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NCT07324473
Background： Hepatocellular carcinoma (HCC) stands as a formidable global health challenge. It ranks as the sixth most common malignant solid tumor worldwide and the third leading cause of cancer-related mortality. The disease is characterized by its insidious onset, rapid progression, and high recurrence rates, contributing to a dismal 5-year survival rate of approximately 18%. A critical factor in this poor prognosis is that nearly 57% of patients are diagnosed at an advanced stage, where curative surgical resection is no longer feasible. For these patients with unresectable advanced HCC (uHCC), effective systemic therapies are paramount to extend survival and improve quality of life. The advent of immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis, has revolutionized the treatment landscape for numerous advanced cancers, including uHCC. These agents work by blocking the inhibitory signals that tumor cells exploit to evade immune surveillance, thereby reactivating cytotoxic T cells to attack the cancer. However, the clinical benefit of ICI-based therapies is not universal. A substantial proportion of patients-estimated between 15% to 40%-derive limited or no benefit. Primary resistance is defined as a lack of initial response, while acquired resistance refers to disease progression after an initial period of clinical benefit. There is no established, evidence-based standard of therapy for uHCC patients who progress following first-line ICI combination therapy, highlighting an urgent need for novel therapeutic approaches. The mechanisms underlying acquired resistance to ICIs are multifaceted and intricately linked to dynamic remodeling of the tumor immune microenvironment (TME). Several key pathways contribute: 1. Loss of Tumor Immunogenicity: Immune editing during treatment can select for tumor cell clones with low neoantigen expression, making them less visible to the immune system. 2. Immune Suppressive Cell Infiltration: The TME in resistant tumors often exhibits an accumulation of immunosuppressive cell populations, including regulatory T cells (Tregs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs). These cells create a profoundly inhibitory milieu that dampens anti-tumor T cell function. 3. T Cell Exhaustion: Persistent antigen exposure leads to a state of CD8⁺ T cell exhaustion, rendering them dysfunctional. These interconnected mechanisms collectively foster an immunosuppressive TME that allows tumors to evade ongoing immune attack, underscoring the need for combination strategies that can reshape the TME and re-sensitize tumors to immunotherapy. The JAK-STAT pathway serves as a critical signaling hub for numerous cytokines and growth factors, playing a pivotal dual role in immunity and inflammation. In the context of HCC and ICI resistance, its activation is particularly relevant: 1. Pathway Activation in HCC: The JAK/STAT pathway is ubiquitously activated in both primary and recurrent HCC tumors and contributes to the proliferation and survival of tumor-initiating cells. 2. Driver of an Immunosuppressive TME: Hyperactivation of this pathway, often via cytokines like IL-6, promotes the recruitment and activation of immunosuppressive MDSCs and M2-polarized TAMs. It also contributes to T cell exhaustion. 3. Preclinical and Clinical Proof-of-Concept: In preclinical models, JAK/STAT inhibition has been shown to reduce MDSC infiltration and restore T cell function. Most compellingly, recent clinical studies in other cancer types published in high-impact journals like Science (2024) have demonstrated that adding a JAK inhibitor to PD-1 blockade can re-sensitize tumors and yield significant clinical responses in patients who had developed resistance to immunotherapy alone Purpose: This single-arm, exploratory clinical study aims to evaluate the efficacy and safety of Ivarmacitinib (a selective JAK1 inhibitor) combined with Camrelizumab (anti-PD-1) and Apatinib (anti-VEGFR2) in patients with advanced unresectable HCC who have progressed after first-line ICI-based combination therapy. Methods: This study plans to enroll 65 patients with advanced unresectable hepatocellular carcinoma (unresectable BCLC stage B or stage C) who have been clinically or pathologically diagnosed, have previously received at least 4 cycles of guideline-recommended first-line targeted therapy combined with PD-1/PD-L1 immunotherapy, achieved a partial response, but subsequently experienced disease progression confirmed by RECIST 1.1 criteria after at least 4 cycles (indicating acquired resistance). All enrolled patients will receive triple therapy consisting of Ivarmacitinib + Apatinib + Camrelizumab. Treatment will continue until disease progression, unacceptable toxicity, or for up to 2 years.
