IL-21 makes herceptin much more effective by boosting Natural KillerCells

[Lani]

Boosting Killer Cells Might Improve Breast Cancer Drug [Ohio State University]
COLUMBUS, Ohio - Preliminary research suggests that a drug that targets a particular type of breast cancer might be more effective if patients are also given a substance made by the body that stimulates certain immune cells.

The laboratory and animal study suggests that the substance interleukin 21 (IL-21) might improve the effectiveness of the drug Herceptin. The findings suggest that this happens because the IL-21 boosts the cancer-killing activity of immune cells called natural killer (NK) cells, which attack the tumor.

The findings by researchers at the Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute are published in the July 1 issue of The Journal of Immunology. The researchers hope to begin a clinical trial to test the strategy in humans soon.

Herceptin is used to treat HER2-positive breast cancer — about 20 percent of all breast-cancer cases. HER2 breast cancers have a protein called HER2 on the surface of the tumor cells. Herceptin attaches to the HER2 protein and coats the cells.

The findings indicate that IL-21 stimulates NK cells to attack and destroy the Herceptin-coated cells.

"Only 25 to 35 percent of patients with this form of breast cancer respond to Herceptin," says principal investigator William E. Carson, III, associate professor of surgery and associate director for clinical research at the OSU Comprehensive Cancer Center .

"Our results suggest that giving IL-21 along with the Herceptin might increase the patient's immune response to the tumor and perhaps boost the drug's effectiveness."

Many researchers believe that Herceptin works because it stops tumor cells from growing and causes them to self-destruct through a natural process called programmed cell death, explains first author Julie M. Roda, a graduate research associate in Carson 's laboratory.

But, Roda says, "our findings provide new evidence that Herceptin works at least in part by stimulating NK cells activity, and that IL-21 enhances that action."

Carson, Roda and their collaborators chose to study IL-21 because the substance is known to activate NK cells and causes them to release substances that attract other immune cells to a tumor site.

This study's findings came from several experiments. First, the scientists exposed NK cells in Petri dishes to both Herceptin and IL-21. This caused the cells to release three to 10 times more of a substance called interferon gamma than would cells exposed to either agent alone.

Interferon gamma is an immune-system signaling agent that causes the NK cells to become more active. It also increases the activity of other immune cells and forces tumor cells to self-destruct.

The researchers then repeated this experiment in mice. They found that animals given both IL-21 and Herceptin-coated tumor cells had nearly three times more interferon gamma in their blood than did animals injected with either of those items alone.

Still another experiment used mice with HER2-positive tumors. When the animals were treated with both the mouse version of Herceptin and IL-21, the tumors shrunk by nearly half compared to those in mice receiving either agent alone.

Last, to test whether the interferon gamma was important for causing the tumors to shrink, the researchers repeated this experiment using mice that cannot make the substance.

The researchers were surprised to find that when interferon gamma was missing, the mouse drug and IL-21 combination had no effect on the tumors.

"We thought if we took out interferon gamma, the NK cells would still be able to kill the tumor cells," Roda says.

But that didn't happen

"This is very interesting because it suggests that interferon gamma production might be critical to the response to Herceptin, and I believe that we are the first to show this."

Overall, says Carson , "Our results suggest that IL-21 might enhance the effectiveness of Herceptin, and perhaps similar anticancer drugs."


ABSTRACT: Interleukin-21 Enhances NK Cell Activation in Response to Antibody-Coated Targets [Journal of Immunology; Subscribe]
NK cells express an activating FcR (Fc?RIIIa) that mediates Ab-dependent cellular cytotoxicity and the production of immune modulatory cytokines in response to Ab-coated targets. IL-21 has antitumor activity in murine models that depends in part on its ability to promote NK cell cytotoxicity and IFN-? secretion. We hypothesized that the NK cell response to FcR stimulation would be enhanced by the administration of IL-21. Human NK cells cultured with IL-21 and immobilized IgG or human breast cancer cells coated with a therapeutic mAb (trastuzumab) secreted large amounts of IFN-?. Increased secretion of TNF-? and the chemokines IL-8, MIP-1?, and RANTES was also observed under these conditions. NK cell IFN-? production was dependent on distinct signals mediated by the IL-21R and the FcR and was abrogated in STAT1-deficient NK cells. Supernatants derived from NK cells that had been stimulated with IL-21 and mAb-coated breast cancer cells were able to drive the migration of naive and activated T cells in an in vitro chemotaxis assay. IL-21 also enhanced NK cell lytic activity against Ab-coated tumor cells. Coadministration of IL-21 and Ab-coated tumor cells to immunocompetent mice led to synergistic production of IFN-? by NK cells. Furthermore, the administration of IL-21 augmented the effects of an anti-HER2/neu mAb in a murine tumor model, an effect that required IFN-?. These findings demonstrate that IL-21 significantly enhances the NK cell response to Ab-coated targets and suggest that IL-21 would be an effective adjuvant to administer in combination with therapeutic mAbs.

