The Missing Link in T-cell activation using a Vaccine, "The Danger Signal" may be due to an enzyme called IDO

The Missing Link in T-cell activation using a Vaccine, "The Danger Signal" may be due to an enzyme called IDO

As I research why some patients respond to therapies i.e. vaccination and other immunotherapy and others don’t, I ask WHY? In my quest to get the answer or answers, I came across a paper called “Marked Differences in Human Melanoma Antigen-Specific T Cell Responsiveness after Vaccination Using a Functional Microarray”.

Daniel S. Chen1,2#, Yoav Soen3#, Tor B. Stuge4, Peter P. Lee4, Jeffrey S. Weber5, Patrick O. Brown2,3, Mark M. Davis2,6* 1 Department of Internal Medicine/Division of Oncology, Stanford University, Stanford, California, United States of America, 2 Howard Hughes Medical Institute, Stanford University, Stanford, California, United States of America, 3 Department of Biochemistry, Stanford University, Stanford, California, United States of America, 4 Department of Medicine, Stanford University, Stanford, California, United States of America, 5 Norris Cancer Center, University of Southern California, Los Angeles, California, United States of America, 6 Department of Microbiology and Immunology, Stanford University, Stanford, California, United States of America

This is what I was looking for! It may hold the answer or could possibly point me in the right direction. In the paper I came across a diagram that peaked my interest. It was a comparison between responders and non-responders.

We concluded from these studies that IL-1 and perhaps IL-6 play a critical role in the differentiation and expansion of Th17 cells. Yoshihiro Miyahara et al

 

IL-6 controls Th17 immunity by inhibiting the conversion of naive CD4⁺ T cells into Foxp3⁺ regulatory T cells.

Using in vitro and in vivo approaches, we determined that under neutral conditions, simultaneous activation of Tregs and naive CD4⁺ conventional T cells in the presence of APCs resulted in conversion of Tregs into IL-17–producing cells, and endogenous IL-1β was mandatory in this process according to Vassiliki A. Boussiotis et al. “IL-1β–Mediated Signals Preferentially Drive Conversion of Regulatory T Cells but Not Conventional T Cells into IL-17–Producing Cells”

IL-6 protects CD4 T cells from cell death but also inhibits the suppressive effect of T regs.

“Thus, the addition of IL-6 to the tumor microenvironment skews the balance toward Th17 cells in a murine model of pancreatic cancer. The delayed tumor growth and improved survival suggests that induction of Th17 in the tumor microenvironment produces an antitumor effect.” David C. Linehan  et al

They were looking at the cytokines secreted after the vaccine was given. When I saw what the cytokines were, I knew I was on the right track. These cytokines help in the differentiation of the CD4+ T-cells. What a find!!

Naïve CD4 T cells in the presence of   TGF-b and IL-2 and others differentiate into Tregs.

TGF-b accelerates the CTLA-4 expression by stimulated CD4+ CD25- T-cells

TGF-b requires CTLA-4 early after T-cell activation to induce FoxP expression generating CD4+ CD25+ Treg  Regulatory cells.

The Th-17 cells produce IL-17. .IL-17 induces the production of many other cytokines (such as IL-6, G-CSF, GM-CSF, IL-1β, TGF-β, TNF-α)

 

So what was the non-responder missing, IL-6.  With the missing IL-6, they weren’t able to produce Th-17 that secreted IL-17.

While TGF-β is a critical differentiation factor for Treg cells, IL6 completely inhibits the generation of Treg cells induced by TGF-β. Instead, IL6 and TGF-β together induce the differentiation of pathogenic Th17 cells. With IL-6 missing in the microenvironment, Treg Cells flourish.

If the CD4 + T cells differentiate into TH2 cells that produce IL-4, the other cells inhibited to produce IL-6. IL-4 was found to inhibit TNF-α and IL-1β by activated monocytes almost 100 %. The Secretion of IL-6 was decreased by approximately 80 % in the presences of IL-4 Cytokine. TE Velde et al 1990

 They were missing “The Danger Signal”.

Friendly inflammation “The Danger Signal”

Most of the time you have no notion of the microbial life-and-death struggle being waged within your body. At other times, though, you are acutely aware of the exact location of the battleground, thanks to the unmistakable signs of inflammation — heat, pain, redness, and swelling. Inflammation, the buildup of fluid and cells at the point of infection/cancer, is put into motion by cytokines — proteins that are released into the blood by the innate immune system when it encounters germs. Cytokines function like police dispatchers. They signal there's a problem, which activates the immune system's highway patrol force: the circulating lymphocytes of the adaptive immune system. These lymphocytes cruise the highways of the blood vessels and lymphatic system. In response to the chemical signal from the cytokines, increased blood flow rushes these circulating cells to the trouble spot.

