Hallwang Clinic #9 – Removab antibody treatment (Catamaxomab)

Updated 25 January 2014 with US FDA approval guidelines

Life at the clinic was on fast forward all the time.

Barely two days after my arrival at the clinic I was put on my first treatment, Removab, a tri-functional antibody.

Here’s my layman understanding of what it is all about:

Antibody.svg

Antibody (from wikipedia)

What is an antibody?

An antibody is a large Y-shaped protein. It is used by the immune system to identify and neutralize foreign organisms like bacteria and viruses.

An antibody recognises what organism to attach itself to and attack, by matching up to a specially-shaped receptor on the organism.  This receptor is called an antigen.

An antigen is a molecule capable of stimulating an immune response, and is often produced by cancer cells or viruses.

Think of the tip of the Y of the antibody as a lock, and the antigen as the only key that fits that particular lock.

lock and key

photo credit: thecolour.com, with edits

Herceptin is an example of a monoclonal antibody that targets the human epidermal growth factor receptor 2 (HER2) protein on the surface of tumour cells.

What is a tri-functional antibody?

A tri-functional antibody allows two antigens to key into it at the same time.

Another way is to think of it as a person shaking hands with two different people at the same time, and creating a three-way connection.

The pair of antigens that are linked by the Removab tri-functional antibody are the CD3 and tumour antigens.

In addition, Removab binds to FcγR-positive accessory cells.  Fc cells are proteins found on certain cells like macrophages, natural killer cells, mast cells, follicular dendritic cells.  Waking them up activates phagocytosis and cytoxicity of these cells, so they can destroy microbes and infected cells.

RemovabRevised1

Tri-functional antibody group hug

The CD3 antigens stimulate the production of T-cells (the mightiest killers in the immune system army), and macrophages and Natural Killer cells which are the body’s way of fighting tumours.

500px-Catumaxomab_mechanism.svg

Removab Tri-functional antibody (aka Catumaxomab)

The tumour antigen is a specific type called the EpCAM (Epithelial Cell Adhesion Molecule)  receptor.  This EpCAM receptor is expressed on almost all tumours, such as breast, lung, colorectal, gastric, prostate and ovarian cancer.

Because Removab creates a 3-way connection between the body’s immune system and the tumour cells, it’s almost like the immune system can recognise the enemy because it’s suddenly brought into close proximity with it.

RemovabRevised2

Tri-functional antibody mortal kombat

I had already tested positive for the EpCAM receptor using the RGCC test.  If I hadn’t, I wouldn’t have had Removab.

I’d spent two years questioning every drug, and researching side effects of medication that doctors wanted to give me.  But when it came to Removab, I hardly did any research.  I had a briefing given to me and Dr Kopic drew some stick diagrams and talked science to me, but for once, my research brain was switched off.  

Which is probably a good thing, because I later found out that Removab was manufactured from mice/rat hybrids (eek!) antibodies, and in some of the early trials, there were some near deaths because of toxic dose overload.  Some of the side effects can be lethal too.  So my ignorance saved me.  

Fortunately for me, Hallwang had perfected the art of using the lowest dose of Removab possible, that would give the highest benefit.

What it’s like having Removab

Removab is given in a cycle of 3 doses.  My first dose of Removab was a 5mcg infusion, administered with an infusion pump, over an 8 hour period, in the infusion room (a room filled with comfortable lounge chairs, next to the nurses’ station). The second dose is usually 10mcg and the third 20mcg.  This may vary according to the health of the patient.

Some side-effects of Removab

I had been warned that Removab causes something called a cytokine storm.

Cytokines are messengers produced by T-cells to signal to the immune system:  “warning … warning … dangerous intruder in sight – attack!” However, cytokines also produce an inflammatory response in the body.

Some of the side effects of Removab included flu-like symptoms, nausea, fatigue.  One person apparently vomited almost continuously for several days.  It was like being told how frightening a horror movie was going to be before seeing it.  But until you see the movie, it’s like listening to a bedtime story.

Six hours into the infusion and still no reaction.  I was beginning to despair and worried that it was Euro750 wasted.  People kept coming up to me and asking me whether anything was happening and looking disappointed.  I don’t know what was more stressful, my lack of reaction to Removab or dreading what was to come.  I even ate a hearty breakfast and lunch even though I’d been told nausea was one of the potential symptoms.  I read a book, I meditated, I listened to music, I did QiGong (an impressive feat when chained to an infusion machine).  Still nothing happened.

