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Journal For Immunotherapy of Cancer Jun 2024Treatment with the immune checkpoint inhibitor anti-programmed cell death protein-1 (PD-1) often causes immune-related adverse events (irAEs). Since irAEs resemble...
INTRODUCTION
Treatment with the immune checkpoint inhibitor anti-programmed cell death protein-1 (PD-1) often causes immune-related adverse events (irAEs). Since irAEs resemble autoimmune diseases, autoantibodies might play a role and could potentially be used to identify patients at risk. Therefore, we investigated the association between autoantibody-positivity and toxicity as well as clinical response in patients with melanoma treated with anti-PD-1.
MATERIALS AND METHODS
This two-center, retrospective study included 143 patients with melanoma treated with anti-PD-1. Toxicities grade ≥2 and recurrences/responses were captured until 6 months after treatment initiation. Autoantibody measurements were performed at baseline and 3 months after treatment initiation, including IgM-rheumatoid factor (RF), antinuclear antibodies (ANA), extractable nuclear antigen, anti-cyclic citrullinated peptide antibodies (anti-CCP2) and anti-thyroid antibodies.
RESULTS
169 irAEs were experienced by 86/143 patients (137 grades 1-2, 32 grades 3-4), the most common being thyroiditis (n=25), dermatitis (n=24), and sicca problems (n=19). Patients with autoantibodies at baseline experienced more irAEs (p=0.001), predominantly associated with anti-thyroid antibodies and thyroid dysfunction. No association was observed between any irAE and anti-CCP2, RF or ANA. In women, baseline and on-treatment anti-thyroid antibody-positivity as well as seroconversion during treatment was associated with thyroid dysfunction. In men, this association was only observed on-treatment. The presence of autoantibodies was not associated with melanoma recurrence (p=0.776) or response (p=0.597).
CONCLUSION
The presence of autoantibodies prior to anti-PD-1 therapy is associated with irAEs in patients with melanoma. Both baseline positivity and seroconversion of anti-thyroid antibodies were strongly associated with thyroid dysfunction. This association was stronger in women, with all women who were baseline positive developing thyroid dysfunction.
Topics: Humans; Melanoma; Female; Male; Autoantibodies; Middle Aged; Retrospective Studies; Aged; Immune Checkpoint Inhibitors; Seroconversion; Adult; Aged, 80 and over; Programmed Cell Death 1 Receptor
PubMed: 38945553
DOI: 10.1136/jitc-2024-009215 -
The Journal of Dermatological Treatment Dec 2024Bullous pemphigoid induced by secukinumab in treatment of psoriasis is rare. We report a 49-year-old man with psoriasis who developed bullous pemphigoid during...
Bullous pemphigoid induced by secukinumab in treatment of psoriasis is rare. We report a 49-year-old man with psoriasis who developed bullous pemphigoid during treatment with secukinumab. Scattered tense vesicles with itching appeared all over the body after the fourth treatment. Bullous pemphigoid was confirmed by pathological examination and direct immunofluorescence. The patient was treated with topical corticosteroids, oral nicotinamide and minocycline hydrochloride. The lesions of bullous pemphigoid improved significantly after 7 days of treatment. Bullous pemphigoid is a rare adverse event following administration of secukinumab.
Topics: Humans; Pemphigoid, Bullous; Male; Middle Aged; Antibodies, Monoclonal, Humanized; Psoriasis; Minocycline; Niacinamide; Dermatologic Agents; Treatment Outcome
PubMed: 38945532
DOI: 10.1080/09546634.2024.2366535 -
Nature Communications Jun 2024Evolution of SARS-CoV-2 alters the antigenicity of the immunodominant spike (S) receptor-binding domain and N-terminal domain, undermining the efficacy of vaccines and...
Evolution of SARS-CoV-2 alters the antigenicity of the immunodominant spike (S) receptor-binding domain and N-terminal domain, undermining the efficacy of vaccines and antibody therapies. To overcome this challenge, we set out to develop a vaccine focusing antibody responses on the highly conserved but metastable S subunit, which folds as a spring-loaded fusion machinery. We describe a strategy for prefusion-stabilization and high yield recombinant production of SARS-CoV-2 S trimers with native structure and antigenicity. We demonstrate that our design strategy is broadly generalizable to sarbecoviruses, as exemplified with the SARS-CoV-1 (clade 1a) and PRD-0038 (clade 3) S subunits. Immunization of mice with a prefusion-stabilized SARS-CoV-2 S trimer elicits broadly reactive sarbecovirus antibodies and neutralizing antibody titers of comparable magnitude against Wuhan-Hu-1 and the immune evasive XBB.1.5 variant. Vaccinated mice were protected from weight loss and disease upon challenge with XBB.1.5, providing proof-of-principle for fusion machinery sarbecovirus vaccines.
