consolidation approaches including myeloablative chemotherapy followed by autologous stem cell rescue, nonmyeloablative chemotherapy, radiation, and medical maintenance regimens reduce rates of relapse. The recent development of targeted agents such as Bruton tyrosine kinase inhibitors and immunomodulatory strategies have shown promise in the treatment of CNS lymphoma. Immunotherapy in the form of checkpoint inhibitors and chimeric antigen receptor T cells is being studied. More indolent forms of lymphoma may be treated with radiation or targeted therapy.
ESSENTIAL POINTS
CNS lymphoma is an uncommon but clinically meaningful manifestation of extranodal lymphoma. The diagnosis requires a high level of suspicion for rapid initiation of potentially curative treatment.
Topics: Humans; Neoplasm Recurrence, Local; Lymphoma; Antineoplastic Agents; Central Nervous System Neoplasms; Methotrexate; Central Nervous System; Recurrence
PubMed: 38085895
DOI: 10.1212/CON.0000000000001356 -
Nature Cell Biology Dec 2023The bone marrow contains peripheral nerves that promote haematopoietic regeneration after irradiation or chemotherapy (myeloablation), but little is known about how this...
The bone marrow contains peripheral nerves that promote haematopoietic regeneration after irradiation or chemotherapy (myeloablation), but little is known about how this is regulated. Here we found that nerve growth factor (NGF) produced by leptin receptor-expressing (LepR) stromal cells is required to maintain nerve fibres in adult bone marrow. In nerveless bone marrow, steady-state haematopoiesis was normal but haematopoietic and vascular regeneration were impaired after myeloablation. LepR cells, and the adipocytes they gave rise to, increased NGF production after myeloablation, promoting nerve sprouting in the bone marrow and haematopoietic and vascular regeneration. Nerves promoted regeneration by activating β2 and β3 adrenergic receptor signalling in LepR cells, and potentially in adipocytes, increasing their production of multiple haematopoietic and vascular regeneration growth factors. Peripheral nerves and LepR cells thus promote bone marrow regeneration through a reciprocal relationship in which LepR cells sustain nerves by synthesizing NGF and nerves increase regeneration by promoting the production of growth factors by LepR cells.
Topics: Bone Marrow; Receptors, Leptin; Bone Marrow Cells; Nerve Growth Factor; Hematopoietic Stem Cells; Nerve Regeneration
PubMed: 38012403
DOI: 10.1038/s41556-023-01284-9 -
Nature Communications Oct 2023Hematopoietic stem cell (HSC) gene therapy has curative potential; however, its use is limited by the morbidity and mortality associated with current chemotherapy-based...
Hematopoietic stem cell (HSC) gene therapy has curative potential; however, its use is limited by the morbidity and mortality associated with current chemotherapy-based conditioning. Targeted conditioning using antibody-drug conjugates (ADC) holds promise for reduced toxicity in HSC gene therapy. Here we test the ability of an antibody-drug conjugate targeting CD117 (CD117-ADC) to enable engraftment in a non-human primate lentiviral gene therapy model of hemoglobinopathies. Following single-dose CD117-ADC, a >99% depletion of bone marrow CD34 + CD90 + CD45RA- cells without lymphocyte reduction is observed, which results are not inferior to multi-day myeloablative busulfan conditioning. CD117-ADC, similarly to busulfan, allows efficient engraftment, gene marking, and vector-derived fetal hemoglobin induction. Importantly, ADC treatment is associated with minimal toxicity, and CD117-ADC-conditioned animals maintain fertility. In contrast, busulfan treatment commonly causes severe toxicities and infertility in humans. Thus, the myeloablative capacity of single-dose CD117-ADC is sufficient for efficient engraftment of gene-modified HSCs while preserving fertility and reducing adverse effects related to toxicity in non-human primates. This targeted conditioning approach thus provides the proof-of-principle to improve risk-benefit ratio in a variety of HSC-based gene therapy products in humans.
Topics: Animals; Busulfan; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Immunoconjugates; Proto-Oncogene Proteins c-kit; Macaca mulatta
PubMed: 37828021
DOI: 10.1038/s41467-023-41153-5 -
Blood Advances Nov 2023Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy....
