immunotherapy

NMDA receptor encephalitis is a rare disease first described in 2007. Anti-NMDA receptor encephalitis affects mostly young women as neoplasms, mostly ovarian teratomas, are the underlying cause. The disease is caused by antibodies binding to extracellular epitopes of neuronal cell-surface, which leads to an internalization of NMDA-receptors. The characteristic syndrome of patients with anti-NMDAR as well as its recovery follows a certain pattern. Treatment includes immunotherapy and removal of the immunologic trigger. This case report describes a young woman with anti-NMDA receptor encephalitis caused by an ovarian teratoma. 

Breast cancer is the most common cancer in women and is a major public health problem. It is divided into several subtypes, including triple negatives. The general objective of our study is to establish the profile and the management of patients with triple negative breast cancer over a period of 2 years, operated in our department. During our study period, triple-negative breast cancers accounted for 10% of our population. The most affected age group ranges from 50 to 60. The majority of patients in our sample are pauciparous. In the group of patients who received hormone therapy, it was mainly HRT for 4 to 6 years. 96.77% of patients consulted a health worker within 3 months of the discovery of the signs. Adenopathies are frequently present at the time of diagnosis. 93.54% of the cases have an invasive ductal carcinoma. Triple negative cancers are essentially poorly differentiated. Triple-negative cancer has a high rate of cell renewal. In our study, neoadjuvant chemotherapy is mostly indicated for triple-negative breast cancers ≥ 30 mm at diagnosis and a delayed lumpectomy is then performed in 23.52% of the patients. For tumors of < 30 mm size, a lumpectomy is performed immediately in 76.47% of the patients, followed by adjuvant chemotherapy. Mastectomy was performed in 45.16% of patients; it was mainly indicated in front of a large tumor size associated with a small breast volume, then multifocal breast tumors. Breast reconstruction was performed in 21.42%. Radiation therapy is indicated in the majority of patients, postoperatively. In our population, 11 patients were proposed to have an oncogenetic survey; it was mainly indicated based on the Manchester criteria in front of a young age and a family history of cancer. There are two BRCA 1 mutations, one BRCA 2 mutation, and one case of absence of mutation. The therapeutic intake in case of a mutation is directed towards a prophylactic bilateral mastectomy and adnexectomy, proposed at the age of 40. Two patients had presented triple negative recurrences of their already treated breast cancer; first case PDL1 positive PD-L1 ≥ 1% treated with immunotherapy combined with chemotherapy (atezolizumab/abraxane) while the second and second PDL1 negative treated with chemotherapy alone. Despite their low frequency, triple negative breast cancers represent a subgroup marked by pejorative characteristics, a reserved prognosis, with limited treatment options.

Varicella zoster virus behaves differently from other herpes viruses as it differs from them in many aspects. Recently, there has been growing evidence on the beneficial effects of the virus in immune compromised hosts and these effects are translated into prolongation of survival. The reported beneficial effects of the virus include: (1) stimulation of bone marrow activity in patients with hematologic malignancies and bone marrow failure syndromes, (2) antitumor effects in various hematologic malignancies and solid tumors, and (3) association with graft versus host disease which has anticancer effects. Additionally, there are several reports on the safety of the live-attenuated even in severely immune suppressed individuals and on the emerging role of the virus in cancer immunotherapy. In this review, the following aspects of the virus will be thoroughly discussed: (1) new data on the genetic background, pathogenesis, vaccination, and new therapeutic modalities; (2) bone marrow microenvironment and hematopoiesis; (3) cells involved in the pathogenesis of the virus such as: mesenchymal stem cells, dendritic cells, natural killer cells, T-cells and mononuclear cells; (4) cellular proteins such as open reading frames, glycoproteins, promyelocytic leukemia protein, chaperons, and SUMOs; (5) extracellular vesicles, exosomes, and micro-RNAs; and (6) signaling pathways, cytokines, and interferons.

Allergen immunotherapy (AIT) is the unique curative treatment to help allergic patients to get over their allergies. With a personalized approach, AIT is the best example of precision medicine. After a century of intensive studies and innovative discoveries, allergists have in their hands many tools to orchestrate the best strategy to re-educate the hypersensitive immune systems that decrease the quality of life of their patients. This review describes both the historical and the promising acquisitions in this field, focusing the biochemical and Bioengineering tools that render an allergen more suitable for a secure, convenient and effective immunotherapy.