[Tom]

Good reading Lani. Now I wonder if IP-6 would stimulate a similar response if added to Herceptin. I have been using IP-6 as a PI3K inhibitor for Mom. Inositol hexaphosphate (IP-6) also has NK cell stimulating properties as well. It seems to present an interesting question, as IP-6 is available over the counter. It might be something to look into.

Tom

[Barbara2]

I mentioned a similiar trial to my onc one time and he said interleukin is really a nasty drug as far as side effects are concerned. He said I wouldn't want it......

[Lani]

As far as I know interleukins are not available as drugs, with the exception of interleukin2 which has been tried in kidney cance(where it is FDA approved) and AIDS(where it is not)

Interleukins of many kinds are available from a lab supply company called invitrogen for research scientists under the heading cytokines:


Proteins, Peptides, Inhibitors
BioSource offers a wide selection of recombinant proteins for cell culture, as well as peptides and inhibitors for intracellular studies. Recombinant proteins from BioSource are produced and packaged with customer needs in mind. Most proteins are available from 5-10 µg up to 1 mg sizes. Recombinant proteins from BioSource exhibit:
• High biological activity – more results with less protein
• High purity – no interference from other proteins or contaminants
• Freeze/thaw stability – reproducible data from one experiment to the next
Wide Selection of Proteins for Human, Mouse, Rat, and Swine Models:
• Growth factors
• Cytokines
• Chemokines
• Signal transduction
All recombinant proteins from BioSource are thoroughly tested for:
• Biological activity using relevant bioassays
• Freeze thaw stability under normal cell culture conditions
• Structural homogeneity
• Endotoxin levels via the LAL method

