Immune Response

Background: Almost 3 billion people worldwide, including 89% people in Bangladesh, are exposed to harmful household air pollutants (HAP) emitted from combustion of biomass fuel (wood, agricultural residue, cow dung, etc.) used for cooking. While health risks associated with air-pollution have been reasonably well-studied in developed countries, there is little evidence on health benefits achievable by HAP reduction through clean fuel use such as Liquid Petroleum Gas, especially in low- and middle-income countries (LMICs). Rationale: In the earlier GEOHealth (Round-I) study, the investigators have shown that LPG for 24 months, reduced personal PM2.5 exposure by 58.2 percent which induced novel changes in innate immune and inflammatory responses in women but the changes in chronic cardio-pulmonary markers were not prominent, most likely due to short duration of follow up and probably impact of ambient pollution. Moreover, sustained use of LPG could be challenging as earlier GEOHealth (Round-I) study provided the cook stove and supply of LPG free of cost. A post-completion screening showed \>70% households continued using LPG albeit not exclusively. It is plausible that an intervention using mobile phone-based application can improve the exclusive use of LPG in the communities. Hypothesis: 1. The mobile phone based (mHealth) Behavioural Change Communication (BCC) intervention can be easily incorporated in Government policy that can promote adoption, and increase exclusive use of LPG in the communities. The long-term effect of HAP reduction can be associated with- 2. subclinical measures of cardio-vascular and pulmonary dysfunction. 3. balanced changes in innate/ inflammatory and adaptive immune function (vaccine response). Objectives: To evaluate 1. The effects of a scalable educational intervention (using mHealth application) on adoption and exclusive use of LPG. 2. The long-term effects of HAP reduction on subclinical measures of cardio-vascular and pulmonary dysfunction. 3. The long-term effects of HAP reduction on innate/ inflammatory immune function among women and children and to investigate the influence of HAP exposure on antibody response to vaccines (adaptive immunity). Methods: The investigators will conduct a large household level randomized controlled trial by educational intervention using mobile phone (mHealth) based technology. In addition, the investigators will continue following the cohort and will conduct rigorous and repeated personalized (24 hours) and area-wise (over 5 days) assessments of PM2.5 and black carbon (BC) exposure to examine the long-term effects of HAP reduction on subclinical measures of cardio-pulmonary and immune dysfunction including effect of HAP exposure on antibody response to vaccine. Outcome measures/variables: Personal and surrounding area PM2.5 and BC level will be measured at pre- and post-intervention. Lung function and lung pathology will be assessed through spirometry, Chest X-ray, and High-resolution Computed tomography of the chest (HRCT). Preclinical makers of cardiovascular diseases (CVD) will include blood pressure and EKG. Markers of metabolic dysfunction will be assesses by measuring HbA1c and fasting lipid profile. Immune function will be assessed by phenotyping of Immune cells, functional cytotoxic killer cells, oxidative stress of lymphocytes.

Currently, there are limited methods available in clinical practice to distinguish pseudoprogression after immunotherapy. Most patients rely on follow-up observations to monitor the disease, which does not meet clinical needs. 68Ga-grazytracer is a novel imaging agent targeting granzyme B. By detecting the concentration of granzyme B, it reflects the localization of cytotoxic T cells in the tumor region and their potential ability to kill tumor cells. This study aims to leverage the simplicity, non-invasiveness, visualization, and semi-quantitative advantages of 68Ga-grazytracer PET imaging to evaluate its effectiveness and feasibility in diagnosing pseudoprogression.