 “The CD8+ T-cell-mediated Immune Response to Eradicate the Tumors”

 “Three major events must occur to induce CD8+ T cell–mediated, tumor-protective immunity against syngeneic melanoma. First, the T-cell receptor must be triggered by a (or multiple) self antigen–derived peptide MHC class I complex . Therefore, this event depends entirely on appropriate antigen presentation, which is most efficiently provided by mature dendritic cells. Peripherally tolerant or “ignorant” self-reactive T-cell clones, once properly activated, may serve as tumor-specific effector T cells .Second, simultaneously with T-cell receptor triggering, a distinct second costimulatory signal must be delivered, mediated by IL-2, B7-1, or B7-2, which engage IL-2 receptors and CD28 on the surface of the T cell, respectively. A source of these cofactors for effective CD8+ T-cell stimulation can be provided by CD4+ T cells that release critical amounts of IL-2, or by mature dendritic cells that display an increased level of B7-1/B7-2 costimulatory molecules on their cell surfaces. Third, inflammatory cytokines, including IL-1, IL-6, IL-12, IL-17 and IFN-γ provide a third signal that acts directly on T cells, referred to as the “danger signal”. This signal was found to optimally activate TH1 differentiation and lead to clonal expansion of T cells.

 

 

 

The responder was able to produce inflammatory cytokines, including IL-1, IL-6, IL-12, IL-17 and IFN-γ provides a third signal that acts directly on T cells, referred to as the “danger signal”. This signal was found to optimally activate TH1 differentiation and lead to clonal expansion of T cells and invoke a robust immune response to the Melanoma Cancer.

 

 

Conclusion:  Based on my observation, the cytokine that ties this “Danger Signal” to the immune system is IL-6.

• IL-6 protects CD4 T cells from cell death but also inhibits the suppressive effect of Tregs.
• IL-6 controls Th17 immunity by inhibiting the conversion of naive CD4⁺ T cells into Foxp3⁺ regulatory T cells.

So what is causing the lack of IL-6 in the non-responders? The IDO enzyme. This enzyme catalyzes the degradation of the essential amino acid L-tryptophan to N-formylkynurenine.

IDO enzyme degrades tryptophan and through the GCN2 kinase pathway inhibits the transcription of IL-6. Without the transcription of IL-6, the IL-6 cytokine cannot be produced leading to the T-cell differentialtion toward the T Regulatory cell instead of the TH17 phenotype.

My guess is the tumor induced enzyme called IDO may the Missing Link to intiating an immune response.IDO produced by Tumor cells significantly inhibited interleukin (IL-2) expression and proliferative response in T-cells and increased apoptosis (death) of T-cells. Tryptophan depletion is known to halt cell cycle progression by triggering the antiproliferative GCN2 pathway in lymphocytes.

Also, IDO is upregulated in antigen-presenting dendritic cells (DC) by autocrine IFN-γ released as a result of T_reg cell–induced CTLA-4/B7-dependent cell-cell signaling.

It is well established that IDO expression by APCs or tumors can inhibit immune responses.

Tryptophan depletion by IDO-expressing tumors is a common mechanism of immune evasion inducing regulatory T cells and inhibiting effector T cells.

So adding IDO inhibitor to a combinatorial therapy like Yervoy for melanoma cancer should see a synergist response.

 

 

 

 

Bristol Myer Squibb and Incyte Corporation are following this Science along
Newlink.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.” ~Charles Darwin~

Take Care,

Jimmy B

How to integrate immunotherapies into treatment timelines? Timing is everything! Melanoma..Jim Breitfeller

Dr. Gomella,

I want to thank you for sharing your thoughts on immunotherapy in the article in “High Points and Hurdles: Immunotherapy Moves Forward” online at OncLive.

As a patient/survivor/researcher of stage IV melanoma I know first hand of the importance of integrating immunotherapy into a patient’s treatment. Timing of the therapy is everything, along with the patient’s tumor burden and stage.

In the early phase of cancer, the tumor cells are trying to establish a foothold in a foreign land. They do this by recruiting Tregs with cytokines (Il-10, TFG-b etc.) along with chemoattractants and suppressive cells.

Two of the first arrivals are Tregs along with IL-10. In the early phase of cancer, it has been discovered that the patient’s Tregs are elevated along with IL-10 concentration.

So when the macrophages and immune cells arrive at the tumor’s microenvironment, they encounter suppressive conditions allowing the tumor to continue with growth and progress. The elevated IL-10, IL-4 concentration polarizes the monocyte to the M2, and the T-cells to the Th2 phenotypes and shutting down the immune response.

The macrophage also secretes some chemokines (CCL17, CCL22& CCL18). These chemokines attract other cells that have the cell surface chemokine receptors such as CCR4.