By researching the factors related to exposure to indoor and outdoor allergens, such seasons, climate changes and particulate matter, allergists can screen the sensitization profile of individuals according to their exposures and conduct preventive treatment and individualized immunotherapy. Molecular allergology has improved aerobiological screening of allergenic components toward more specific results on allergic exposure, sensitization, and symptoms [1,2]. The Enzyme-Linked Immunosorbent Assay (ELISA) is a colorimetric enzyme immunoassay technique used to quantify soluble substances such as proteins, peptides, antibodies, and hormones. Due to its high sensitivity and specificity, ELISA can quantify substances at low concentrations, such as allergens [3].

Herpes simplex virus (HSV)-1 encephalitis is the most common infectious cause of sporadic encephalitis. Despite treatment with acyclovir, HSV encephalitis is still associated with severe morbidity characterized by persistent neurological deficits. HSV encephalitis usually follows a monophasic course, however, some patients might develop relapsing symptoms caused by the formation of auto-antibodies directed against the N-methyl-D-aspartate receptor (NMDAR). Here we present an 82-year-old male patient with HSV encephalitis who developed shortly after his hospital discharge a Post-HSV NMDAR encephalitis, characterized by recurrent epileptic seizures and deterioration of his residual aphasia. First-line immunotherapy with intravenous immunoglobulins (IgIV) was administered and the patient returned almost to his baseline residual deficits of HSV encephalitis. Subsequently, he presented with recurrent relapses of NMDAR encephalitis. Since periodic treatment with IgIV has been started the patient is seizure-free and his neuropsychiatric condition is stable. In conclusion, the recognition of Post-HSV NMDAR encephalitis is very important because neurological manifestations can markedly improve with immunotherapy. Interestingly, in some patients cerebral HSV infection seems to trigger a chronic inflammatory disorder with persistent autoimmune activation which requires chronic treatment.

Flow cytometry (FCM) is a unique technique that allows rapid quantitative measurement of multiple parameters on a large number of cells at the individual level. FCM is based on immunolabelling with fluorochrome-conjugated antibodies, leading to high sensitivity and precision while time effective sample preparation. FCM can be performed on tissue following enzymatic or mechanical dissociation. The expression of epithelial antigens and cytokeratin isoforms help in distinguishing tumor cells from adjacent epithelial cells and from tumor infiltrating leukocytes. Tumor phenotypes can be characterized on expression intensity, aberrancies and presence of tumor-associated antigens as well as their cell proliferation rate and eventual heteroploidy. FCM can measure quantitative expression of hormone or growth factor receptors, immunoregulatory proteins to guide adjuvant therapy. Expression of adhesion molecules tells on tumor’s capacity for tissue invasion and metastasis seeding. Tumor heterogeneity can be explored quantitatively and rare, potentially emerging, clones with poor prognosis can be detected. FCM is easily applicable on fine needle aspiration and in any tumor related biological fluids. FCM can also be used to detect circulating tumor cells (CTC) to assess metastatic potential at diagnosis or during treatment. Detecting CTC could allow early detection of tumors before they are clinically expressed although some difficulties still need to be solved. It thus appears that FCM should be in the pathologist tool box to improve cancer diagnosis, classification and prognosis evaluation as well as in orientating personalized adjuvant therapy and immunotherapy. More developments are still required to better known tumor phenotypes and their potential invasiveness

Introduction: Even after surgical resection and adjuvant chemotherapy in pancreatic cancer the 5-year disease-free survival times (DFS), as well as overall survival rates (OS), are still low and median survival times are below 2 years. Here we retrospectively analyzed the outcome of immunotherapy in the additional adjuvant treatment of pancreatic cancer with long antigen exposition dendritic cell therapy (LANEX-DC®) in 28 patients who were treated at our institution. Patients: Data were available from 28 patients. Dendritic cells (LAEX-DC®) were produced according to a recently published protocol.Results: Therapy was well tolerated and no serious side effects were observed. The median disease-free survival times and the median survival times were 16,9 months and 29,4 months respectively. Five-year DFS and OS were 14,3% and 17,9%. Conclusion: We were able to show in a small cohort of patients that additional treatment with dendritic cells (LANEX-DC®) is highly effective and extends the median disease-free survival times as well as the median survival in the adjuvant treatment of pancreatic cancer, whereas the five-year overall survival still remains unsatisfactory.