Under IL2 used for treatment of patients I found the following:
Interleukin-2 (IL-2, Aldesleukin, Proleukin®)
Carolyn Vachani, RN, MSN, AOCN
The Abramson Cancer Center of the University of Pennsylvania
Posting Date: March 9, 2006
Interleukin-2 is in the class of medications called biologic response modifiers. It is a type of protein called a cytokine that works to increase the production and function of various components of the body's immune system. This protein is normally produced in the body, but in small amounts. By increasing levels of IL-2, the increase in immune system components (specifically T cells and natural killer cells) will mount an attack against any cancer cells.
Facts about interleukin-2
• Interleukin-2 is used to treat patients with renal cell cancer (kidney cancer) and melanoma.
How to take interleukin-2
Interleukin-2 is given in two different ways. It can be given in higher doses into a vein (intravenously) while the patient is monitored in the hospital. It can also be given in a low-dose regimen via a shot placed under the skin (subcutaneous injection). The low-dose regimen is given on an outpatient basis (at home or in the doctor's office). The actual dose is dependent on your body size. Premedication may be given to lower the risk of infusion reactions, like fever, chills, nausea, and low blood pressure.
How long should you take interleukin-2?
This is dependent on the regimen you are receiving and how your body responds to the treatment.
Side effects of interleukin-2
Some of the possible side effects and suggestions for dealing with them include:
Infusion Related Side Effects
The interleukin-2 infusion (the high dose regimen) can cause a reaction that may include low blood pressure, increased heart rate or arrhythmias, shortness of breath, rash, nausea, diarrhea and joint and muscle stiffness. The infusion may be stopped or slowed down if this occurs and medications may be given to stop the reaction. These reactions generally occur within 24 hours of the dose and most often resolve when the medication is stopped Nearly all patients on the high dose regimen will experience flushing of the face and body or skin rash.
Flu-Like Syndrome
This occurs in a majority of patients because of the “revving-up” of the immune system. Flu-like syndrome occurs hours to days after the infusion and is characterized by fever, chills, weakness, muscle and joint aches. Medications such as acetaminophen can be used to manage these symptoms. Try to keep warm with blankets and warm clothes and drink plenty of non-alcoholic fluids. These symptoms tend to lessen over time on low-dose regimens.
Diarrhea
Your doctor or nurse can recommend medication to relieve diarrhea. Also, try eating low-fiber, bland foods, such as white rice and boiled or baked chicken. Avoid raw fruits, vegetables, whole grain breads and cereals, and seeds. Soluble fiber is a type of fiber found in some foods. Soluble fiber absorbs fluid and can help relieve diarrhea. Foods high in soluble fiber include: applesauce, bananas (ripe), canned fruit, orange and grapefruit sections, boiled potatoes, white rice, products made with white flour, oatmeal, cream of rice, cream of wheat and farina. Drink 8-10 glasses of non-alcoholic fluid a day to prevent dehydration.
Rash and Itching
Rash with or without itching may occur. Antihistamines (like diphenhydramine) or topical steroids can be used to control symptoms, if needed. It is important to prevent scratching and breaking of the skin, given the risk for skin infections with lowered white blood cell counts on this therapy. Oatmeal baths can also be used to help with dry, itchy skin.
Low White Blood Cell Count
White blood cells are important for fighting infection. While receiving treatment, you are at a higher risk of getting infections. You should wash your hands frequently, avoid large crowds and people who are sick or have colds. You should let your doctor or nurse know right away if you have a fever (temperature greater than 100.4), sore throat, cough or cold, or a sore that doesn't heal.
Low Platelet Count
Platelets help your blood clot, so when the count is low you are at a higher risk of bleeding. You should not use a razor (an electric razor is fine), and try to avoid any contact sports. Do not take aspirin or ibuprofen products (as these can increase the risk of bleeding). Let your doctor or nurse know if you have any bleeding, including nose bleeds or bleeding gums. If the count becomes too low you may receive a transfusion of platelets.
Low Red Blood Cell Count (Anemia)
Your red blood cells are responsible for carrying oxygen to the tissues in your body. When the red cell count is low, you may feel tired or weak. You should let your doctor or nurse know if you experience any shortness of breath, difficulty breathing, or pain in your chest. If the count gets too low, you may receive a blood transfusion.
Nausea and/or Vomiting
There are many effective drugs that will prevent, eliminate, or lessen the severity of nausea and vomiting if you need them, just ask your doctor which is best for you. In addition, dietary adjustments may help. Avoid things that worsen the symptoms, try antacids like milk of magnesia and calcium tablets like Tums, or have saltines or ginger ale to lessen symptoms. Eat smaller, more frequent meals rather than 3 large meals.
Capillary Leak Syndrome
Capillary leak syndrome is a potentially serious complication in which fluids from the veins and capillaries leak into the tissue outside the bloodstream. This results in low blood pressure and poor blood flow to the internal organs. Capillary leak syndrome is characterized by the presence of 2 or more of the following 3 symptoms: low blood pressure, swelling, and low levels of protein in the blood (hypoalbuminemia). Your doctor will monitor these levels while you are taking interleukin-2. You should notify your doctor immediately if you notice dizziness (especially when changing position), sudden swelling or rapid weight gain, little or no urine output (for 8-12 hours), shortness of breath, difficulty breathing, irregular heart beats, or chest pain. This syndrome generally occurs within about 2 weeks of treatment.
Fatigue
See OncoLink's section on fatigue for helpful tips.
Decrease in Appetite
Interleukin-2 may affect your appetite.

INTERLEUKIN-2 *

• WHAT IS INTERLEUKIN-2?
• WHO SHOULD TAKE INTERLEUKIN-2?
• HOW IS INTERLEUKIN-2 TAKEN?
• WHAT ARE THE SIDE EFFECTS?
• HOW DOES INTERLEUKIN-2 REACT WITH OTHER DRUGS?
• THE BOTTOM LINE

WHAT IS INTERLEUKIN-2?
Interleukin-2 (IL-2) is a protein made by the body. T-helper cells, a kind of white blood cell, produce IL-2 when they are stimulated by an infection. IL-2 makes infection-fighting cells multiply and mature. Patients who use IL-2 have large increases in their T-cell (CD4+ cell) counts. IL-2 is called an immune modulator.

Interleukin-2 has been approved by the FDA for the treatment of some types of cancer, but has not yet been approved for the treatment of HIV disease. Doctors can use it "off label" in patients with HIV (see Fact Sheet 105).
Using gene splicing, the Chiron Corporation developed a way to manufacture IL-2. Their version is called Proleukin®.