Topics: Animals; Mice; Antibodies, Neutralizing; Antibodies, Viral; Spike Glycoprotein, Coronavirus; SARS-CoV-2; Humans; COVID-19; Female; COVID-19 Vaccines; Mice, Inbred BALB C
PubMed: 38944664
DOI: 10.1038/s41467-024-49656-5 -
The Journal of Biological Chemistry Jun 2024Aggregation of aberrant fragment of plasma gelsolin, AGelD187N, is a crucial event underlying the pathophysiology of Finnish gelsolin amyloidosis, an inherited form of...
Aggregation of aberrant fragment of plasma gelsolin, AGelD187N, is a crucial event underlying the pathophysiology of Finnish gelsolin amyloidosis, an inherited form of systemic amyloidosis. The amyloidogenic gelsolin fragment AGelD187N does not play any physiological role in the body, unlike most aggregating proteins related to other protein misfolding diseases. However, no therapeutic agents that specifically and effectively target and neutralize AGelD187N exist. We employed phage display technology to identify novel single-chain variable fragments (scFvs) that bind to different epitopes in the monomeric AGelD187N that were further maturated by variable domain shuffling and converted to antigen-binding fragment (Fab) antibodies. The generated antibody fragments had nanomolar binding affinity for full-length AGelD187N, as evaluated by biolayer interferometry. Importantly, all four Fabs selected for functional studies efficiently inhibited the amyloid formation of full-length AGelD187N as examined by thioflavin fluorescence assay and transmission electron microscopy. Two Fabs, neither of which bound to the previously proposed fibril-forming region of AGelD187N, completely blocked the amyloid formation of AGelD187N. Moreover, no small soluble aggregates, which are considered pathogenic species in protein misfolding diseases, were formed after successful inhibition of amyloid formation by the most promising aggregation inhibitor, as investigated by size exclusion chromatography combined with multi-angle light scattering. We conclude that all regions of the full-length AGelD187N are important in modulating its assembly into fibrils and that the discovered epitope-specific anti-AGelD187N antibody fragments provide a promising starting point for a disease-modifying therapy for gelsolin amyloidosis, which is currently lacking.
PubMed: 38944121
DOI: 10.1016/j.jbc.2024.107507 -
Cancer Science Jun 2024Recent studies have shown that transmembrane-type tight junction proteins are upregulated in various cancers compared with their levels in normal tissues and are...
Recent studies have shown that transmembrane-type tight junction proteins are upregulated in various cancers compared with their levels in normal tissues and are involved in cancer progression, suggesting that they are potential therapeutic targets. Here, we demonstrated the expression profile and a novel role of junctional adhesion molecule-A (JAM-A) in breast cancer. Immunohistochemistry of surgical specimens showed that JAM-A was highly expressed from carcinoma in situ lesions, as in other adenocarcinomas, with higher expression in invasive carcinomas. High expression of JAM-A contributed to malignant aspects such as lymph node metastasis and lymphatic involvement positivity. In breast cancer cells, JAM-A expression status affects malignant potentials including proliferation and migration. Multilayered proteomics revealed that JAM-A interacts with the amino acid transporter LAT1 in breast cancer cells. JAM-A regulates the expression of LAT1 and interacts with it on the whole cell membrane, leading to enhanced amino acid uptake to promote tumor growth. Double high expression of JAM-A and LAT1 predicts poor prognosis in patients with breast cancer. Of note, an antibody against an extracellular domain of JAM-A suppressed the proliferation of breast cancer cells. Our findings indicate the possibility of JAM-A-targeted therapy ideally combined with LAT1-targeted therapy as a new therapeutic strategy against breast cancer.
PubMed: 38943512
DOI: 10.1111/cas.16259 -
Nigerian Journal of Clinical Practice Jun 2024Mesenteric panniculitis is rare, usually idiopathic, caused by inflammation of the fatty tissue of the mesentery, especially in the small intestine. The relation between...
Mesenteric panniculitis is rare, usually idiopathic, caused by inflammation of the fatty tissue of the mesentery, especially in the small intestine. The relation between cancer and mesenteric panniculitis is unclear. In some studies, mesenteric pannicullitis precedes cancer diagnosis; on the other hand, some studies suggest no correlations. Immunotherapeutics have a wide range of side effects; virtually, every system and organ in the body can be affected. Herein, we presented a rare case of mesenteric panniculitis in a patient with larnyngeal cancer as a side effect of nivolumab treatment. The patient was presented with nausea and vomiting and diagnosed with intravenous contrast-enhanced computed tomography and fully recovered with corticosteroid treatment. The case report highlights the importance of noticing rarely seen side effects of immunotherapy which can be treated easily with immunosuppressive agents.