Introduction: Allergen immunotherapy is the only targeted therapy that can modify the natural course of allergic diseases. In pediatric patients, SCIT with aeroallergens is an effective treatment and should be considered as a preventive strategy in the treatment of allergic diseases, even though one of the major concerns about it is its safety. The main purposes of this study were to assess the safety of SCIT ultra-rush schedules with polymerized extracts in a pediatric population and to determine the impact of the COVID-19 pandemic on the safety and time of administration of subcutaneous immunotherapy among pediatric patients.Methods: A retrospective medical records review of patients under 18 years of age undergoing SCIT was made and re-scheduling due to restrictions imposed by the COVID-19 pandemic was recorded. Results: A total of 192 pediatric patients were included. Fifty-nine (31%) had local reactions and systemic reactions were not reported. In March 2020, the first case of COVID-19 was diagnosed in Portugal and all non-urgent appointments and procedures were postponed. In our group of pediatric patients, 43 (22%) were referred to primary care, 38 (20%) stopped AIT definitively and 111 (58%) maintained administrations in the hospital. Only 2 (2%) of them had reactions upon reinitiation. Conclusion: In this study, the ultra-rush protocol using polymerized extracts was safe in pediatric patients. Although the effectiveness of AIT may be compromised due to prolonged suspension of the treatment, it is important to note that despite longer interruptions, administrations may continue without compromising safety, maintaining shorter visits and a lower number of injections.

mRNA drugs are synthesized using cell-free systems without complex and stringent manufacturing processes, which makes their preparation simple, efficient, and economical. Over the past few years, mRNAs encoding antibodies have been one of the research frontiers of antibody drug development. In cancer immunotherapy, mRNAs encoding immune checkpoint antibodies may be advantageous regarding antibody persistence and durability of the anti-tumor immune response of patients. In our previous study, a candidate antibody—AET2010—targeting the novel immune checkpoint TIGIT was reported. Its anti-tumor activity was also investigated using adoptive transfer of NK-92MI cells in a xenograft mouse model, but the limitations of the model did not facilitate precise evaluation. In the present study, we further investigated the therapeutic potential of AET2010 for cancer in TIGIT-humanized BALB/c mice. Next, we explored the design, synthesis, and optimization of mRNAs encoding AET2010 and ultimately obtained a candidate mRNA (mRNA-BU) with favorable in vitro and in vivo expression levels of active AET2010. Particularly, lipid-nanoparticle-encapsulated mRNA-BU delivered to mice produced AET2010 with significantly higher peak concentration and expression duration than an equivalent dose of original AET2010. This study provides a sound basis for developing novel drugs targeting TIGIT.

As the introduction of immune checkpoint inhibitors in the treatment of various cancers is now proven to be already acquired knowledge, so does a new challenge arise for clinicians; the understanding, diagnosis, and management of the rarest adverse effects of immunotherapy. We present a case of type-1 diabetes Mellitus (T1DM) in a patient with non-small cell lung carcinoma (NSCLC) treated with pembrolizumab. Following ten cycles of treatment, our patient was diagnosed with T1DM after being admitted for diabetic ketoacidosis and stayed hospitalized in the ICU. Later, they continued treatment with insulin, having shown disease response to pembrolizumab, and resumed immunotherapy while on insulin. Immunotherapy-induced T1DM can sometimes occur with PD1/PD-L1 blockage therapies. It has a rapid onset, is characterized by insulin deficiency due to the autoimmune destruction of beta-cells, and usually presents itself with diabetic ketoacidosis. Unlike most of the other adverse effects of immunotherapy, glucocorticoids don’t seem to be of therapeutic value, and insulin substitution is required. Regular glucose monitoring can be key to early diagnosis and prevention of hospitalization. 

Neurodegenerative disorders (NDDs) pose a significant global health challenge, impacting millions with a gradual decline in neurons and cognitive abilities. Presently, available NDD therapies focus on symptom management rather than altering the disease trajectory. This underscores the critical necessity for groundbreaking treatments capable of addressing the root causes of neurodegeneration, offering both neuroprotection and neuro-restoration. This in-depth review delves into the forefront of emerging NDD therapies, encompassing gene therapy, stem cell therapy, immunotherapy, and neurotrophic factors. It sheds light on their potential advantages, hurdles, and recent advancements gleaned from both preclinical and clinical studies. Additionally, the document outlines existing NDD treatments, spanning pharmacological and non-pharmacological interventions, along with their inherent limitations. The overarching conclusion emphasizes the immense potential of emerging therapies in NDD treatment, yet underscores the imperative for continued research and optimization to ensure their safety, efficacy, and specificity.

