Clinical Trial Details
— Status: Recruiting
Administrative data
NCT number |
NCT04438564 |
Other study ID # |
CMUH108-REC1-113 |
Secondary ID |
|
Status |
Recruiting |
Phase |
N/A
|
First received |
|
Last updated |
|
Start date |
May 18, 2020 |
Est. completion date |
July 31, 2023 |
Study information
Verified date |
February 2023 |
Source |
China Medical University Hospital |
Contact |
Hung-Rong NA Yen |
Phone |
04-22053366 |
Email |
hungrongyen[@]gmail.com |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
The immune system is our body's defense mechanism, which helps us to resist foreign pathogens
and cancer cells in the body. However, if the immune system is too weak, too strong, or
unbalanced, it will be susceptible to get bacterial and viral infections, unable to fight
cancer, or cause allergies, autoimmune and rheumatic diseases. At present, there is no good
western medicine to strengthen immunity when the body is insufficient immunity. However,
strong immunity causes autoimmune diseases and need to be treated by steroids and
immunosuppressive agents. These drugs have limited efficacy and often have many side effects.
In the clinical practice of traditional Chinese medicine, tonify qi, supplement blood and
nourish yin are often used to enhance immunity. However, there is no clinical test to
demonstrate the modulation of immune response after traditional Chinese medicine treatment.
In our preliminary study, the investigators identified that the basic immune response of
cancer patients is weaker than healthy people by testing the level of IFN-r (promoting T cell
activity, anti-tumor, anti-viral), TNF-a (promoting B cell proliferation, producing
antibodies, anti-tumor, anti-viral) and IL-2 (regulate the proliferation and
differentiation). Besides, some Chinese herbal extracts can significantly stimulate the
immune response higher than the general average basic immunity of cancer patients. Further,
we will use the stimulatory Chinese medicine extract to administer to cancer patients and
examine the immune response of cancer patients after taking them. Therefore, this test can
provide actual data on the basic immunity of healthy people or cancer patients and the
modulation of immune response by traditional Chinese medicine treatment. This analysis
platform provides patients to select the medicines that can enhance the immune response for
individuals and analyze the changes of the immune response after conditioning with the
candidate Chinese medicines. Therefore, this test could be applied clinically to validate the
immunological regulation of Chinese herbal medicine as well as analyze the immunological
modulation against different cancer by various Chinese herbal medicine.
Description:
Traditional Chinese medicine (TCM) and dendritic cells (DCs) activation/maturation One of the
important approaches to successful cancer immunotherapy is generation of specific T cell
responses by dendritic cells (DCs). DCs are the most potent antigen-presenting cells for
naive T cells, because their high expression of MHC and co-stimulatory molecules. DCs
comprise several subsets, and their roles in the presentation of antigens derived from
pathogens, vaccines and self tissues are now beginning to be elucidated. Immature DCs (iDCs)
resided in periphery have a high ability to endocytose antigens and become to mature DCs
(mDCs) upon a variety of stimuli through Toll-like receptors (TLRs). However, iDCs facilitate
immune tolerance and fully mDCs can promote immune responses. Until now, there are some
studies have demonstrated that TCM could promote the activation status of DC to enhance
immune responses through TLR, which are characterized by increased expression of
co-stimulatory moleculars, MHC class II and several cytokines. Ganoderma lucidum and
Cordyceps sinensis have been widely used in Asian countries to have beneficial effects on
human health. Ganoderma lucidum polysaccharides have been reported to induce DCs maturation
and promote the cytotoxicity of specific CTL. Moreover, Ganoderma lucidum polysaccharides
were able to induce DC activation markers production and cytokines expression through TLR-4
signaling pathway. However, this character about TCM acted as TLR agonists could apply to
develop safe and effective adjuvant in vaccine generation.
Traditional Chinese medicine (TCM) and T cell activation T cells are the master regulators of
adaptive immune responses. Proper T cell responses are essential for the hosts to orchestrate
sufficient adaptive immunity. Classically, the TH1/TH2 hypothesis has served the immunology
community well, particularly in understanding infectious and allergic diseases. Regulatory T
cells (Treg) are suppressive T cells that regulate effector T cell immunity. Nevertheless,
this model dose not fit all systems when it comes to the study of organ-specific autoimmune
diseases. It has also become more and more clear, however, that many complicated pathological
situations cannot be simply explained by the TH1 cell and TH2 cell paradigm. Efforts to
resolve these issues in recent years have resulted in the discovery of TH17 cells.
T cell immunity is crucial for anti-tumor immunity. Given their importance in immune
responses and diseases, it is important to understand the regulation of T cell immunity. In
immune system, different lineages of immune cells were conventionally distinguished by the
morphology and expression of a cluster of differentiation markers on the cell surface. TH1
cells that make IL-2 and IFN-r are important for delayed-type hypersensitivity reactions,
whereas TH2 cells that make IL-4 promote IgE production and allergic reaction. The
differentiation of TH1 and TH2 cells mainly through the induction of distinct transcriptional
programs. Activation of Signal Transducers and Activators of Transcription 1 (STAT1) by IFN-r
and STAT4 by IL-12 drives expression of T-bet for TH1 programming. On the other hand,
activation of STAT6 by IL-4 promotes GATA3 expression in TH2 cells. A revise of the TH1/TH2
hypothesis was proposed until the discovery and IL-23 and IL-17. TH17 cell is a distinct T
helper cell population that plays a crucial role in CD4+ T cell-mediated adaptive immunity.