Temperature

Feels like Removab …

After about six-and-a-half hours, I felt the room had got a trifle chilly.  Because it was evening and minus 10 outdoors, I asked if the central heating had been turned off.  I was told that wasn’t the case.  Almost immediately, I had to suppress the desire to sit on my hands to warm them because they felt like blocks of ice.

And then the fun began.  I started feeling cold, like little shivers running up and down my body.  I was ordered up to my room. One of the nurses accompanied me upstairs, even though I felt fine, just a bit shivery.

I was told to get into bed as soon as I got to my room, but me being me, I said I had to get into my pyjamas, and also make sure that my blanket was properly folded.

By the time I got into bed, and this was barely 5 mins after leaving the infusion room, I was shivering so hard I was shaking.  My teeth went guh-guh-guh.  The bed started shaking and the lamp attached to the bed rattled against the wall.  Very dramatic.  It was something like out of the Exorcist.

My temperature shot up from 37 deg to 40.1 in about 10 minutes.  It was apparently, a good reaction.  That was the only thing that consoled me because I felt really ill from the high fever.

I wanted the nurse to leave me to shiver with the fever because I thought it was free hyperthermia and would zap the cancer cells.  Unfortunately, Hallwang are not licensed to use Removab as a hyperthermia agent (!).  I was given IV paracetamol and my temperature soon fell back to normal.

This happened twice more that night, and I had to change out of my pyjamas twice.  The bed was soaked with sweat.  I was checked every 1/2 hour, then hour by the nurses.  My blood pressure also fell dangerously low and there was a flurry of action as fluids were given to raise it.

The day after I felt relatively fine.  I think it’s because in general (apart from the cancer), I was fit.  However, there were internal side effects which I couldn’t feel but apparently were throwing my system off balance.

Because the liver also contains EpCAM cells, Removab also affects liver cells.  This can cause the liver enzymes to go sky high.  The normal reference range was less than 60, mine went up to 600.  So even though I felt well, I was told I had to rest and not exert myself.  I was told of a patient who had Removab, did not follow the advice, went for a walk in the Black Forest and when she returned, collapsed from exhaustion for the rest of the week.

For someone used to going to the gym, it was very hard not to take any exercise.  The most I was allowed to do was go for a short and gentle walk.  I was gutted.  I wanted to go on a day-trip to a tourist town, and was told “no”.

In the meantime, in order to bring the liver enzymes down, I was on infusions daily, up to six-hours per day, of Hepa-Merz, a liver detox.  Also, in terms of diet, I was told to eat less raw food and juices and more cooked food because that was easier for the liver to process.

The second time I had Removab, it was a 10mcg dose.  It was also the day when an evening do was being organised to celebrate the life of a long-term patient who had died.  I groaned.  I didn’t want to miss out on the celebration.

By now I knew what to expect.  So right after my third set of shivers and sweats, I had a long hot shower.  I then went downstairs to the restaurant, still slightly sweaty, still connected to the infusion.  The look on one of the doctor’s face was priceless!  But I figured that if I was going to faint or have a dramatic reaction, where better to do it then at a party where all the doctors and nurses were present?

(so I sat there, stuffing my face with prawn canapes until to be truthful, I started feeling a bit sick, so I trotted off to the nurses’ station only to discover my blood pressure had fallen again)

Each dose of Removab was given about 5-7 days apart to allow the liver enzymes to return to reference range.  My third dose was 20mcg.  Even though it was a higher dose, the symptoms were the same.

My liver enzymes took longer to return to normal with that third 20mcg dose and that delayed the start of my next treatment – the Trans-Arterial Chemo-embolisation.

Also, after the third dose of Removab, my feet started swelling. I only noticed this when I was having a massage at Caracalla Spa in Baden-Baden, and my feet felt sore.  The following morning, I had a session with Manuela and she noticed my ankles were swollen.  She told me to to tell one of the doctors as it could be the precursor to something more serious.  I felt that it wasn’t important enough to justify disturbing the doctors – after all, there were people who had more serious issues, and all I had was swollen ankles.  In the end I shyly approached Dr Kopic, and he gave me an ultrasound just in case there was a blood clot that was causing the swelling.  I still felt like a fool for bringing it to their attention but better safe than sorry.

