An enzyme called tryptophan 2,3-dioxygenase or (TDO) enables tumors to avoid detection and rejection by the immune system..Melanoma .Jim Breitfeller

An enzyme called tryptophan 2,3-dioxygenase or (TDO) enables tumors to avoid detection and rejection by the immune system





NEW YORK, NY, May 3, 2012 – The Ludwig Institute for Cancer Research (LICR) announced today the launch of a private biotechnology enterprise, iTeos Therapeutics SA, to develop a novel pre-clinical pipeline of immunomodulators to stimulate the immune system's ability to attack cancer


iTeos co-founder and CEO Michel Detheux, Ph.D. "We now know that combination treatments are likely to be more effective than single therapies in controlling and eventually eliminating cancer. iTeos will pursue this approach by combining existing vaccines with new immunodulatory compounds based on research that has just emerged from the Ludwig Institute."

Cancer immunotherapy

— leveraging the body’s own immune system to attack and destroy tumors — is emerging as a promising method for cancer treatment. Clinical testing of several immunotherapeutic approaches has shown variable success. Tumors often develop survival mechanisms to prevent the attack from the immune system. Researchers are now looking to evaluate the mechanisms that enable these tumors to escape detection by the immune system.

Previously, Brussels scientists from LICR and the de Duve Institute at the Université catholique de Louvain (UCL) studied one enzyme that proved to do just that. It is known as indoleamine 2,3 dioxygenase or IDO1 for short. IDO1 is expressed in many cancers, including prostate, colon, pancreas and cervical tumors. IDO1 blocks the immune system’s ability to reject those tumors, by depriving immune cells of tryptophan. Tryptophan is one of the essential amino acids for the body.

Tryptophan is an amino acid needed for normal growth in infants and for nitrogen balance in adults. It is an essential amino acid, which means your body cannot produce it -- you must get it from your diet.

Tryptophan can be found in:

• Cheese
•Chicken
• Eggs
• Fish
• Milk
• Nuts
• Peanut butter
• Peanuts
• Pumpkin seeds
• Sesame seeds
• Soy
• Tofu
• Turkey
Scientists from the Ludwig Institute for Cancer Research (LICR) in Brussels identified a new target for cancer therapy, an enzyme which prevents the immune system from recognizing and destroying certain types of tumors. Called tryptophan 2,3-dioxygenase or TDO, the enzyme works by depriving immune cells of tryptophan, an amino acid essential to their activity. TDO is produced by a significant number of human tumors including melanomas.

The Ludwig Institute is now applying this knowledge and now is investigating inhibitors of these two enzymes (IDO and TDO).

“Little is known about the TDO enzyme and its ability to trick the immune system and prevent it from destroying deadly tumors” said study lead investigator, Benoit J. Van den Eynde, M.D., Ph.D., Brussels Branch Director at LICR.

The (Belgium) team of scientists then developed an active compound to inhibit TDO enzymatic activity. “Our study showed quite beautifully that the TDO inhibitor restored the ability of mice to reject tumors despite the presence of TDO in tumor cells,” said Dr. Van den Eynde

Cancer research is like analyzing an onion; you pull one layer off at a time and discover another layer of suppression from the tumor’s microenvironment. We are forever gaining knowledge about the immune system. The CURE will come from Combinatorial Therapy!!!

“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

 

Lloyd J. Old, Champion of Using Cells to Fight Cancer, Dies at 78..Melanoma..Jim Breitfeller

Lloyd J. Old, Champion of Using Cells to Fight Cancer, Dies at 78

My theory on how the immune system works on Melanoma had it's starts with papers from Dr. Lloyd Old.

Lloyd J. Old, Champion of Using Cells to Fight Cancer




“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

The Perfect Storm..Therapeutic use of Anti-CTLA-4 Blockage and IL-2 to enhance T-cell responses in vivo

The Perfect Storm..Therapeutic use of Anti-CTLA-4 Blockage and IL-2 to enhance T-cell responses in vivo
Dr. Cassian Yee
Fred Hutchinson Cancer Research Center
Clinical Research
Program in Immunology
Member Appointed: 2009
University of Washington School of Medicine Medicine

Oncology

Associate ProfessorAppointed: 2004
Fred Hutchinson Cancer Research Center
Immune Monitoring Laboratory
Director Appointed: 2003


In my studies, I contacted Dr. Cassian Yee about what I think would revolutionize Melanoma Treatment. Dr. Yee is noted for one of the first Scientists to harness the Immune system to fight Melanoma (2008).

