Combinatorial immunotherapy of anti-MCAM CAR-modified expanded natural killer cells and NKTR-255 against neuroblastoma.

Pediatric patients with recurrent metastatic neuroblastoma (NB) have a dismal 5-year survival. Novel therapeutic approaches are urgently needed. The melanoma cell adhesion molecule (MCAM/CD146/MUC18) is expressed in a variety of pediatric solid tumors, including NB, and constitutes a novel target for immunotherapy.

Efficiently targeting neuroblastoma with the combination of anti-ROR1 CAR NK cells and N-803 and in NB xenografts.

The prognosis for children with recurrent and/or refractory neuroblastoma (NB) is dismal. The receptor tyrosine kinase-like orphan receptor 1 (ROR1), which is highly expressed on the surface of NB cells, provides a potential target for novel immunotherapeutics. Anti-ROR1 chimeric antigen receptor engineered expanded peripheral blood natural killer (anti-ROR1 CAR exPBNK) cells represent this approach.

Safety and Efficacy of Inactivated SARS-CoV-2 Vaccine in Patients with Rheumatic Diseases and Serum Antibody Changes Post-Omicron Variant Infection.

Introduction: The purpose of this study was to investigate whether the inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine has a similar effectiveness and safety profile in patients with rheumatic and musculoskeletal diseases (RMDs) and healthy controls (HCs).

Methods: Between August 10, 2021 and September 30, 2021, 134 HCs and 269 patients with RMDs were recruited. All participants who tested negative for COVID-19 were vaccinated with SARS-CoV-2 inactivated vaccine.

Abnormal presentation of pregnancy and postpartum initial-onset systemic lupus erythematosus combined with diffuse alveolar hemorrhage: A case report.

Systemic lupus erythematosus (SLE) is an autoimmune disease that most commonly occurs in women of childbearing age. However, cases of SLE with abnormal pregnancy as the initial manifestation, involving the development of diffuse alveolar hemorrhage (DAH), have rarely been reported. Herein, we report the case of a young woman who underwent a cesarean section for fetal distress and growth restriction at 35 + 1 weeks' gestation.

Inflammation-mediated fibroblast activation and immune dysregulation in collagen VII-deficient skin.

Inflammation is known to play a critical role in all stages of tumorigenesis; however, less is known about how it predisposes the tissue microenvironment preceding tumor formation. Recessive dystrophic epidermolysis bullosa (RDEB), a skin-blistering disease secondary to mutations and associated with chronic wounding, inflammation, fibrosis, and cutaneous squamous cell carcinoma (cSCC), models this dynamic. Here, we used single-cell RNA sequencing (scRNAseq) to analyze gene expression patterns in skin cells from a mouse model of RDEB.

Cellular and humoral immunotherapy in children, adolescents and young adults with non-Hodgkin lymphoma.

The prognosis is dismal (2-year overall survival less than 25%) for childhood, adolescent, and young adult (CAYA) with relapsed and/or refractory (R/R) non-Hodgkin lymphoma (NHL). Novel targeted therapies are desperately needed for this poor-risk population. CD19, CD20, CD22, CD79a, CD38, CD30, LMP1 and LMP2 are attractive targets for immunotherapy in CAYA patients with R/R NHL.

Manufacture and Characterization of Good Manufacturing Practice-Compliant SARS-COV-2 Cytotoxic T Lymphocytes.

Background: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 virus-specific cytotoxic T-cell lymphocytes (vCTLs) could provide a promising modality in COVID-19 treatment. We aimed to screen, manufacture, and characterize SARS-CoV-2-vCTLs generated from convalescent COVID-19 donors using the CliniMACS Cytokine Capture System (CCS).

Donor chimerism and immune reconstitution following haploidentical transplantation in sickle cell disease.

Introduction: We previously reported the initial results of a phase II multicenter transplant trial using haploidentical parental donors for children and aolescents with high-risk sickle cell disease achieving excellent survival with exceptionally low rates of graft-versus-host disease and resolution of sickle cell disease symptoms. To investigate human leukocyte antigen (HLA) sensitization, graft characteristics, donor chimerism, and immune reconstitution in these recipients.