Results

So what were the results of Removab?  A few days after my third dose, I had an ultrasound and it showed that one of the suspect lymph nodes had shrunk, and others had vanished.  I was so pleased.  But when I got back to the UK, I had tumour markers done, and they were only slightly lower, and CEA (a marker of inflammation) was elevated.

Here is more information on Removab [aka Catumaxomab]:

http://www.removab.de/home.html [unfortunately this requires professional accreditation to login, and information is restricted]

http://en.wikipedia.org/wiki/Catumaxomab

http://www.mcrc4.com/?p=4617 – Ren, who was at Hallwang, writes about his Removab experience.  Please note – Ren’s reactions, as he explains, are extreme, the rare 1%.  He had extensive liver mets which may have accounted for his reactions.

http://www.tga.gov.au/pdf/auspar/auspar-catumaxomab-121004.pdf – this is a trial conducted by the Australian government which rejected the use of Removab because of the less than shiny results, and bad side effects (not surprising seeing they were using high doses of up to 150mcg, administered three days’ apart!).

Caveats

I think what you have to bear in mind is that Removab is not a magic wand.  It is another tool to attack cancer.  It may or may not shrink tumours.  My lymph nodes had shrunk, but the tumour had not shrunk in any measurable way.  I’ve heard from Hallwang that there have been spectacular results for some patients – well, we’re all individuals, and that’s as good a reason to try Removab.

What Removab does is stimulate the immune system to recognise and attack the cancer cells.  This immunity is short term – up to six months.  With repeated doses of Removab, resistance develops to the mouse/rat hybrid antibodies which make subsequent doses less effective.

Also, bear in mind that reactions to Removab vary.  Mine were, apparently, mild.  Some people have had severe reactions, extreme nausea, cramping, fever.

Contraindications

Taken from the Fresinius Biotech site:

For patients with the following laboratory abnormalities and co-morbidities no study data are available:

  • renal impairment of a higher severity grade than mild (> CTCAE 1: Serum creatinine > 1.5 x upper limit of normal [ULN])
  • hepatic impairment of a higher severity grade than moderate (> CTCAE 2: Bilirubin > 1.5 x ULN; AST, ALT, GGT ≥ 5.0 x ULN)
  • platelets > 80000 cells/mm3
  • neutrophils > 1500 cells/mm3
  • more than 70 % of the liver metastasized
  • portal vein thrombosis/obstruction
  • patients with parenteral nutrition who are more susceptible to develop ileus symptoms

Treatment of these patients with Removab should only be considered after a thorough evaluation of benefits and risks.

So what’s the advantage of using Removab?

Removab is an anti-cancer treatment that is used as part of an arsenal to attack cancer in as many different ways as possible.  It educates the immune system to recognise a specific type of cancer cell and attack it.  Cancer cells are canny beasts and usually manage to elude detection by the body’s immune system.

Also, the side-effects of Removab are, compared to chemotherapy and radiotherapy, mild, short-term, and manageable.  And it can be used for metastatic cancer patients.  It is, however, not a substitute for chemotherapy or radiotherapy.

At the moment, Removab as a treatment is only available in certain centres in Europe, and as far as I know, not in the UK.  It is being used for the treatment of malignant ascites [fluid caused by peritoneal cancer], ovarian cancer and gastric cancer.

Hallwang is unique in its use of Removab – I don’t think it is available in any other German cancer clinic, and it’s because Hallwang works closely with Trion Pharma, the makers of Removab.

It seems, however, that German cancer clinics have more laissez-faire to use off-label treatments, and it’s a shame that these treatments are not allowed in the UK, and only obtainable if you can afford to go to Germany for treatment.

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US FDA approval

It appears that it is possible to get Removab (Catumaxomab) in the US.  However, it is only for specific types of cancer.  It is unlikely that a hospital will use it off-label as they do at Hallwang.

The FDA has granted approval for Catumaxomab for the following categories/types of caner:

2006 – FDA (US Food and Drug Administration) grants orphan drug status to Removab® (INN: Catumaxomab) for ovarian carcinoma

2008 – FDA grants orphan drug status to ATG-Fresenius® S as prophylaxis against rejection reactions in organ transplantations

2009 – FDA grants orphan drug status to Removab (INN: Catumaxomab) for gastric carcinoma

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