"In what could be a breakthrough in cancer therapy, researchers report in The New England Journal of Medicine today that they succeeded in bolstering a patient's immune system enough to wipe out late-stage malignant tumors on its own. The scientists say the successful experiment could pave the way for new treatments of advanced cancer that spare patients the side effects of chemotherapy, which kills healthy as well as malignant cells."

Source: http://www.scientificamerican.com/article.cfm?id=patient-heal-thyself-body



Dear James,
i have not gone over in detail the information you sent, but i and think others will agree that anti-CTLA4 augments / lowers the threshold for a productive anti-tumor response once that is initiated in some form ('spark'). the role of aCTLA4 and Tregs is still not entirely worked out. I am glad that this has worked out well for you and with the emergence of immunotherapy in general as a treatment modality, with studies coming from Drs. Wolchok, Allison and others, we all hope that the
'Message keeps getting clearer'

Best
Cassian Yee


As you can see by the reply, I think we are onto something big.

I don’t want to waste your time but I think this issue is of the utmost importance. Your Ipilimumab is the major factor in keeping the CD4+ T-cells activated, but it can’t do it alone.



"You need the tumor specific antigens, (The Keys), you need the (Spark Plug) Anti-CTLA-4 and you need the (Gas) IL-2. Without these three key components your car won’t run." ~jimmy B~



As a patient/survivor/researcher of stage IV Melanoma I have scientifically accounted for why my therapy has worked. Above are supporting documents and also a paper (draft) I have written that describes my treatment journey. Please, take time out of you busy schedule and take a look these documents. Bristol Meyer Squibb holds a very promising drug, and when administered in the correct timing and dose, can jumpstart the (Car) The Immune system.

I think they are making great strides in the fight against Melanoma

We need to put it into practice.


“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

Unleashing the Immune System to Destroy Melanoma..Jim Breitfeller

Applying dosing schedules to the clinical protocols of combinatorial therapy, we can optimize the clinical outcome 4-14-2010




The Making of an Immune Response using Anti-CTLA-4 Blockade with Interluekin 2

There is one missing link in all of this. The "DANGER SIGNAL"

How do we generate the Danger Signal so our immune system knows that there are foreign invaders (Melanoma Cancer cells)are present? I have been researching this for quite some time now. I call it the "Missing Link". Bristol Myer Squibb thinks that their Ipilimumab can be used as a monotherapy, but they are mistaken. They want you to believe that their drug is doing all the work but behind the sences there is real Biochemistry taking place. Interluekin-2 is one of the most important players in this Orchestra.

In the next couple of weeks I will elaborate on my theory of the Danger Signal and reveal the pieces of the puzzle that i have discovered in my research.

But for now, let the light shine on Ipilimumab, (anti-CTLA-4 blockade) from Bristol Myer Squibb


“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

Inherent Complexities in Melanoma Research..Jim Breitfeller

Inherent Complexities in Melanoma Research

NCI Conference Highlights Promising Advances in Immunotherapy
EASTMAN, PEGGY

Oncology Times:
25 October 2008 - Volume 30 - Issue 20 - p 32-35


Still challenging researchers and slowing progress in the field of cancer immunology and immunotherapy are the inherent complexities of immunity, said other speakers at the meeting.
Regulation of T-cell responses is a lot more complex than we had initially thought, noted James P. Allison, PhD, Director of the Ludwig Center of Cancer Immunotherapy and Chairman of the Immunology Program at Memorial Sloan-Kettering Cancer Center.


Dr. Allison said that one reason there have not been more successful clinical strategies to mobilize the immune system to attack cancer cells is that until recently not enough attention has been paid to the multiple inhibitory mechanisms that serve to shape the immune response and minimize harm to normal tissues.

These mechanisms, he said, are a collective obstacle that can frustrate generation of effective anti-tumor responses.
His research has shown that the prototype of these inhibitory pathways is CTLA4, which limits T-cell proliferation. We have shown that blockade of CTLA4 can greatly enhance anti-tumor responses in a number of experimental tumors in mice, he said, noting that the CTLA4 blocker ipilimumab is now being developed by Medarex, Inc., and Bristol-Myers Squibb.

The results of clinical trials in more than 3,500 patients [for ipilimumab] have demonstrated objective, durable responses in a subset of melanoma, renal, ovarian, and prostate cancer patients. Thus for the first time we have objective responders, which he called exciting.

James C. Yang, MD, Senior Investigator in NCI's Surgery Branch, said that one immunotherapy combination of special clinical interest is ipilimumab plus interleukin-2 (IL-2). Dr. Yang, who chaired a symposium session, noted that in a Phase I/II study of 36 melanoma patients who received dose-escalating ipilimumab with a high-dose bolus of IL-2, the overall response rate was 22%. Long-term follow-up shows that six of the eight responders achieved ongoing complete responses with durations all exceeding four years.