Topics: Humans; Panniculitis, Peritoneal; Nivolumab; Male; Antineoplastic Agents, Immunological; Middle Aged; Tomography, X-Ray Computed
PubMed: 38943307
DOI: 10.4103/njcp.njcp_655_23 -
Molecular Therapy : the Journal of the... Jun 2024NK cells eliminate infected or cancer cells via their cytotoxic capacity. NKG2A is an inhibitory receptor on NK cells and cancer cells often overexpress its ligand HLA-E...
NK cells eliminate infected or cancer cells via their cytotoxic capacity. NKG2A is an inhibitory receptor on NK cells and cancer cells often overexpress its ligand HLA-E to evade NK cell surveillance. Given the successes of immune checkpoint blockade in cancer therapy, NKG2A is an interesting novel target. However, anti-NKG2A antibodies have shown limited clinical response. In the pursuit of enhancing NK cell-mediated anti-tumor responses, we devised a Cas9-based strategy to delete KLRC1, encoding NKG2A, in human primary NK cells. Our approach involved electroporation of KLRC1-targeting Cas9-ribonucleoprotein resulting in effective ablation of NKG2A expression. Compared to anti-NKG2A antibody blockade, NKG2A-knockout NK cells exhibited enhanced activation, reduced suppressive signaling, and elevated expression of key transcription factors. NKG2A-deficient NK cells overcame inhibition from HLA-E, significantly boosting NK cell activity against solid and hematologic cancer cells. We validated this efficacy across multiple cell lines, a xenograft mouse model, and primary human leukemic cells. Combining NKG2A knockout with antibody-coating of tumor cells further enhanced cytotoxicity through ADCC. Thus, we provide a comprehensive comparison of inhibition of the NKG2A pathway using genetic ablation and antibodies and provide novel insight in the observed differences molecular mechanisms, which can be translated to enhance adoptive NK cell immunotherapy.
PubMed: 38943249
DOI: 10.1016/j.ymthe.2024.06.034 -
Parasites & Vectors Jun 2024Chicken coccidiosis is a protozoan disease that leads to considerable economic losses in the poultry industry. Live oocyst vaccination is currently the most effective...
Oral vaccination with a recombinant Lactobacillus plantarum expressing the Eimeria tenella rhoptry neck 2 protein elicits protective immunity in broiler chickens infected with Eimeria tenella.
BACKGROUND
Chicken coccidiosis is a protozoan disease that leads to considerable economic losses in the poultry industry. Live oocyst vaccination is currently the most effective measure for the prevention of coccidiosis. However, it provides limited protection with several drawbacks, such as poor immunological protection and potential reversion to virulence. Therefore, the development of effective and safe vaccines against chicken coccidiosis is still urgently needed.
METHODS
In this study, a novel oral vaccine against Eimeria tenella was developed by constructing a recombinant Lactobacillus plantarum (NC8) strain expressing the E. tenella RON2 protein. We administered recombinant L. plantarum orally at 3, 4 and 5 days of age and again at 17, 18 and 19 days of age. Meanwhile, each chick in the commercial vaccine group was immunized with 3 × 10 live oocysts of coccidia. A total of 5 × 10 sporulated oocysts of E. tenella were inoculated in each chicken at 30 days. Then, the immunoprotection effect was evaluated after E. tenella infection.
RESULTS
The results showed that the proportion of CD4 and CD8 T cells, the proliferative ability of spleen lymphocytes, inflammatory cytokine levels and specific antibody titers of chicks immunized with recombinant L. plantarum were significantly increased (P < 0.05). The relative body weight gains were increased and the number of oocysts per gram (OPG) was decreased after E. tenella challenge. Moreover, the lesion scores and histopathological cecum sections showed that recombinant L. plantarum can significantly relieve pathological damage in the cecum. The ACI was 170.89 in the recombinant L. plantarum group, which was higher than the 150.14 in the commercial vaccine group.
CONCLUSIONS
These above results indicate that L. plantarum expressing RON2 improved humoral and cellular immunity and enhanced immunoprotection against E. tenella. The protective efficacy was superior to that of vaccination with the commercial live oocyst vaccine. This study suggests that recombinant L. plantarum expressing the RON2 protein provides a promising strategy for vaccine development against coccidiosis.