Treg cell migration to Melanoma tumors is mediated by CCL22 released by cancer cells and tumor-associated macrophages. This cytokine plays a role in the trafficking of activated/effector T-lymphocytes to inflammatory sites and other aspects of activated T-lymphocyte physiology. Chemotactic for monocytes, dendritic cells and natural killer cells. Mild chemoattractant for primary activated T-lymphocytes and a potent chemoattractant for chronically activated T-lymphocytes but has no chemoattractant activity for neutrophils, eosinophils, and resting T-lymphocytes This attraction is the beginning of the suprresiveness of the the tumor’s microenviroment.

TAM exert strong immune suppressive activity, not only by producing IL-10 but also by the secretion of chemokines (e.g., CCL17 and CCL22), which preferentially attract T cell subsets devoid of cytotoxic functions such as Treg and Th2.


IL-10 promotes the development of a type 2 cytokine pattern by inhibiting the IFN-γ production of T lymphocytes particularly via the suppression of IL-12 synthesis in accessory cells.

IL-10 suppresses many functions of (NK) cells and T cells, primarily by preventing APCs from producing proinflammatory cytokines

So how can we integrate immunotherapies into treatment timelines to generate the wanted immune response toward the cancer?

1. First, you need to evaluate the cancer patient and establish their stage.
2. Second, check the tumor’s genetic code for mutations.


3. Third, evaluate the patient’s overall health and the ability to go through the therapy
   
   Here is a generic graphic on how to activate an innate and adaptive response.

1) You need to generate tumor-associated Antigens


2) You need to generate “The Danger Signal” (proinflammatory cytokines secreted, IL-1, IL-6, IL-12, TNF-alpha, Nitric Oxide, PGE2)

3) Block the Suppressive factors that inhibit T-cell activation (Anti-CTLA-4, Anti-PD-1, Anti IL-10r) IL-10 suppresses many functions of (NK) cells and T cells, primarily by preventing APCs from producing proinflammatory cytokines, “The Danger Signal”)

4) Tilt the T-cell Differentiation toward the TH1 phenotype and the Macrophage (TAM), Tumor Associated Macrophage polarization toward the M1 phenotype

5) Alter the tumor’s Microenvironment (addition of Multikine)

6) Produce activated CTLs and Memory T-cells(addition of IL-2)

The Bottom line is we need Sequential Combinatorial Therapy with timing and dosage as the major limiting factors in creating the innate and adaptive immune response.


“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

 ~Charles Darwin~

Take Care,

Jimmy B

Researchers develop new cancer vaccine mobilizing immune cells

Researchers develop new cancer vaccine mobilizing immune cells

(Mainichi Japan) August 18, 2010


Japanese researchers have developed a cancer immunotherapy vaccine that mobilizes two types of immune cells at the same time, providing hope for the development of more effective cancer treatment.

The vaccine, developed by researchers including Takashi Nishimura of Hokkaido University, activates immune system cells called killer T cells and helper T cells at the same time, which is said to boost patients' immunity. The researchers confirmed that the vaccine cleared up cancer in a patient for whom anticancer drugs and radiation therapy had proven ineffective.

"We want to conduct more clinical trials and make decisions on its detailed effectiveness. At the same time we want to conduct research on synthesis processes for more effective vaccines," Nishimura said.

Helper T cells are a type of lymphocyte, a kind of white blood cell in the immune system, that help keep track of antigens, including cancer antigens. They aid the action of killer T cells, which attack cancer cells directly.

Previous vaccines focused on the activity of killer T cells alone, but Nishimura and the other researchers set about making both helper and killer T cells active. They created a vaccine dubbed "H/K-HELP" that artificially bound about 40 amino acids that work against cancer from peptides, which are strings of amino acids.

In clinical tests performed at Hokkaido University Hospital and Kinki University Hospital, the researchers administered the vaccine to a breast cancer patient and a patient whose lung cancer had spread to cause bowel cancer. They found that the cancer cleared up or restrained the focus of the cancer.

The researchers plan to announce their findings at a symposium of the International Congress of Immunology beginning in Kobe on Aug. 22.

Source:http://mdn.mainichi.jp/mdnnews/news/20100818p2a00m0na017000c.html


We are getting closer!!!!!!CURE!!!!!!

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,
Jimmy B

Understanding Cancer Vaccines

Source: http://www.cancer.net/patient/All+About+Cancer/Cancer.Net+Feature+Articles/Treatments,+Tests,+and+Procedures/Understanding+Cancer+Vaccines

I know some of you are doing or are looking into Cancer Vaccines. This may help you.

Understanding Cancer Vaccines

A vaccine helps the body fight disease. Most people are familiar with vaccines for diseases like chicken pox or the flu. Vaccines (sometimes called vaccinations) help train the immune system to recognize and destroy harmful substances, such as bacteria or viruses, before they can cause disease.