Anti-CTLA4 antibodies have also been tried with other cancers, said Dr. Yang. He added that to extend the role of anti-CTLA4 therapy to a broader array of cancers, it will likely be necessary to combine it with other immunological manipulations, a combination approach which will hopefully boost the host immune response to cancer.


Take Care,

Jimmy B

Immunotheraphy of Melanoma - July 15, 2009 ..audio file Melanoma..Jim Breitfeller

http://www.melanoma.org/upload%5C2214.mp3


Immunotheraphy of Melanoma - July 15, 2009 ..audio file


the latest information on immunotherapies of melanoma. Whether you are newly diagnosed or are years after diagnosis, this program will provide quality information about melanoma. The conference is intended for patients with melanoma or friends or family member so that you have the information you need to understand melanoma from diagnosis, to treatment, to long term follow up.





Speaker: Jedd Wolchok, M.D., Ph.D.



Moderator: Lynn Schuchter, M.D.




After Dr. Wolchok’s presentation, there will be time for live question and answer period.





Take Care,

Jimmy B

MHC Class 1 Complex and Processing and How it relates to the Tcells.Melanoma..Jim Breitfeller

Movie Day!!!!! Yeh!!!!!!








Frontiers of Biomedical Engineering (BENG 100) Professor Saltzman continues his discussion of cell communication in the body, extending the description to the nervous and immune system



Take Care,

Jimmy B

Cancer and the Immune System: The Vital Connection.. Melanoma.. Jim breitfeller

Cancer and the Immune System: The Vital Connection

One thing I learned about being a cancer patient, is that you must understand your disease. This will enable you to make educated life and death decisions. Truly informed patients can play a more active role in decisions about their care, working with their health care providers to find options that match their needs and preferences.

Like I always said, "Homework,Homework and more Homework".

Cancer and the Immune System




Take Care,

Jimmy B

First, how did I get the right antigen to be presented on the Antigen Presenting Cell (APC)? Melanoma..Jim Breitfeller

drI am so excited I could not stay away!!!!!!

So now we know what had transpired with the therapy, we need to know how and why it happened. I will try to decipher and or postulate each step of the therapy.

First, how did I get the right antigen to be presented on the Antigen Presenting Cell (APC)?

There are three types of Antigen Presenting Cells:
• Macrophages
• Dendritic Cells
• B Cells

We will focus our attention on the Dendritic cells (DCs ) because I postulate that these cells played a major roll in help generating an immune response. Induced Dendritic cells go through a developental program call maturation, which transforms them into efficient antigen-presenting cells (APCs) and T-cell activators. They are the most potent of the three APCs.
So what really happened? Well, Dr. Kirkwood started me out on Dacarbazine with PaTrin-2. Dacarbazine is a chemotherapy agent, approved by the FDA for fighting Melanoma. Dacarbazine alkylates and cross-links DNA during the phases of the cell cycle, resulting in disruption of DNA function, causing cell cycle arrest, and apoptosis.17 The only problem is that the Melanoma Cells overexpresses this enzyme called MGMT.
Proteins known as DNA repair enzymes are present in cells to target damaged DNA and reverse the modifications caused by alkylating agents. One such enzyme is methylguanine methyltransferase (MGMT). MGMT directly reverses the chemical modification guanine, one of the four building blocks of DNA, allowing normal replication to take place.

The DNA-repair enzyme MGMT is a key factor in resistance to alkylating agents. This is one reason why the Dacarbazine therapy doesn’t have a very successful response rate. The MGMT enzyme repairs what the dacarbazine cross-links. So, PaTrin-2 was added to the trial. This drug is known to inactivate the MGMT activity. By inactivating the MGMT enzyme, it makes the tumors cells more susceptible to the chemotherapy.

This therapy was able to get the tumors cells to shed some antigenic Protein which I theorize and was used as the presenting antigen. This made the antigen “tumor-specific.”

Base on a paper by Dr. Olivera J.Finn called Cancer Immunology published in the New England Journal of Medicine in June 19, 2008, there are three ways for self antigens to become Tumor Antigens:

1. Mutation
2. over expression
3. Post-translational Modification

I postulate that some failure of the tumor cells to repair the DNA damage cause by the Dacarbazine in the present of PaTrin-2 resulted in a mutation causing the cancer cells to shed an antigenic peptide. But I was still missing a signal or signals to activate my immune system.




I am still here plugging away.