Immune Checkpoint Inhibitors (PCIs,) are monoclonal antibodies directed against immune checkpoint regulatory molecules. These antibodies inhibit T-cell activation and prolong survival in patients with different types of cancer. However, they can produce adverse effects related to the immune response such as renal damage.We present the clinical case of a 75-year-old man with a personal history of Chronic Kidney Disease (CKD) and metastatic renal cancer with lung, bone, and mediastinal involvement. He started treatment with immunotherapy with Nivolumab-Ipilimumab. Then, after 4 cycles of immunotherapy, the patient was admitted to the Urology Department for an adverse reaction to immunotherapy with the development of nephritis and toxic hepatitis. Despite treatment with methylprednisolone, he evolved poorly, and a palliative approach was finally decided.The incidence of acute renal failure attributed to PCIs is estimated at 2% - 3%, being grade I-II in most cases. Among the renal complications associated with PCIs, acute interstitial nephritis is the most predominant with an incidence of 80% - 90% of cases. In addition, an increased risk is observed in patients with intermediate or poor risk metastatic renal cancer.Despite their fundamental role in metastatic renal cancer, we must take into account the potential for renal failure as an adverse effect of PCIs, especially in patients with previous CKD.

Introduction: Gentian Violet (GV) is a triphenylmethane industrial dye that is known for its antibacterial, antiviral, anti-helminthic, and anti-tumor effects. Although many studies focused on determining the biological and pharmacological applications of GV, its exact effect on the immune response has not been elucidated yet. Methods: In this study, we investigate the immunomodulatory effects of GV in BALB/c mice after intraperitoneal injection of the dye by assessing cytokines levels in the spleen. Results: Our data show that GV-treated mice have decreased levels of proinflammatory cytokines (IL-1β and TNF-α) and increased levels of anti-inflammatory cytokines (IL-4) in their spleens. In addition, IFN-γ which can modulate pro-inflammatory cytokine production was upregulated in GV-treated mice. Conclusion: Together, these findings suggest an anti-inflammatory activity of GV that warrants further studies investigating the potential of GV in immunotherapy. 

Cholangiocarcinoma (CCA), a rare malignancy originating from bile duct epithelial cells, often presents a challenging prognosis due to its rarity, delayed diagnosis, and early recurrence post-curative-intent treatments. Additional complexities include difficulties in achieving R0 resection during surgical intervention and the lack of effective second-line treatments following the failure of first-line regimens, particularly in unresectable advanced cases.In this case study, we demonstrate a durable response to a combination regimen of pembrolizumab and lenvatinib in a patient with distal CCA. Despite the regimen’s interim median Progression-Free Survival (PFS) of 6.1 months (95% CI, 2.1-6.4), our patient achieved a clinical and radiological PFS of approximately two years. The underlying mechanisms, potentially involving the upregulation of immune response pathways through undisclosed means or influenced by lenvatinib’s activation of T cells, might augment the sensitivity to PD-1 antibodies like pembrolizumab, contributing to the patient’s sustained response over two years.This case also highlights the significance of the patient’s initial good health condition, multidisciplinary care, and the potential impact of molecular subtyping on treatment selection in a patient with distal CCA who underwent numerous diagnostic procedures, intricate surgical interventions, and subsequent treatment regimens over seven years. Additionally, we underscore significant landmark trials and emerging combination therapies, including chemotherapies, immunotherapy, and targeted treatments in this report.

Immune Checkpoint Inhibitors (ICPIs), while revolutionizing cancer therapy through potentiation of anti-tumour responses via targeted blockade of T-lymphocyte inhibitory receptors, are associated with immune-related adverse events (irAEs), including diverse renal manifestations. This report presents a case of a 69-year-old male with urothelial carcinoma who developed Acute Kidney Injury (AKI) and nephrotic-range proteinuria following initiation of nivolumab, an anti-PD1 antibody, necessitating renal biopsy to clarify the aetiology. The biopsy revealed Focal Segmental Glomerulosclerosis (FSGS) with endotheliopathy, suggesting a direct ICPI-induced glomerular injury. This case underscores the need for heightened awareness of ICPI-associated glomerular disease, alongside more common renal adverse events such as Acute Interstitial Nephritis (AIN), and for the need for renal biopsy in such cases. While the incidence of ICPI-associated AKI is approximately 17%, and AIN is a more frequent finding, FSGS and other glomerular pathologies should also be considered. Current treatment for such renal events involves discontinuation of the ICPI agent and initiation of immunosuppression with glucocorticoids. The management of these cases requires prompt detection, timely diagnosis, and often interdisciplinary collaboration, thus highlighting the need for more case reports, research, and better treatment strategies.