Methods: CD34 cells were enriched using the CliniMACS system with a target dose of 10 x 10 CD34 cells/kg with a peripheral blood mononuclear cell (PBMNC) addback dose of 2x10 CD3/kg in the final product.

The Future of Natural Killer Cell Immunotherapy for B Cell Non-Hodgkin Lymphoma (B Cell NHL).

Natural killer (NK) cells have played a critical-if largely unrecognized or ignored-role in the treatment of B cell non-Hodgkin lymphoma (NHL) since the introduction of CD20-directed immunotherapy with rituximab as a cornerstone of therapy over 25 years ago. Engagement with NK cells leading to lysis of NHL targets through antibody-dependent cellular cytotoxicity (ADCC) is a critical component of rituximab's mechanism of action. Despite this important role, the only aspect of B cell NHL therapy that has been adopted as standard therapy that even indirectly augments or restores NK cell function is the introduction of obinutuzumab, a CD20 antibody with enhanced ability to engage with NK cells.

Combinatorial immunotherapy of N-803 (IL-15 superagonist) and dinutuximab with ex vivo expanded natural killer cells significantly enhances in vitro cytotoxicity against GD2 pediatric solid tumors and in vivo survival of xenografted immunodeficient NSG mice.

Background: Children with recurrent and/or metastatic osteosarcoma (OS), neuroblastoma (NB) and glioblastoma multiforme (GBM) have a dismal event-free survival (<25%). The majority of these solid tumors highly express GD2. Dinutuximab, an anti-GD2 monoclonal antibody, significantly improved event-free survival in children with GD2 NB post autologous stem cell transplantation and enhanced natural killer (NK) cell-mediated antibody-dependent cell cytotoxicity.

Novel cytokine-antibody fusion protein, N-820, to enhance the functions of ex vivo expanded natural killer cells against Burkitt lymphoma.

Background: The prognosis of patients with relapsed or progressive B cell (CD20) non-Hodgkin's lymphoma (B-NHL), including Burkitt lymphoma (BL), is dismal due to chemoradiotherapy resistance. Novel therapeutic strategies are urgently needed. N-820 is a fusion protein of N-803 (formerly known as ALT-803) to four single-chains of rituximab.

Obinutuzumab (GA101) vs. rituximab significantly enhances cell death, antibody-dependent cytotoxicity and improves overall survival against CD20+ primary mediastinal B-cell lymphoma (PMBL) in a xenograft NOD-scid IL2Rgnull (NSG) mouse model: a potential targeted agent in the treatment of PMBL.

Primary mediastinal large B-cell lymphoma (PMBL), a distinct mature B-cell lymphoma, expresses CD20 and has recently been successfully treated with the combination of a type I anti-CD20 monoclonal antibody, rituximab, with multiple combination chemotherapy regimens. Obinutuzumab is a glycoengineered type II anti-CD20 monoclonal antibody (mAb), recognizing a unique CD20 extracellular membrane epitope with enhanced antibody dependent cellular cytotoxicity (ADCC) vs rituximab. We hypothesize that obinutuzumab vs rituximab will significantly enhance and cytotoxicity against PMBL.

Immunophenotypic, cytotoxic, proteomic and genomic characterization of human cord blood vs. peripheral blood CD56 NK cells.

Unrelated cord blood (CB) is an excellent alternative as an allogeneic donor source for stem cell transplantation. CB transplantation is associated with lower incidence of severe acute graft versus host disease (GVHD) and chronic GVHD but similar rates of malignant relapse compared with other unrelated donor cell transplants. NK cells are critical innate immune components and the comparison of CB vs.

Overcoming Resistance to Natural Killer Cell Based Immunotherapies for Solid Tumors.

Despite advances in the diagnostic and therapeutic modalities, the prognosis of several solid tumor malignancies remains poor. Different factors associated with solid tumors including a varied genetic signature, complex molecular signaling pathways, defective cross talk between the tumor cells and immune cells, hypoxic and immunosuppressive effects of tumor microenvironment result in a treatment resistant and metastatic phenotype. Over the past several years, immunotherapy has emerged as an attractive therapeutic option against multiple malignancies.