NCT06218225
The goal of this clinical trial is to evaluate the efficacy of the product in developing immune reinforcement that results in decreased susceptibility to respiratory infections of viral origin in children aged 3 to 10 years with a number of respiratory tract infectious events in the previous year greater than 4. The main questions it aims to answer are: * Has the number of infectious events been reduced from last year? * Does the severity of symptoms decrease with the use of the product? Participants will be treated for 4 months. Treatment efficacy will be evaluated by: * 2 scheduled visits with the investigating pediatrician (T0 - enrollment and start of treatment; T1- end of treatment). * Verification of progress during the study by scheduled telephone meetings. * The use of a diary where the patient or parent/caregiver will report all events (even mild) affecting the respiratory tract, taking care to fully complete the Wisconsin Upper Respiratory Symptom Survey for kids (WURSS-k) questionnaire.
NCT05087498
Multi-omics (analysis of peripheral blood immune cells subset, peripheral blood MNCs transcriptome, soluble inflammatory cytokine profile in blood and airway secretion, lung and gut microbiota, and the interaction) analysis was used to profile immune alternation of infants with intravenous ACBMNC infusion in very preterm monozygotic twins
NCT06017661
The aim of the study is to demonstrate, under clinical conditions, the effectiveness of the standard product 'Nutridrink' enriched with a mixture of plant extracts rich in polyphenolic compounds in the aspect of supporting the recovery of oncology patients undergoing surgical resection of tumours.
NCT04375176
SARS-CoV-2 belong to beta-coronavirus family and its transmission route and symptoms follow those of all community-acquired coronaviruses. The main difference of the novel Coronavirus is the higher mortality rate, that is around 3%. Death rate is over 1% only for patients over 50 years old, whereas until 40 years old is under 0,4%. No fatalities are declared among children under 10 years old to date. Death rate is almost double for male rather than female. This distribution of mortality rate according to age of infected patients could be only partially ascribed to other comorbidities in addition to great age. In fact, patients with no pre-existing conditions have however a case fatality rate of 0,9%. The almost null rate of severe illness in children and generally in patients younger than 40 years old is quite un-explicable. Infant, children and young people could be infected but infection is rapidly self-limited or without symptoms. Older patients undergo severe lung injury as consequence of an immune response that is late in coming. Possible explanation of these phenomena could be something, which assure ability to prompt response to SARS-CoV-2 in younger people independently from the novelty of the virus itself. It would seem to be that younger people are already sensitized to the antigens of the virus without a previous contact. This immunity is not really specific, but "partially specific" for many antigens of the virus, however able to limit the infection in the organism. Something stimulated the immune system and it scattered immunity against more and more antigens present. Children are the age group mostly exposed to all community-circulating viruses. This immunity is not persistent but progressively fade out. It protects from the age of two, when the hypothetical stimulation occurs, to the fifth decade because of its slow decrease. The only external stimulation, which healthy people receive are vaccines. All vaccinations and especially tetanic, diphtheria toxoids and inactivated bacteria as pertussis could stimulate immune system. They develop the specific immunity but generate also a sprouting immunity against antigens in transit, as coronaviruses and other community-circulating viruses. The developed immunity gives some protection against multiple viral infection for years until the natural fade out. After the fifth decade, that immunity is slower to be recall and reactivated. Additionally, transplant recipients and HIV infected patients, which have an immune system inhibited, unexpectedly, do not seem to suffer the worst complications of SARS-CoV-2 infection. An immune system imbalance could be play a pivotal role during the reaction to the virus, limiting destructive consequences of excessive inflammation. According to the medical hypothesis on which the protocol is based on, young people could benefit from a functional adaptation of innate immune cells induced through epigenetic reprogramming and, especially, a pre-existing "partially specific" immunity to the community viruses caused by "bystander effect" of preceding vaccinations. In this study, we will explore the main differences existing among patients infected by SARS-CoV-2 who experience the illness at different degree of severity. We suppose to recognize different populations of patients, each one with a specific immunological pattern. It could differ in terms of cytokines, soluble factors serum level and immune cells activity both of the innate compartment and of the acquired one. The proof of a role of these immunological phenomena in the pathogenesis of Covid-19 are bases for implementation of therapeutic immunomodulatory treatments. In addition, the definition of an immunological risk profile could tailor established therapies to each kind of patient.