Topics: Animals; Eimeria tenella; Chickens; Coccidiosis; Poultry Diseases; Protozoan Vaccines; Lactobacillus plantarum; Administration, Oral; Protozoan Proteins; Vaccination; Antibodies, Protozoan; Vaccines, Synthetic
PubMed: 38943202
DOI: 10.1186/s13071-024-06355-w -
Critical Care (London, England) Jun 2024In a phase 3 trial (PANAMO, NCT04333420), vilobelimab, a complement 5a (C5a) inhibitor, reduced 28-day mortality in mechanically ventilated COVID-19 patients. This post... (Randomized Controlled Trial)
Randomized Controlled Trial
In a phase 3 trial (PANAMO, NCT04333420), vilobelimab, a complement 5a (C5a) inhibitor, reduced 28-day mortality in mechanically ventilated COVID-19 patients. This post hoc analysis of 368 patients aimed to explore treatment heterogeneity through unsupervised learning. All available clinical variables at baseline were used as input. Treatment heterogeneity was assessed using latent class analysis (LCA), Ward's hierarchical clustering (HC) and the adjudication to previously described clinical sepsis phenotypes. The primary outcome was 28-day mortality. For LCA, a 2-class latent model was deemed most suitable. In the LCA model, 82 (22%) patients were assigned to class 1 and 286 (78%) to class 2. Class 1 was defined by more severely ill patients with significantly higher mortality. In an adjusted logistic regression, no heterogeneity of treatment effect (HTE) between classes was observed (p = 0.998). For HC, no significant classes were found (p = 0.669). Using the previously described clinical sepsis subtypes, 41 patients (11%) were adjudicated subtype alpha (α), 17 (5%) beta (β), 112 (30%) delta (δ) and 198 (54%) gamma (γ). HTE was observed between clinical subtypes (p = 0.001) with improved 28-day mortality after treatment with vilobelimab for the δ subtype (OR = 0.17, 95% CI 0.07-0.40, p < 0.001). No signal for harm of treatment with vilobelimab was observed in any class or clinical subtype. Overall, treatment effect with vilobelimab was consistent across different classes and subtypes, except for the δ subtype, suggesting potential additional benefit for the most severely ill patients.
Topics: Humans; Female; Male; Middle Aged; Aged; COVID-19 Drug Treatment; Antibodies, Monoclonal, Humanized; Treatment Outcome; COVID-19
PubMed: 38943192
DOI: 10.1186/s13054-024-05004-z -
Diagnostic Pathology Jun 2024Waldenström's macroglobulinemia (WM) is defined as a lymphoplasmacytic lymphoma (LPL) involving the bone marrow (BM) with presence of IgM monoclonal protein, and...
BACKGROUND
Waldenström's macroglobulinemia (WM) is defined as a lymphoplasmacytic lymphoma (LPL) involving the bone marrow (BM) with presence of IgM monoclonal protein, and comprises > 95% of all LPL cases. Rituximab-based regimens have been predominant in the management of WM. Infusion-related reactions (IRRs) are a primary concern with rituximab, although it is generally better tolerated with less toxicity than conventional anticancer agents. Here, we present an autopsy case of an elderly man who died suddenly after receiving the initial infusion of rituximab for WM/LPL.
CASE PRESENTATION
An 84-year-old man was found dead in his bedroom. He had undergone the initial intravenous rituximab infusion for progressive anemia related to Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) approximately 15 h before death. Although the protocol for rituximab administration and additional medication was considered appropriate, he exhibited several symptoms consistent with infusion-related reactions (IRRs) during the infusion. Autopsy revealed monotonous proliferation of small-to-medium-sized lymphocytic cells in the bone marrow, consistent with the premortem diagnosis of WM/LPL. Additionally, immunoglobulin λ-light chain-derived amyloid (ALλ) deposition was identified in all organs other than the brain. Although ALλ deposition and LPL infiltration were found in the heart, they were not severe enough to cause severe functional impairment. Severe congestion and/or edema were observed in the lungs, liver, and brain. Although significant inflammatory cell infiltration was not found in any organs, laboratory tests revealed elevated serum levels of inflammatory cytokines, including interleukin-1β, interleukin-6, tumor necrosis factor-α and the presence of IgM-λ monoclonal protein.
CONCLUSION
Acute IRRs associated with the initial rituximab infusion were the major contributing factor to his sudden unexpected death. The autopsy findings of present case suggest the necessity for thorough monitoring of older patients with WM/LPL undergoing rituximab treatment, particularly when pronounced IRRs occur during the first administration, in addition to investigating complications of WM/LPL before infusion.
Topics: Humans; Waldenstrom Macroglobulinemia; Rituximab; Male; Aged, 80 and over; Autopsy; Death, Sudden; Antineoplastic Agents, Immunological; Bone Marrow; Fatal Outcome; Infusions, Intravenous
PubMed: 38943126
DOI: 10.1186/s13000-024-01519-9