There are two types of cancer vaccines: prevention vaccines and treatment vaccines. A prevention vaccine is given to a healthy person to prevent the development of a specific type of cancer. The U.S. Food and Drug Administration (FDA) has approved three vaccines for cancer prevention. Gardasil and Cervarix are two different vaccines that prevent infection with the human papillomavirus (HPV). A long-lasting infection with HPV can cause cervical cancer. (HPV is also thought to cause other types of cancer, but so far, the vaccine is only approved for cervical cancer.) The third approved vaccine prevents infection with the hepatitis B virus (HBV); long-term infection with HBV can lead to the development of liver cancer.

A cancer treatment vaccine is a type of immunotherapy. Immunotherapy, also called biologic therapy, helps the body’s immune system fight the cancer. A treatment vaccine may prevent cancer from coming back, destroy any remaining cancer cells after other types of treatment, or stop cancer cell growth. A cancer vaccine is designed to be specific, which means it is supposed to get rid of the cancerous cells and not the healthy cells. Most vaccines for cancer treatment are still in development and only available through a clinical trial (research study involving people). However, in 2010, the FDA approved sipuleucel-T (Provenge) for men with metastatic prostate cancer. Although it is often called a “vaccine,” it is not like getting a flu shot. Sipuleucel-T is an immunotherapy that is adapted for each individual patient. First, white blood cells are removed from the patient. They are then modified in a laboratory and infused back into the patient to allow the immune system to find and destroy prostate cancer cells. Researchers hope that having such therapy approved spurs the development and eventual approval of additional immunotherapies for cancer.

How a cancer vaccine works

The task of a person’s immune system is to tell the difference between something that is part of the body and a substance that is potentially harmful to the body, such as a virus. This identification is made through antigens, which are substances on the surface of cells that are not normally part of the body. The immune system recognizes the antigens and attacks them, typically eliminating them. Some immune system cells release specialized proteins called antibodies that help destroy the antigens. Other immune system cells may attack antigens directly, without the help of antibodies. The immune system is left with a “memory” that helps it respond to those antigens in the future.

A cancer vaccine takes advantage of the immune system’s response to antigens. Often, cancer cells have specific molecules or more numerous ones that are not present on healthy cells. When injected into a person, these specific molecules act as antigens, which stimulate the immune system to recognize and destroy cancer cells with these antigens. Most cancer vaccines also contain adjuvants, substances that may help improve the immune response.

There are two sources of antigens: those made from a patient’s cells and those from cells or proteins that are developed in a laboratory. A vaccine that is customized for each patient, such as sipuleucel-T, may be more effective because the antigens are specific to the patient’s tumor. However, they are also more expensive. A vaccine made in the laboratory may not be as specific for an individual patient, but are somewhat less expensive and may be easier to make.

Limitations of cancer vaccines

Developing successful cancer treatment vaccines is difficult. Some limitations of cancer vaccines are:

Cancer cells suppress the immune system—this is how the cancer is able to grow and develop in the first place. An adjuvant may help overcome this problem.


The immune system doesn’t always recognize that cancer cells are harmful. Because cancer cells develop from a person’s own healthy cells, they may not “look” harmful to the immune system. Instead of being eliminated, the cancer cells are ignored.


Larger or more advanced tumors are hard to destroy, especially with only a vaccine. This is a reason why cancer vaccines are given in addition to other treatments.


The immune systems of people who are sick may not be able to produce a good immune response. Also, a person’s immune system slows with age, limiting the effectiveness of the vaccine.
Because of these reasons, some researchers think that a cancer treatment vaccine may be more effective in patients with smaller tumors or early-stage cancers.

Vaccines and clinical trials

Several vaccines are being tested in clinical trials. According to the National Cancer Institute (NCI), vaccines for melanoma (both skin and ocular [eye]), leukemia, non-Hodgkin lymphoma, multiple myeloma, brain tumors, bladder cancer, kidney cancer, lung cancer, and pancreatic cancer are being evaluated in clinical trials. Usually, these vaccines are given in addition to other treatment, such as chemotherapy.

Clinical trials are important for learning more about cancer vaccines. Talk with your doctor about the possibility of a cancer vaccine clinical trial. Some questions to ask the doctor include:

What is the vaccine and how does it work?


How is this vaccine made?


How often is the vaccine given?


How long will I need the vaccine?


What are the possible side effects?


Is there another treatment option for this cancer?


Is there anything else I need to know?
More Information

ASCO Expert Corner: HPV Vaccination for Cervical Cancer

Understanding Immunotherapy

Additional Resources

National Cancer Institute: Treating and Preventing Cancer With Vaccines

http://www.cancer.gov/clinicaltrials/learning/cancervaccines

National Cancer Institute: Cancer Vaccine Fact Sheet

http://www.cancer.gov/cancertopics/factsheet/cancervaccine

"Knolwedge is power. The power to understand."


“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,
Jimmy B