Commitment to the TH17 pathway requires the presence of both IL-6 and TGF-a during in vitro
culture. These cells, different from the classical TH1 and TH2 cells, do not produce IFN-r or
IL-4 but on the other hand express the IL-23 receptor and IL-21, IL-22, and IL-17F. ROR-rt ,
ROR-rt are also highly expressed in TH17cells and can be induced by TGF-a and IL-6. Our
previous studies showed for the first time an in vivo requirement for STAT3 in TH17 mediated
autoimmunity. In addition, the investigators found that STAT3 is required for the maintenance
of endogenous TH17 cells. In a more recent report, the investigators also found that CD8 T
cells, like their CD4 counterparts TH17, can be skewed toward IL-17 production in vitro and
in vitro.
Manipulating T cell immunity by Chinese herbs is a promising field to explore. Many herbs
were reported to regulate the T cell activation. Tanshinlactone A from Salvia miltiorrhiza
Bunge significantly decreased the IL-2 and IFN-γ gene expression through reduction of MAPK
activation in phytohemagglutinin-activated peripheral blood mononuclear cells. Periplocoside
E (PSE) was shown to dose-dependently inhibit anti-CD3 induced primary T cell proliferation,
activation for IL-2R (CD25) expression, and IFN-γ and IL-2 production at the transcriptional
level by inhibited the activation of ERK and JNK. Furthermore, kurarinol was reported to
increase level of HBV specific CTL by down-regulating peripheral blood HBV specific CTL
surface PD-1 expression of CHB patients.
All of these will support investigators' hypothesis that modulation of dendritic cell and T
cell immunity by Chinese herbs or cytokines may be an applicable intervention to modulate
immunity, for example, to promote anti-tumor immunity against cancer. The successful
completion of the proposed studies will provide a strong support for future development of
anti-cancer immunotherapy by Chinese herbs.
Traditional Chinese herbs as a pharmacologic approach to modulate immunity Cancer
immunotherapy, allergy, and autoimmune diseases are among the chronic illness that accounts
for the death and economic burdens in Taiwan and other modern countries. Diseases such of
Rheumatoid arthritis (RA), SLE, multiple sclerosis, ankylosing spondylitis, vasculitis,
psoriasis and Sjogren's syndrome are common autoimmune diseases that cause not only life-long
discomfort but also disabilities of the patients. Cancer immunotherapy is promising. Many of
autoimmune disease and difficult-to-treat allergies are now found to be associated with IL-17
mediated pathology. However, the current treatment is limited. Recently, targeted therapy
such as Etanercept (trade name Enbrel), a biopharmaceutical that interferes with tumor
necrosis factor (TNF; a soluble inflammatory cytokine), has been developed to treat some of
the autoimmune diseases. However, nhibition of TNF has substantially advanced the treatment
of inflammatory diseases. Because TNF and IL-17 have shared functions, the rationale for
testing IL-17 inhibitors in the clinic is often based on the concept that patients who do not
respond to TNF inhibitors may have an IL-17-driven disease. Autoimmune diseases such of
rheumatoid arthritis and multiple sclerosis are common autoimmune diseases that cause not
only life-long discomfort but also disabilities of the patients. The current treatment for
these autoimmune diseases is limited to analgesia, anti-inflammatory drugs, steroids,
disease-modifying antirheumatic drugs (DMARDs), and immunosuppressants. Recent studies in
mouse models and in humans have identified a key role of IL-17 and TH17 cells in the
pathogenesis of inflammation and autoimmunity as well as in host defense against certain
pathogens.
Meanwhile, there are some studies using Chinese herbs to modulate CD4 TH17 immunity. Compound
extracted from Chinese herbs, such as berberine exhibited potent efficacy inhibiting TH17 in
the EAE model. Triptolide also inhibited collagen-induced arthritis (CIA), a model of
rheumatoid arthritis, through inhibition of CD4 TH17 cells. Periplocoside A was found to
ameliorate EAE by suppressing IL-17 production and inhibited the differentiation of Th17
cells in vitro. Eriocalyxin B was also found to be effective to inhibit TH17 and EAE through
targeting Janus Kinase/Signal Transducer and Activator Of Transcription and Nuclear
factor-kappaB signaling pathways. TCM formula such as Qingkailing injection was found to
ameliorate rat experimental autoimmune uveitis (EAU). Qingkailing injection can alleviate
autoimmune uveitis in rats, inhibit the differentiation toward Th1 and Th17 effector cells
and the relevant cytokines secretion. Pure compound from Daphne odora var. marginata (D.
marginata) was also found to inhibit TH17 and thus exhibit inhibitory effects in CIA model.
One of the landmark study published in Science and Nature Chemical Biology is the example of
halofuginone, an active component of traditional Chinese herb hydrangea root (Dichroa
febrifuga), used to treat malaria for thousands of years. A collaborative research team led
by Dr. Mark Sundrud at the Department of Pathology, Harvard Medical School and Immune Disease
Institute, Boston, MA, has reported that halofuginone halted the progression of experimental
autoimmune encephalomyelitis (EAE) mice and TH17. Importantly, unlike other therapies for
autoimmune diseases, halofuginone does not have the undesirable effect of suppressing the
other immune system.
The investigators have established some platforms for screening Chinese herbs not only for
modulating PD-1/PD-L1, IL-17, but also for detection of dendritic cell and T cell activation
(Immunogen Test Panel).
The hypothesis is that modulation of dendritic cells and T cells by traditional Chinese
medicine may be an applicable intervention to treat some of the immunologic diseases such as
cancer, allergy, and autoimmune diseases. Studies that can fit the niche, understanding the
function and mechanism of Chinese herbs on immune cells and its pathway, will have broad
clinical and immunological significance. The successful completion of the proposed studies
will provide a strong support for a clinical trial of traditional Chinese medicine to treat
patients with immunologic diseases.