Advances in cellular and humoral immunotherapy - implications for the treatment of poor risk childhood, adolescent, and young adult B-cell non-Hodgkin lymphoma.

Patients with relapsed, refractory or advanced stage B non-Hodgkin lymphoma (NHL) continue to have a dismal prognosis. This review summarises current and novel cellular and immunotherapy for these high-risk populations, including haematopoietic stem cell transplant, bispecific antibodies, viral-derived cytotoxic T cells, chimeric antigen receptor (CAR) T cells, and natural killer (NK) cell therapy, as discussed at the 6th International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin Lymphoma on September 26th-29th 2018 in Rotterdam, the Netherlands, and explores the future of NK/CAR NK therapies.

Ibrutinib significantly inhibited Bruton's tyrosine kinase (BTK) phosphorylation, proliferation and enhanced overall survival in a preclinical Burkitt lymphoma (BL) model.

Pediatric and adult patients with recurrent/refractory Burkitt lymphoma (BL) continue to have poor outcomes, emphasizing the need for newer therapeutic agents. Bruton's tyrosine kinase (BTK) is activated following B-cell receptor stimulation and in part regulates normal B-cell development. Ibrutinib, a selective and irreversible BTK inhibitor, has been efficacious in chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), Waldenström's macroglobulinemia, and marginal zone lymphoma.

Romidepsin alone or in combination with anti-CD20 chimeric antigen receptor expanded natural killer cells targeting Burkitt lymphoma and in immunodeficient mice.

Facilitating the development of alternative targeted therapeutic strategies is urgently required to improve outcome or circumvent chemotherapy resistance in children, adolescents, and adults with recurrent/refractory de novo mature B-cell (CD20) non-Hodgkin lymphoma, including Burkitt lymphoma (BL). Romidepsin, a histone deacetylase inhibitor (HDACi), has been used to treat cutaneous T-cell lymphoma. We have demonstrated the significant anti-tumor effect of anti-CD20 chimeric antigen receptor (CAR) modified expanded peripheral blood natural killer (exPBNK) against rituximab-sensitive and -resistant BL.

Genetically re-engineered K562 cells significantly expand and functionally activate cord blood natural killer cells: Potential for adoptive cellular immunotherapy.

Natural killer (NK) cells play a significant role in reducing relapse in patients with hematological malignancies after allogeneic stem cell transplantation, but NK cell number and naturally occurring inhibitory signals limit their capability. Interleukin-15 (IL-15) and 4-1BBL are important modulators of NK expansion and functional activation. To overcome these limitations, cord blood mononuclear cells (CB MNCs) were ex vivo expanded for 7 days with genetically modified K562-mbIL15-41BBL (MODK562) or wild-type K562 (WTK562).

Modification of Expanded NK Cells with Chimeric Antigen Receptor mRNA for Adoptive Cellular Therapy.

NK cells are bone marrow-derived cytotoxic lymphocytes that play a major role in the rejection of tumors and cells infected by viruses. The regulation of NK activation vs inhibition is regulated by the expression of a variety of NK receptors (NKRs) and specific NKRs' ligands expressed on their targets. However, factors limiting NK therapy include small numbers of active NK cells in unexpanded peripheral blood and lack of specific tumor targeting.

Immunotherapeutic approaches for the treatment of childhood, adolescent and young adult non-Hodgkin lymphoma.

With the introduction of the anti-CD20 monoclonal antibody rituximab, B-cell non-Hodgkin lymphoma was the first malignancy successfully treated with an immunotherapeutic agent. Since then, numerous advances have expanded the repertoire of immunotherapeutic agents available for the treatment of a variety of malignancies, including many lymphoma subtypes. These include the introduction of monoclonal antibodies targeting a variety of cell surface proteins, including the successful targeting of immunoregulatory checkpoint receptors present on T-cells or tumour cells.