Take Care,

Jimmy B

Characteristics of the Innate Immune ResponseMelanoma ..Jim Breitfeller

The immune system protects against pathogens that penetrate the physical barriers of the skin and mucous membranes lining the digestive, respiratory, and reproductive tracts. It is subdivided into the innate and the adaptive immune systems. These two systems work differently, but collaboratively, to provide a powerful defense against microbial invaders. Increasing evidence suggests that the immune system also plays a role in detecting and eliminating tumor cells, and can be manipulated therapeutically against cancer.

Innate Immunity

Characteristics of the Innate Immune Response

The innate immune system provides a rapid but nonspecific response to the most common foreign pathogens.1 This system, in some form, is present in all animals, and some elements of it have existed for more than 500 to 700 million years.2 Cells of the innate immune system have specialized receptors (eg, Toll-like receptors) that recognize molecular structures or patterns that are characteristic of—and often indispensable parts of—common pathogens.3 As such, they recognize these pathogens immediately, even without having encountered them previously, and can react promptly. Disadvantages of the innate immune system are that it can recognize only a limited number of molecules, has limited ability to recognize viruses once they have entered normal cells, and has no "memory" and therefore cannot provide lasting protective immunity against these molecules.
The innate immune system is often sufficient to protect against the small quantities of common pathogens humans come into contact with on a day-to-day basis.2 When additional "help" is needed, the innate immune system activates and modulates the adaptive immune system.2,3
Cells of the Innate Immune Response

Macrophages.
Macrophages are the "sentinels" of the immune system. Present in large quantities under the skin, in the lungs, and in the tissues surrounding the intestines, these cells are in key positions to detect microbes where they first enter the body.2 The name macrophage means "large eater," and its primary responsibility is to rid the body of debris as well as pathogens, largely but not exclusively via phagocytosis.2,3

In their usual resting state, macrophages sample their environment and serve as "housekeepers," scavenging dead cells, cellular debris, oxidized lipoproteins, and other normal cellular by-products.2,3 When exposed to certain cytokines (eg, interferon gamma) released by other immune cells, such as helper T-cells and natural killer cells, macrophages become primed or activated. The activated macrophage engulfs a pathogen, containing it in a phagosome, which then fuses with a lysosome full of antimicrobial enzymes that destroy the pathogen. After digesting the pathogen, macrophages release various chemicals that increase the flow of blood to the area, trigger capillaries to allow extravasation of blood cells into the affected tissue, stimulate pain signals from nerves in the area, and release cytokines that facilitate communication with other cells in the immune system. As will be described in more detail later, activation also causes the macrophage to upregulate major histocompatibility complex (MHC) class II receptors on its cell surface, and protein fragments from the invading pathogen are transported to the MHC receptors and presented there for detection by helper T-cells and natural killer cells.2

Macrophages also have cell surface receptors (eg, the Toll-like receptors mentioned above) that enable them to detect molecules (eg, lipopolysaccharide, mannose) that are not normally found on human cells but are common cell wall components in typical pathogens.2 When a macrophage detects such molecules, it becomes "hyperactivated." The macrophage stops proliferating and becomes a virtual killing machine, growing larger and increasing the number of lysosomes and its rate of phagocytosis. It also actively migrates toward a foreign invader, even extending out "feet" to grab it up.2 In this state, macrophages also secrete tumor necrosis factor (TNF) alpha, interleukin (IL) 1, IL-6, and IL-8. These inflammatory cytokines help kill tumor cells and virus-infected cells and activate and summon other cells in the immune system.2,3

Neutrophils.
Neutrophils are highly phagocytic cells. Produced from myeloid precursors and with a lifespan of only 2 to 5 days, these cells circulate through the bloodstream, where they are within easy reach of all cells in the body until they are summoned.2,3

Cytokines and chemokines released by macrophages and mast cells draw neutrophils to the area of infection.2,3 It takes only about 30 minutes for neutrophils to exit the bloodstream and arrive fully activated at the site of an infection.2 Once there, they not only perform phagocytosis, they secrete cytokines (eg, TNF) to summon other immune cells and release various antimicrobial products from granules into the extracellular space.1-3

Mast cells and eosinophils.

These cells lie beneath exposed surfaces of the body (ie, the skin and mucosal barriers) and can survive for years. Their best-known function is to provide a defense against parasites. Mast cells are phagocytic and also contain granules of chemicals, most notably histamine. Eosinophils are poor phagocytes but do carry granules. When a mast cell or eosinophil detects a parasite, it "degranulates," that is, it unloads the chemicals.

