CancerGuide: Interleukin-2

What Is Interleukin-2?

Interleukin-2 is the only drug approved in the US for the treatment of metastatic RCC. It is also approved in many other countries. But IL-2 isn't just a drug. IL-2 is a natural part of your immune system, a messenger protein called a cytokine which activates parts of your immune system. IL-2 does not kill tumor cells directly like classical chemotherapy. Instead, IL-2 activates and stimulates the growth of immune cells, most importantly T-Cells, but also Natural Killer Cells (NK Cells), both of which are capable of destroying cancer cells directly.

There are several types of T-Cells but, without going into detail, certain T-Cells are capable of killing tumor cells if they recognize a specific antigen on the surface of the tumor cell. Antigens are normally proteins. Each T-Cell is specific for only one antigen but you have many different T-Cells. NK Cells have the ability to kill tumor cells without needing to recognize a specific antigen (I'm not sure how!). While this sounds good, NK cells are weaker cancer killers than T-Cells. The so called LAK cells which were used in some of the early immunotherapy experiments are actually NK cells.

Why IL-2?

Back in 1989 my goal was a cure or at least a long remission and it is probably your goal now. In my view, the proven chance of getting such a result is the reason to try IL-2. At this time the only other therapy I know of that has this kind of long term result is surgery in some cases. I explore the documentation for and odds of getting that kind of result from IL-2 in detail in my pages on specific IL-2 therapies.

Why Not IL-2?

Although the therapy rarely causes serious permanent damage, it's more or less miserable while you're getting it, and often more rather than less. Most importantly, only a small minority of patients get the kind of long term relief that is the reason to try it. In the end whether it's worth it to endure the side-effects of IL-2 for a small (but the best known unless surgery is also an option) chance at a great result is strictly a personal decision. In my case, I was 33 years old and quality of life wasn't an issue since the disease had already taken that from me. I had nothing to lose. You might feel differently.

IL-2 Eligibility

IL-2 eligibility always a matter of clinical judgment - it's not like eligibility for a clinical trial which is mainly determined by rigidly specified criteria and it's not a legal thing either. Requirements to take IL-2 vary somewhat according to which IL-2 therapy it is and I do discuss additional requirements for specific IL-2 therapies in articles on each therapy, particularly high dose IL-2, which is more rigorous than other IL-2 therapies.

Some Typical Requirements

Some patients are too sick to tolerate IL-2 treatment. If you cannot get out of bed for more than short periods, or require oxygen, then IL-2 is probably not an option. At the same time, you can still be quite ill and take IL-2 treatment, even high dose IL-2. At the time I started my treatment, I had lost a great deal of weight, was not quite recovered from surgery, was slightly anemic, and in rather severe pain from my bone metastases. Despite this, all of my major organs were functioning normally, and as it turned out, I not only tolerated a high dose IL-2 protocol but was able to take more of the treatment than most. Don't count yourself out!
If you have brain active metastasis, IL-2 is contraindicated. If you had brain metastasis but it was surgically removed or effectively treated with radiosurgery and now have metastases in other areas, such as the lungs, then IL-2 based treatment is a possibility. I once met a patient who had very widespread metastasis, including a brain lesion. He had surgery for this brain lesion, and then had high dose IL-2 and all of his remaining tumors vanished! When I saw him, this formerly "hopeless case" looked and felt well and he has good prospects of staying well. If you have active brain metastasis then you need to get that taken care of first. See my article on brain metastasis for more.
If you need to take steroids such as cortisone, decadron, or predinsone, then IL-2 treatment is unlikely to be effective because these drugs suppress the immune response. Many patients with brain metastasis require steroids after surgery for some time to control brain swelling. Steroids are prescribed for many other unrelated conditions as well, and you may wish to consult with your doctor to see if other methods of treatment would be possible if this is the case. If you've lost adrenal function because both adrenal glands were removed surgically, then you will need steroids to replace the amount your adrenals would have made. I don't think this use of steroids merely to give you a normal level would prohibit IL-2 treatment.
If you have another serious medical condition, you may not be able to take IL-2. This would include diseases which seriously affect the function of your heart, lungs, kidney(s) or liver, as well as serious auto-immune diseases such as lupus. Again, many people with another medical problem can still take IL-2 treatment. In some cases they would be limited to outpatient versions. Again don't automatically count yourself out. I recommend getting an opinion from an expert in IL-2 treatment if there is any doubt at all. For instance, if you've lost both kidneys and are on dialysis IL-2 may still be possible.