WHO SHOULD TAKE INTERLEUKIN-2?
IL-2 stimulates the immune system and increases the number of CD4+ cells. People who start with higher T-cell counts get larger CD4+ cell increases.

Scientists do not agree on the value of the new T-cells generated by IL-2. That is, a T-cell count of 700 after IL-2 therapy might not be as good as a count of 700 before IL-2 therapy. The difference has to do with how many different types of T-cells you have.
Before HIV disease attacks your immune system, you have a full range of T-cells. There are actually millions of different types of T-cells, but an easier way to think about them is like the letters of the alphabet. Each letter is programmed to respond to one particular type of infection. With a healthy immune system, you have many copies of each letter. As your T-cell count goes down, you have fewer copies of each letter, and you might run out of some letters.
Let's say that you need to spell the word "zebra" in order to fight pneumonia. If you have lost all your copies of the letter "z", you can't spell zebra and you might develop pneumonia.
People who take IL-2 seem to get more copies of the "letters" (types of T-cells) that they still have, but don't get back the ones they have lost. They could still have gaps in their immune defenses.
Scientists are still studying the benefits of the CD4+ cells produced by IL-2 therapy. We do not know if these higher T-cell counts mean that people will stay healthier. Two major international studies are underway, studying thousands of patients. The results should be known within the next few years.
Researchers also used IL-2 to try to clear infected "resting" T-cells from the blood. These experiments were not successful. Studies are also examining the possible benefits of IL-2 during treatment interruptions (See Fact Sheet 406).

HOW IS INTERLEUKIN-2 TAKEN?
IL-2 has been given as an intravenous infusion and as twice-daily subcutaneous (below the skin) injections. Early research showed that the largest increases in T-cells occurred when IL-2 was given every day for 5 days, once every 8 weeks. If the T-cell count climbs enough after the first few cycles, future cycles can occur less frequently.

The best dosage of IL-2 has not been determined. The dosage is stated as "millions of international units", or MIU. Some patients taking IL-2 have been followed for six years or more. After initially using IL-2 every 2 months, they increased the time between cycles to as much as 3 years. They still had significantly higher T-cell counts.

WHAT ARE THE SIDE EFFECTS?
Without antiviral treatment, IL-2 can increase HIV viral load up to six times its pre-treatment level. These increases disappear within one month. Combination antiviral medication controls these "spikes" in viral load. You should not use IL-2 unless you are taking antiviral drugs.

When IL-2 is given by intravenous infusion, the most common side effect is called capillary leak syndrome. This causes weight gain, swelling, low blood pressure, and other problems.
At lower doses, people taking IL-2 get flu-like symptoms, including fever, chills and muscle aches. Because IL-2 stimulates the immune system, it can make some immune disorders get worse, including arthritis, psoriasis, and diabetes. It can also reduce the number neutrophils, a particular type of infection-fighting cell, and can cause low levels of thyroid.
When IL-2 is given by subcutaneous injection, the side effects are usually milder than with intravenous infusions. There is the added side effect of irritation where the injection is given. Side effects show up from 2 to 6 hours after injection of IL-2, and disappear quickly after the end of each cycle.
IL-2 can cause mood changes including irritability, insomnia, confusion, or depression. These can continue for several days after IL-2 is stopped.

HOW DOES INTERLEUKIN-2 REACT WITH OTHER DRUGS?
The body naturally produces IL-2. No serious interactions with antiviral medications have been noted. Also, there is no evidence that the body develops resistance to IL-2 when it is given in cycles.

THE BOTTOM LINE
IL-2 stimulates the immune system and can lead to large increases in the number of CD4+ (T-helper) cells. We still don't know if these increases in T-cells help people stay healthy longer.

IL-2 is usually administered in 5-day cycles of 2 subcutaneous injections a day. At first, one cycle is given every 8 weeks. IL-2 causes irritation where the injections are given and flu-like symptoms. These side effects usually start within a few hours of IL-2 injections and disappear after the end of a cycle. Long-term users of IL-2 can increase the time between cycles up to 3 years and still maintain their T-cell counts.
IL-2 has not yet been approved for use in HIV disease.