Contributing Writer: Lauren Cerruto
Contributing Editor: Bernard A. Fox, PhD
Editor-in-Chief: Jeffrey S. Weber, MD, PhD





Take Care,

Jimmy B

“CD4+ T-regulatory cells: toward therapy for human diseases”Melanoma ..Jim Breitfeller

“CD4+ T-regulatory cells: toward therapy for human diseases”

Thanks to Dr. Megan Levings for taking time out of her busy schedule to email me her research paper on Tregs cells. In my research, I have come to the conclusion that that major barrier to initiating an immune response is over coming the Treg suppression. Remember I said “BLAME IT ON THE TREGS”, well most of the research finding are supporting this piece of the Melanoma Puzzle.

“T-regulatory cells (Tregs) have a fundamental role in the establishment and maintenance of peripheral tolerance. There is now compelling evidence that deficits in the numbers and/or function of different types of Tregs can lead to autoimmunity, allergy, and graft
rejection, whereas an over-abundance of Tregs can inhibit anti-tumor and anti-pathogen immunity.”

“Several different types of Tregs exist in humans, including specialized subsets of CD4+, CD8+, double negative CD3+ CD4-CD8-, alpha /gamma T cells, and natural killer T (NKT) cells. While it is likely that these different types of Tregs work together in a network to maintain immune homeostasis, the majority of current research is focused on defining the normal function of CD4+ Tregs, because these cells mediate dominant, long-lasting, and transferable tolerance in experimental models.”

Levings and colleagues want to harness the Tregs to develop adoptive cellular therapy protocols that would be used in autoimmunity and inflammation. So they wanted to grow the population of Tregs. We on the other hand want to deplete/suppress them, to push the balance towards an immune response.

The Tregs constitute only 1-2 % of the peripheral CD4+ T cells in humans, but is enough to keep the immune system in check. In in-vitro culture conditions, they can expand rapidly when stimulated with an antigen. If you throw Il-2 into the mix, It can increase the cell population by 5-6 fold. This means that the Treg population when activated and Il-2 is secreted or added like (HD IL-2), is now at 10 to 12 % of the population. This can quickly shut down the immune response. So the Takeaway is that one must plan when to introduce the Il-2 to the therapy. So Lets follow nature. Il-2 Is secreted after the CD4+ T cells are activated. THIS MEANS TIMING OF THE IL-2 IS CRUCIAL TO GENERATING A RESPONSE. How Long do we want to hold off before inoculation of the IL-2? We need the growth profiles of each of the CD4+ T cells.

Based on the data gather by Itoh and Colleagues we want to add the Il-2 at the Maximum propagation of the CD8+ T cells. I t has been reported that when the CD8+ T-cells are grown in the presence of Il-2 , they develop in to (CTL) Cytotoxic T Lymphocytes. That is just what we wanted.

This is where Itoh and Colleagues come in:

In 1988, a paper was published “Autologous Tumor Specific Cytotoxic Lymphocytes in the Infiltrate of Human Metastatic Melanomas Activation by Interleukin 2 and Autologous Tumor Cells, and Involvement of the T Cell Receptor “ by Itoh and Colleagues. In their studies, they propagated (TILs) Tumor infiltrate lymphocytes cells from 12 Metastatic Melanoma patients. They preformed kinetic growth studies in IL-2 and even broke it down three Surface markers (CD3, CD4 and CD8).

The results are as follows:
The Total average maximum propagation was 43 days. (N=12)
The average maximum propagation for (lung, Axilla) was 40 days (n=3)

The average maximum propagation for (CD3) was 78 +/- 11 days (n=12)

The average maximum propagation for (CD4) was 33 +/- 10 days (n=12)
The average maximum propagation for CD4 (lung, Axilla) was 26 days (n=3)

The average maximum propagation for (CD8) was 49 +/- 17 days (n=12)
The average maximum propagation for CD8 (lung, Axilla) was 57 days (n=3)

Base on the above data, it would take about 49 days for my activated CD8+ T cells to reach maximum propagation. Then add the IL-2.

The Orchestration of an Inmmune Response Unrehearsed

Source: All Quotes are excerpts from Dr. Megan Levings’s Paper

So now if you put a clinical trial together and follow the timelines,

So now lets see My actual timeline.


They Always said Timing is Everything!!!!!


Take Care,

Jimmy B

Remember I said this could be the "YEAR OF THE CURE" Melanoma .. Jim Breitfeller

Researchers reveal how immune cells can be harnessed to target melanoma.

April 10th, 2009

Researchers at the Babraham Institute and the University of Catanzaro "Magna Graecia", Italy, co-ordinating an international network of scientists and clinicians from Europe, the USA and Japan, have identified new mechanisms through which the immune system recognises and responds to tumours like melanomas. This discovery may offer therapeutic approaches for tackling metastatic melanoma, an aggressive form of skin cancer responsible for around 2,000 deaths in the UK each year.