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy. Small observational studies reported allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We report an analysis of patients with BPDCN who received an allo-HCT, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We identified 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007 and 2018. The 5-year overall survival (OS), disease-free survival (DFS), relapse, and nonrelapse mortality (NRM) rates were 51.2% (95% confidence interval [CI], 42.5-59.8), 44.4% (95% CI, 36.2-52.8), 32.2% (95% CI, 24.7-40.3), and 23.3% (95% CI, 16.9-30.4), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age of ≥60 years was predictive for inferior OS (hazard ratio [HR], 2.16; 95% CI, 1.35-3.46; P = .001), and higher NRM (HR, 2.19; 95% CI, 1.13-4.22; P = .02). Remission status at time of allo-HCT (CR2/primary induction failure/relapse vs CR1) was predictive of inferior OS (HR, 1.87; 95% CI, 1.14-3.06; P = .01) and DFS (HR, 1.75; 95% CI, 1.11-2.76; P = .02). Use of myeloablative conditioning with total body irradiation (MAC-TBI) was predictive of improved DFS and reduced relapse risk. Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, whereas MAC-TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes.
Topics: Humans; Middle Aged; Transplantation, Homologous; Neoplasm Recurrence, Local; Hematopoietic Stem Cell Transplantation; Acute Disease; Myeloproliferative Disorders; Chronic Disease; Recurrence; Dendritic Cells
PubMed: 37792849
DOI: 10.1182/bloodadvances.2023011308 -
Critical Reviews in Oncology/hematology Aug 2023Primary central nervous system lymphoma (PCNSL) is a rare extranodal non-Hodgkin lymphoma. Stereotactic biopsy remains the gold standard for the pathological diagnosis... (Review)
Review
Primary central nervous system lymphoma (PCNSL) is a rare extranodal non-Hodgkin lymphoma. Stereotactic biopsy remains the gold standard for the pathological diagnosis of PCNSL. However, certain new auxiliary diagnostic methods are considered to have good application prospects; these include cytokine and tumor circulating DNA, among others. Although new drugs such as immunomodulators, immune checkpoint inhibitors, chimeric antigen receptor T-cells, and Bruton tyrosine kinase inhibitors have brought hope owing to their improved efficacy, the high recurrence rate and subsequent high mortality remain barriers to long-term survival. Increasing emphasis is therefore being placed on consolidation treatments. Consolidation treatment strategies include whole brain radiotherapy, autologous hematopoietic stem cell transplantation, and non-myeloablative chemotherapy. As studies directly comparing the effectiveness and safety of different consolidation treatment schemes are lacking, the optimal consolidation strategy remains uncertain. This article will review the diagnosis and treatment of PCNSL, focusing on the progress in research pertaining to consolidation therapy.
Topics: Humans; Lymphoma, Non-Hodgkin; Central Nervous System Neoplasms; Combined Modality Therapy; Antineoplastic Combined Chemotherapy Protocols; Transplantation, Autologous; Central Nervous System
PubMed: 37277008
DOI: 10.1016/j.critrevonc.2023.104042 -
Frontiers in Oncology 2023Neuroblastoma is the most frequently diagnosed cancer during the first year of life. This neoplasm originates from neural crest cells derived from the sympathetic... (Review)
Review
Neuroblastoma is the most frequently diagnosed cancer during the first year of life. This neoplasm originates from neural crest cells derived from the sympathetic nervous system, adrenal medulla, or paraspinal ganglia. The clinical presentation can vary from an asymptomatic mass to symptoms resulting from local invasion and/or spread of distant disease spread. The natural history of neuroblastoma is highly variable, ranging from relatively indolent biological behavior to a high-risk clinical phenotype with a dismal prognosis. Age, stage, and biological features are important prognostic risk stratification and treatment assignment prognostic factors. The multimodal therapy approach includes myeloablative chemotherapy, radiotherapy, immunotherapy, and aggressive surgical resection. Hyperbaric oxygen therapy (HBOT) has been proposed as a complementary measure to overcome tumor hypoxia, which is considered one of the hallmarks of this cancer treatment resistance. This article aims to review the relevant literature on the neuroblastoma pathophysiology, clinical presentation, and different biological and genetic profiles, and to discuss its management, focusing on HBOT.
PubMed: 37823059
DOI: 10.3389/fonc.2023.1254322