Interleukins are a group of cytokines that were first seen to be expressed by white blood cells (leukocytes, hence the -leukin) as a means of communication (inter-). The name is sort of a relic though; it has since been found that interleukins are produced by a wide variety of bodily cells. The function of the immune system depends in a large part on interleukins, and rare deficiencies of a number of them have been described, all featuring autoimmune diseases or immune deficiency. interleukins are part of the immune system.
A list of interleukins with function:
• IL-1: secreted by macrophages, induces acute phase reaction
• IL-2: secreted by T cells, stimulates growth and differentiation of T cell response. Can be used in immunotherapy to treat cancer.
• IL-3: secreted by T cells, stimulates bone marrow stem cells.
• IL-4: involved in proliferation of B cells, and the development of T cells and mast cells. Important role in allergic responses.
• IL-5: role in stimulation of B cells, eosinophil production, IgA production
• IL-6: secreted by macrophages, induces acute phase reaction
• IL-7: involved in B, T and NK cell survival, development and homeostasis
• IL-8: Neutrophil chemotaxis
• IL-9: stimulates mast cells
• IL-10: inhibits Th1 cytokine production
• IL-11: acute phase protein production
• IL-12: NK cell stimulation, Th1 cells induction
• IL-13: Stimulates growth and differentiation of B-Cells, inhibits Th1 cells and the production of macrophage inflammatory cytokines
• IL-17: Induces production of inflammatory cytokines
• IL-18: Induces production of Interferon-Gamma (IFNy)

One’s own cells normally make interleukins.

Perhaps your oncologist was referring to a nasty drug called Ontak which fuses a protein from diptheria toxin(yes, really) to IL2. It is used to try to decrease the number of T regulatory cells, but can lead to autoimmune diseases among other thiings:


FDA APPROVES NOVEL TREATMENT FOR RARE FORM OF CANCER
FDA today approved a new biologic treatment for cutaneous t-cell lymphoma, (CTCL), a rare slow-growing form of non-Hodgkin's lymphoma. The new biotechnology product, known as a "fusion protein," is approved to treat certain patients with advanced or recurrent CTCL, when other treatments have not worked.
The product, denileukin diftitox (trade name Ontak) is produced by genetically fusing protein from the diphtheria toxin to interleukin-2 (IL-2), a naturally occurring immune system protein. This stable, fusion protein targets cells with receptors for IL-2 on their surfaces, including malignant cells and some normal lymphocytes, resulting in cell death.
Approximately 60% of patients with CTCL were found to have tumors with these IL-2 receptors and only these patients have been shown to benefit from Ontak.
Approximately 1,000 people in the United States are diagnosed with CTCL each year. It often is a slowly progressive disease, causing itchy, dry skin patches that can develop into tumors in the skin and other organs.
Ontak was tested in a phase 3 clinical trial of 71 patients with advanced CTCL who had failed at least one other treatment, such as interferon, chemotherapy or radiation. In this study, 30% of the patients' tumors were reduced 50% or more, with the response lasting an average of 4 months. Ten percent of the patients achieved a complete clinical remission that lasted an average 9 months. Such complete remissions would not be expected in an untreated group.
Because Ontak also affects normal lymphocytes, which are infection-fighting cells, and because patients with CTCL are prone to infections, patients should be monitored carefully during treatment. Severe infections were reported in 23% of patients in the trial, although it is unclear whether Ontak was the cause. Other side-effects related to the intravenous infusion of Ontak include allergic reactions, flu-like symptoms and fluid retention that may lead to other complications.
FDA approved Ontak under its accelerated approval regulations that allow sponsors to demonstrate a product's effectiveness for serious and life-threatening illnesses using surrogate end-points, such as tumor reduction, provided that the end-points are likely indicators of clinical benefit. As part of the accelerated approval, the sponsor of Ontak has committed to conducting a placebo-controlled study to further assess the long-term safety and efficacy of the product.
Ontak will be marketed by Ligand Pharmaceuticals, San Diego, Calif., and manufactured by Seragen, Inc. of Hopkinton, Mass., a subsidiary of Ligand. Ontak was granted orphan drug status in 1996. Orphan status provides incentives to companies to develop products for in use in small patient populations.

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We are talking IL21 here, not IL2 and I don't think anyone has been given IL12 yet.
Hope this helped!

[Rich66]

Article from 1/9/2007 Anything newer out there? Mentions a 5 yr study.


http://www.jamesline.com/viewer/Pages/index.aspx?P=474