These exciting new findings, published in the online edition of the Journal of Clinical Investigation, reveal how a type of white blood cell - Natural Killer (NK) cells - tackles tumours, characterising for the first time the molecular interactions that lead to melanoma destruction. This has advanced understanding of melanoma recognition by the immune system and has the potential to open up new avenues of research into the prevention of metastasis by harnessing NK cells’ natural immunity.

SOURCE:http://www.physorg.com/news158570124.html



Researchers reveal how immune cells can be harnessed to target melanoma.



TAKE CARE

jIMMY b

The Innate Immune System is able to recognize self-targets and initiate Inflammatory Response Melanoma..Jim Breitfller

Recent advance in autoimmunity research reveals that the innate immune system is able to recognize self-targets and initiate inflammatory response in a similar way as with pathogens. This is what anti-CTLA-4 blockage has done. Accordingly, alterations in cell morphology are recognized by the innate immune system resulting in an acute inflammatory response (Carroll and Holers,2005).

"Our immune system is an impressive piece of biological machinery using
specialized cells and soluble mediators to protect us from foreign substances such as bacteria, viruses and cancer cells. The immune system is historically divided into two parts, the innate and the adaptive immune systems. Although working together for effective protection these two systems differ from each other in many respects. The innate immune response has componentsrecognizing characteristic features that are common within groups of microbes and cannot distinguish the fine differences between foreign substances. The principal components of innate immunity are physical and chemical barriers, phagocytic cells, blood proteins and cytokines which all react to repeated infections in essentially the same way in which they first responded. The defining characteristics of adaptive or specific immunity are exquisite specificity and the ability to remember and respond more vigorously
to repeated exposures to the same pathogen. The key components of
the adaptive system are B- and T lymphocytes, which can differentiate to
effector or memory cells after stimulation by foreign molecules known as
antigens (Ags)."

Source: Digital Comprehensive Summaries of Uppsala Dissertations
from the Faculty of Medicine 189

Early Immunostimulatory Effects of IgE- and IgG Antibodies

author FREDRIK HJELM

With this in mind, I had an Innate immune response when the CTLA-4 engage the B7 receptor. The response was an inflamatory response on day 15.

Base on the Innate immune response froma natural antibody. It takes about two week to generate a response.This response I posulate as the danger signal needed for T-cells to begin their frontal attack on the foreign invaders (The Cancer Cells).

I am in contact with Kirkwood and Medarex trying to convince them of my theory. I has been a hard sell.

response:Fine theory but just theory that has never been tested in relevant clinical setting…





Jimmy B

Are you ready to take a course at Univerisity of Cambridge in London??Melanoma..Jim Breitfeller

Well while I was on my way to the candy store, I jumped the cyber plane to London. The concord just would not do.

Immunology Teachings:

This site contains material which was prepared for a course in Pathology, which was delivered to bioscience, veterinary and medical students.

I believe we are all medical students here. So, Lets begin.

The Immune System: Organs and Cells (lecture 6)
B cells and Antibodies (lecture 7)
The Major Histocompatibility Complex (lecture 8)
T cells (lecture 9)
Cell Interactions: cytokines (lecture 10)
The Complement System (lecture 11)
Tolerance (lecture 12)
Autoimmunity (lecture 13)
Hypersensitivity and Chronic Inflammation (lecture 14)
Transplantation (lecture 15)
Immunity to Infection (lecture 16)

There will be a final at the end worth 50% of your Grade.
Can you say "Back to School"

Immunology PartIB Home Page



Take care

Jimmy B

Cellular Immunotherapy I (Supressive cells in Cancer Patients) Melanoma ..Jim Breitfeller

In my research, I ran across this powerpoint presentation on Cellular Immunotherapy. I gave me a better understanding on what may be happening to Us cancer Patients.

It is from Tumor Genetics, Clinic I Internal Medicine
Center for Molecular Medicine Cologne Germany.

Please take time to Review it.
Source:http://www.zmmk.uni-koeln.de/content/seminare/lmm_08/common/lecture_cellular_immunotherapy_I.pdf

Cellular Immunotherapy I

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Jimmy B

EDITORIAL CTLA-4 Blockade: Unveiling Immune Regulation Melanoma ..Jim Breitfeller

Originally published as JCO Early Release 10.1200/JCO.2005.09.923 on December 21 2004

CTLA-4 Blockade: Unveiling Immune Regulation

Glenn Dranoff

Department of Medical Oncology, Dana-Farber Cancer Institute; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA

To maintain tissue homeostasis under the duress of infection or injury, the immune system is endowed with a diverse repertoire of soluble and cellular effectors. The innate response, composed of granulocytes, macrophages, dendritic cells, natural killer cells, and complement, is rapidly triggered into action, detecting tissue disturbance through a set of germline-encoded pattern recognition receptors. The adaptive reaction, consisting of antibody-producing B cells and T lymphocytes, is slower to develop, but manifests exquisite specificity and memory. These attributes reflect the requirement for expansion of rare clones harboring somatically rearranged immunoglobulin molecules or T-cell receptors specific for foreign proteins or processed peptides presented by major histocompatibility complex (MHC) molecules. These innate and adaptive responses are carefully orchestrated through soluble and membrane-bound regulators, resulting in the deployment of the most suitable effectors for containing the disorder, while minimizing tissue damage.