The revolution in rheumatoid arthritis (RA) therapeutics has been transformative for many patient outcomes. Yet most patients continue to experience life disabling pain. Strikingly, even those who achieve full disease remission with state-of-the-art anti-tumour necrosis factor (TNF) treatments report substantially higher levels of pain when compared to the general population. Such disconnect presents one of the greatest contemporary challenges to the care of patients with RA. Considering the ongoing excess burden of pain in this patient population, trials of Janus kinase inhibitors (JAKinibs) present welcome data. JAKinibs deliver superior pain improvements in comparison to those receiving anti-TNF therapy. Of note, the majority of this effect has not been fully explained by markers of peripheral inflammation and remains to be understood. Moreover, JAKinibs appear to offer rapid analgesic benefit. Traditional DMARDS and modern biologics commonly take several weeks to bring relief whereas JAKinibs, such as filgotinib, begin to improve pain as early as 2 weeks, even before the observed attenuation of peripheral clinical inflammation. In light of these clinical observations, the investigators believe that RA is a mixed pain state i.e., pain pathways exist in addition to established peripheral inflammatory nociceptive mechanisms. In particular, the central nervous system (CNS) may have an important role in determining RA pain. Recently our group were the first to delineate distinct neurobiological pain signatures in the brains of RA patients by employing functional connectivity magnetic resonance imaging (fcMRI) - a recent adaptation of functional MRI data that examines the synchrony of neural activity which modulates the efficiency and extent of neuronal transmission between brain regions. Specifically, the investigators identified and replicated two distinct pain signatures: 1. enhanced functional connectivity between the Default Mode Network (DMN) and insula, which was unrelated to levels of peripheral inflammation but, intriguingly, is an established neurobiological marker of fibromyalgia (the prototypical CNS pain sensitization disorder, and 2. enhanced functional connectivity between the Dorsal Attention Network (DAN) and the left inferior parietal lobule (LIPL) which was related to levels of peripheral inflammation. Pre-clinical experiments have not only implicated the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway with peripheral immune system functioning but also the brain. In the CNS, this pathway promotes gene expression associated with inflammation which in turn generates pro-nociceptive cytokines. However, there is now also emerging evidence to support the pathway's direct role in synaptic transmission and neurotransmitter receptor modulation. Specifically, the JAK-STAT pathway appears important in N-methyl-d-aspartate (NMDA) related synaptic plasticity - a ubiquitous glutamate receptor of the human brain. Their induction is selectively blocked by JAK inhibitors. Increases in glutamate and subsequent binding to NMDA receptors cause chaotic and incoherent neuronal functional activity. Human studies of fibromyalgia have consistently evidenced both elevated glutamate levels within the insula and dysfunctional neural connectivity. Moreover, fibromyalgia pharmacotherapy (pregablin), considered to reduce neural glutamate, rectifies both insular glutamate and brain functional connectivity (DMN-insula). JAK inhibition (JAKi) may facilitate the reduction of glutamate-NMDA binding and ultimately pain alleviation by normalising the functional activity of these same neural connections.

Stimulator of interferon gene (STING) protein plays a vital role in the immune surveillance of tumor microenvironment. Monitoring STING expression in tumors benefits the relevant STING therapy. This study will investigate the safety, biodistribution and potential usefulness of a novel 68Ga-labeled agonist (\[68Ga\]Ga-Sa-DABI-4) for noninvasive positron emission tomography (PET) imaging of STING expression in the tumor microenvironment.

This is a clinical study of personalized self-DC vaccine targeting neo-antigen (Neo-DC vaccine) in the treatment of advanced solid tumors (especially head and neck cancer, non-driver gene sensitive mutation of non-small cell lung cancer). The investigators plan to enroll about 9 patients to explore the dose limited toxicity or recommended dose for future study of Neo-DC vaccine. The study is designed as 3 plus 3 model, and set two dose levels.

Head and Neck Squamous Cell Carcinoma (HNSCC) is one of the most common malignant tumors in the head and neck region. Globally, both its incidence and mortality rates have shown a significant upward trend, posing a serious threat to the life and health of patients. Although surgical resection is the main treatment approach for resectable HNSCC, a considerable number of patients still face a high risk of local recurrence and distant metastasis after surgery, which are the key factors contributing to poor prognosis. In recent years, immune-targeted therapy has emerged in the field of malignant tumor treatment and demonstrated unique treatment advantages and potential. It can specifically act on relevant targets of tumor cells, precisely regulate the body's immune system, and effectively enhance the body's immune response to tumor cells, thereby inhibiting the malignant biological behaviors of tumor cells such as growth, proliferation, and metastasis. Oncolytic herpes simplex virus (HSV) has the ability to specifically replicate within tumor cells and lyse them. Meanwhile, it can also induce a strong anti-tumor immune response in the body and has broad application prospects in tumor treatment. Based on the above situation, this study innovatively proposes to combine immune-targeted therapy with oncolytic HSV virus for the neoadjuvant treatment of resectable HNSCC. The aim is to fully utilize the synergistic effect of the two treatment modalities, minimize the tumor volume to the greatest extent, reduce the tumor stage, improve the surgical resection rate and radicality, decrease the risks of postoperative recurrence and metastasis, and ultimately improve the quality of life and prognosis of patients. By conducting this prospective, single-arm clinical study, it is expected to provide a more efficient, safe, and innovative treatment strategy and clinical practice basis for the treatment of resectable HNSCC.