IL-2 Therapies

There is a bewildering variety of different IL-2 regimens. Many different dose levels, methods of administration, and as well as schedules and combinations with other drugs have been tried and more than a few are in current use. While I don't cover them all in CancerGuide, I do cover the most commonly used and of course anything I find that looks especially promising.

For detailed coverage of specific regimens, see:

Classic High Dose IL-2 Therapy, the oldest and best proven version of IL-2 therapy, this is an intensive inpatient treatment usually given in ICU.
Selected Outpatient IL-2 Therapies, including some of the outpatient combination therapies.
New and Experimental Therapies, which includes any new and promising IL-2 therapies.

Notes on IL-2 Administration and Dosing

It's very helpful to understand IL-2 dosing when comparing the details of different IL-2 protocols. You may not be interested in these minutiae now, but as you get further into the details you may want to come back and give this section a closer look.

It will be helpful to read my general article on Understanding Cancer Drug Dosing first.

Administration

Because IL-2 is a protein it can't be given by mouth because you'd simply digest it, so it's normally given by injection (it has also been given by inhalation on an experimental basis). Outpatient IL-2 is given by injection under the skin (subcutaneous), much like the way diabetics inject insulin. Most patients learn to self inject. Inpatient IL-2 is normally given by injection into the vein (Intravenous Infusion). IV dosing can either be a continuous infusion (CIV) or more usually, a dose is given over a short period every few hours. This is called bolus dosing. The Classic High Dose IL-2 Protocol uses bolus dosing.

Dosing Units

IL-2 Units: The standard measure of an amount IL-2 is the International Unit (IU) which technically is not a fixed amount but the amount that produces a fixed effect in a specific assay of biological activity. In practice, the manufacture of IL-2 is standardized and there is a conversion between drug weight and International Units. It is 1.1mg IL-2 = 18 million IU (abbreviated 18 MIU). This is for Chiron IL-2 which is the only IL-2 presently approved in the US, and as far as I know anywhere. If another brand of IL-2 is approved in the future it might have a different conversion factor.

To complicate matters, in very old research papers you may encounter two other units, "Cetus Units" and "Roche Units". Cetus was the company which was first involved in the development of what is now Chiron's IL-2, and Roche apparently also worked with IL-2 at one point.
- 1 Cetus Unit = 6 IU
- 1 Roche Unit = 3 IU
Dosing By Body Size: IL-2 dosing is usually scaled to your body size. True to form, it's not as simple as you'd like it to be, and sure enough there are two different and incompatible ways to do it:
- By Body Weight: Doses are scaled according to your weight in Kilograms, e.g. 600,000IU/kg for high dose IL-2.
- By Body Surface Area (BSA): Body surface area is given in square meters (m ²) and estimated by a combination of your height and weight.
Converting Between Body Weight and Body Surface Area Dosing: Of course, you can compute the amount of IL-2 you'd get in any protocol given your particular weight (and also your height if the dosing is by body surface area), but it would be useful to be able to convert between the two dosing systems so that you could compare dose levels between protocols using the different systems. Unfortunately, since BSA takes height into account as well as weight, there simply is no exact conversion which would allow you to say that a protocol using 125,000 IU/kg is exactly the same as one using, say 5MIU/m ². But there is a good approximation. For a person of average weight and height (50^th percentile for each) it turns out that 25,000IU/kg = 1MIU/m ² . This gives a rough way to compare BSA based dosing to weight based dosing, and so actually 125,000 IU/kg is roughly equal to 5MIU/m ².

How IL-2 is Made

This isn't essential reading but it is pretty interesting!

Proteins like IL-2 are huge molecules made of dozens of amino acids linked together. A single amino acid is a relatively small molecule. A protein is very unlike typical small molecule drugs like aspirin, most chemotherapy drugs, and in fact most drugs you've ever heard of. Small molecules can be synthesized in a chemical plant but it isn't practical to make proteins by ordinary chemical synthesis.

But every cell of every living thing knows how to make proteins which, among other things, catalyze most of the chemical reactions necessary for life. The instructions for making a particular protein are encoded in the gene for that protein. To make IL-2, scientists transferred the gene for human IL-2 into bacteria (nice trick!). The bacteria then make the IL-2 protein in large quantities, which can then be purified as a drug (another nice trick!).

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