Cancer cells similarly provoke immune recognition. In one pathway, innate effectors detect tumor cells directly.1 Natural killer cells and phagocytes express NKG2D molecules that function as receptors for stress-related genes such as MICA and MICB, which are induced as a consequence of cellular transformation. Natural killer cells further scan for the loss of MHC class I molecules on the surface of tumor cells. Dendritic cells use a variety of scavenger receptors to result in the phagocytosis of dying tumor cells.

The adaptive response exploits an indirect pathway, termed cross-priming, to recognize cancer cells.2 In this mechanism, dendritic cells capture tumor cell debris, migrate to regional lymph nodes, and stimulate CD4+ and CD8+ T cells with tumor specificity. Primed T cells thereby acquire the capacity to detect tumor cells directly in a MHC-restricted fashion. CD4+ T cells also contribute to B-cell antibody production.

Antitumor innate and adaptive responses are frequently detected in cancer-bearing hosts, but their biologic importance remains incompletely understood. In some cases, endogenous reactions may function to attenuate disease progression. In multiple cancer types, clinicopathologic studies of early-stage lesions demonstrate that dense intratumoral lymphocyte infiltrates are strongly correlated with reduced frequencies of metastasis and improved patient survival.3 Moreover, in advanced ovarian carcinoma, lymphocyte infiltrates also predict for complete responses and prolonged survival following cytotoxic therapy.4 Consistent with this protective role, several strains of immune-deficient mice display enhanced susceptibility to spontaneous and carcinogen-induced tumors.5 Nonetheless, other compelling data indicate that tumor cells sometimes exploit host responses to promote disease progression.6 Unresolved inflammation may facilitate tumor development by modulating tumor cell growth, apoptosis, invasion, and metastasis. Together, these divergent outcomes underscore a dual role for immunity in carcinogenesis.7

Source:http://jco.ascopubs.org/cgi/content/full/23/4/662
CTLA-4 Blockade: Unveiling Immune Regulation




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Jimmy B

IL-2 Regulates Perforin and Granzyme Gene Expression in CD8+ T Cells Independently ..Melanoma.. Jim Breitfeller

IL-2 Regulates Perforin and Granzyme Gene Expression in CD8+ T Cells Independently of Its Effects on Survival and Proliferation

I know this doesn't sound exciting to you, but it does to me. See I am slowly piecing the puzzle together that made my Sequential Cancer Treatment work so far.If I knew how complex the biochemistry of our immune system was, I would asked for cliff notes.


"Granule-mediated cytotoxicity is one of the major mechanisms used by CD8+ T cells to eliminate harmful or foreign bodies, such as virus-infected cells, tumors, and allografts. After Ag recognition, activated CD8+ T cells release the contents of their cytotoxic granules into the extracellular space, where they are taken up by the target cell, and apoptosis is initiated (1). The cytotoxic granules contain a number of molecules, including the pore-forming protein, perforin, and serine proteases, known as granzymes. Perforin was originally thought to cause cell lysis by penetrating the target cell membrane (2), but recent work favors the theory that perforin functions by enabling the granzymes to escape from endosomes into the cytosol of the target cell (3, 4). Whatever its exact role, perforin is essential, because Ag-specific granule-mediated cytotoxicity is absent in perforin-deficient CD8+ T cells and NK cells (5)."

I think I can do some hand waving but I still need to know how my immune system was able to differentiate between self (the body) and non-self (the tumor). I believe one of the keys may be the T-reg cells.

"These studies suggest that IL-2 itself may either directly or indirectly play an important role in the development and/or function of this unique population of CD25+ suppressor cells."