PD-1/PD-L1 inhibitors have achieved surprising results in lung cancer treatment and have been approved by the FDA for the treatment of different types of lung cancer. Their overall toxicity is lower than that of standard chemotherapy, but a number of immune-related adverse events have been reported clinically. Liver injury is one of the leading causes of death from adverse events due to PD-1/PD-L1 inhibitors. The occurrence of immune-related liver damage has an important impact on the tumor treatment and prognosis of patients. Most of the current domestic and international studies focus on the overall description and study of PD-1/PD-L1 antibody-related adverse events, and there is no definitive description of the risk factors for the development of immune-related liver injury in lung cancer patients. The aim of this project is to review the clinical data of lung cancer patients treated with PD-1/PD-L1 inhibitors from 2020.01 to 2024.06, to investigate the risk factors of PD-1/PD-L1 inhibitor-associated liver injury, to construct a prediction model for the occurrence of liver injury, and to take measures to prevent the occurrence of fatal immune liver injury, which is of great significance to the immunotherapy of clinical tumor patients. It is of great significance to the immunotherapy of clinical tumor patients.

This study is to investigate the safety and efficacy of tumor infiltrating lymphocyte (TIL) therapy in patients with advanced solid tumors. Autologous TILs are expanded from tumor resections or biopsies and infused i.v. into the patient after NMA lymphodepletion treatment with hydroxychloroquine(600mg,single-dose) and cyclophosphamide.

Head and neck squamous cell carcinoma (HNSCC) is a common malignant tumor in the world. Due to its special anatomical location, HNSCC affects patients' appearance and physiological functions. Comprehensive treatments such as surgery, radiotherapy, and chemotherapy are often adopted. More than 60% of patients are diagnosed with locally advanced or metastatic diseases, resulting in a low 5-year survival rate. Locally advanced patients have high recurrence and metastasis rates and a poor prognosis. Neoadjuvant therapy before surgery theoretically can improve the possibility of radical surgery and the organ preservation rate. However, except for nasopharyngeal carcinoma, induction chemotherapy has not brought significant survival benefits to HNSCC patients, and new treatment regimens are urgently needed. EGFR is overexpressed in 90% of HNSCC patients. The PD-1/PD-L1 signaling pathway is an important mechanism of tumor escape. Anti-PD-1/PD-L1 monoclonal antibodies have shown good efficacy and high safety in the treatment of malignant tumors. The combination of radiotherapy and immunotherapy can induce an anti-tumor immune response. Low-dose radiotherapy has low toxicity and can reprogram the tumor immune microenvironment. Multiple studies have confirmed the safety and feasibility of its combination with immunotherapy. The previously conducted "Prospective, Single-arm Clinical Study of Low-dose Radiotherapy Plus Tislelizumab Combined with Afatinib for Neoadjuvant Therapy of Resectable Head and Neck Squamous Cell Carcinoma" has demonstrated good safety and efficacy. Based on this, a head-to-head clinical study is planned to compare the efficacy of low-dose radiotherapy combined with targeted therapy and immunotherapy and pure targeted therapy and immunotherapy in patients with resectable HNSCC, explore the clinical benefits of this new treatment measure, and provide new treatment options for HNSCC patients.

Head and Neck Squamous Cell Carcinoma (HNSCC) is one of the most common malignant tumors in the head and neck region. Globally, both its incidence and mortality rates have shown a significant upward trend, posing a serious threat to the life and health of patients. Although surgical resection is the main treatment approach for resectable HNSCC, a considerable number of patients still face a high risk of local recurrence and distant metastasis after surgery, which are the key factors contributing to poor prognosis. In recent years, immune-targeted therapy has emerged in the field of malignant tumor treatment and demonstrated unique treatment advantages and potential. It can specifically act on relevant targets of tumor cells, precisely regulate the body's immune system, and effectively enhance the body's immune response to tumor cells, thereby inhibiting the malignant biological behaviors of tumor cells such as growth, proliferation, and metastasis. Oncolytic herpes simplex virus (HSV) has the ability to specifically replicate within tumor cells and lyse them. Meanwhile, it can also induce a strong anti-tumor immune response in the body and has broad application prospects in tumor treatment. Based on the above situation, this study innovatively proposes to combine immune-targeted therapy with oncolytic HSV virus for the neoadjuvant treatment of resectable HNSCC. The aim is to fully utilize the synergistic effect of the two treatment modalities, minimize the tumor volume to the greatest extent, reduce the tumor stage, improve the surgical resection rate and radicality, decrease the risks of postoperative recurrence and metastasis, and ultimately improve the quality of life and prognosis of patients. By conducting this prospective, single-arm clinical study, it is expected to provide a more efficient, safe, and innovative treatment strategy and clinical practice basis for the treatment of resectable HNSCC.