Source:http://jem.rupress.org/cgi/content/full/188/2/287

CD4+CD25+ Immunoregulatory T Cells Suppress Polyclonal T Cell Activation In Vitro by Inhibiting Interleukin 2 Production By Angela M. Thornton and Ethan M. Shevach



"Regulatory T cells (sometimes known as suppressor T cells) are a specialized subpopulation of T cells that act to suppress activation of the immune system and thereby maintain immune system homeostasis and tolerance to self-antigens. The existence of a dedicated population of suppressive T cells was the subject of significant controversy among immunologists for many years. However, recent advances in the molecular characterization of this cell population have firmly established their existence and their critical role in the vertebrate immune system. Interest in regulatory T cells has been heightened by evidence from experimental mouse models demonstrating that the immunosuppressive potential of these cells can be harnessed therapeutically to treat autoimmune diseases and facilitate transplantation tolerance or specifically eliminated to potentiate cancer immunotherapy.

T regulatory cell populations

T regulatory cells are a component of the immune system that suppress immune responses of other cells. This is an important "self-check" built into the immune system so that responses do not go haywire. Regulatory T cells come in many forms, including those that express the CD8 transmembrane glycoprotein (CD8+ T cells), those that express CD4, CD25 and Foxp3 (CD4+CD25+ regulatory T cells or "Tregs") and other T cell types that have suppressive function. These cells are involved in closing down immune responses after they have successfully tackled invading organisms, and also in keeping in check immune responses that may potentially attack one's own tissues (autoimmunity).

CD4+Foxp3+ regulatory T cells have been referred to as "naturally-occurring" regulatory T cells to distinguish them from "suppressor" T cell populations that are generated in vitro. The regulatory T cell field is further complicated by reports of additional suppressive T cell populations, including Tr1, CD8+CD28-, and Qa-1 restricted T cells. However the contribution of these populations to self-tolerance and immune homeostasis is less well defined."

Source:Wikipedia

Back to the books

Next Slide Please!!!!!!! Melanoma Jim Breitfeller

BobbyO L, This Slide for You!!!!!!


Follow the "YELLOW BRICK ROAD!!!!!"


Cell-mediated immunity is an immune response that does not involve antibodies or complement but rather involves the activation of macrophages, natural killer cells (NK), antigen-specific cytotoxic T-lymphocytes (CTL), and the release of various cytokines in response to an antigen. Historically, the immune system was separated into two branches: humoral immunity, for which the protective function of immunization could be found in the humor (cell-free bodily fluid or serum) and cellular immunity, for which the protective function of immunization was associated with cells. CD4 cells or helper T cells provide protection against different pathogens.
Cellular immunity protects the body by:

1. activating antigen-specific cytotoxic T-lymphocytes(CTL)that are able to induce apoptosis in body cells displaying epitopes of foreign antigen on their surface, such as virus-infected cells, cells with intracellular bacteria, and cancer cells displaying tumor antigens;

2. activating macrophages and natural killer cells, enabling them to destroy intracellular pathogens; and

3. stimulating cells to secrete a variety of cytokines that influence the function of other cells involved in adaptive immune responses and innate immune responses.
Cell-mediated immunity is directed primarily at microbes that survive in phagocytes and microbes that infect non-phagocytic cells. It is most effective in removing virus-infected cells, but also participates in defending against fungi, protozoans, cancers, and intracellular bacteria. It also plays a major role in transplant rejection.

Source: Wikipedia

And Who says I study the dictionary?????

Jimmy B

Dr. Polly Matzinger Danger!! Danger!! Melanoma..Jim Breitfeller

Danger signals
"In a 1994 article entitled "Tolerance, Danger and the Extended Family", Matzinger went several steps further by laying out the idea that antigen-presenting cells respond to "danger signals" - most notably from cells undergoing injury, or stress or "bad cell death" (as opposed to apoptosis, controlled cell death). The alarm signals released by these cells let the immune system know that there is a problem requiring an immune response. She argued that T-cells and the immune response they orchestrate occurs not because of a neonatal definition of "self", as in the previous model, nor because of ancient definitions of pathogens, as in Janeway's argument, but due to a dynamic and constantly-updated response to danger as defined by cellular damage."


The Danger Model

The self-non-self model, the predominant model in immunology since the 1950s, began to encounter problems in the late 1980s when immunologists began to recognize that T-cells depend on other cells to pick up and then present the things to which they will respond — and that the T-cell response depends on whether the other cell (known as antigen-presenting cells) is sending activation signals to the T-cells.

In 1989, drawing on the ideas of Thomas Kuhn, Charles Janeway proposed that the old immunological paradigm had reached the limits of its usefulness--or, as he described it, the asymptote of the increase in knowledge which it had brought. Janeway argued that the innate immune system was the real gatekeeper of whether the immune system responded or did not respond. He also argued that the innate immune system used ancient pattern-recognition receptors to make these decisions - recognizing a pathogen by its unchanging characteristics.

Source:Wikipedia

Part of my Research

Jimmy B