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New Cancer Drugs Rally the Body’s Troops But They Should Not Be Immune to Criticism

Immunotherapy is the idea of triggering an attack on cancer by the body’s own immune system. Success stories get attention from the press but they are not representative.

Take-home message

  • “Cancer immunotherapy” means waking up your immune system so it can see and kill your cancer

  • Some of these therapies have had moderate success, but they are very expensive, do not work for everyone, and can cause diseases like arthritis and inflammation of the large intestine


New discoveries in cancer research can lead to overhyped write-ups in the media like this one: “When Judy Perkins enrolled in an experimental trial, she only had months to live. Two years later, she’s cancer-free.” Perkins had end-stage breast cancer, meaning that the cancer had spread beyond her left breast, where it had first been detected. She agreed to participate in a clinical trial in the burgeoning field of “cancer immunotherapy” and, lo and behold, the cancer went away. The researchers even published what they did in the prestigious journal Nature Medicine.

So, what is cancer immunotherapy and is it the future of oncology?

Waking up the soldiers

In 1868, Wilhelm Busch, a German surgeon, intentionally infected one of his cancer patients with a type of bacterium that causes erysipelas, which results in a red skin rash and high fevers. Composer Richard Wagner had multiple outbreaks of this infection throughout his life. It even affected Lenin and killed philosopher John Stuart Mill. In the case of Dr. Busch’s patient, it was accompanied by a shrinkage in their tumour.

If you think throwing a nasty bacterium at a patient dealing with cancer is bad, fast forward a few years to 1891 and witness the horror of William Coley injecting multiple cancer patients with bacteria. The good news? He observed tumours shrinking in many of them. Is it a case of sending in a bacterial Godzilla to fight off the cancerous King Ghidorah? Actually, no.

The human body contains a powerful home guard: the immune system. This network of specialized cells and biochemicals keeps an eye out for invaders like viruses and bacteria but, for many reasons, it often fails to stop the growth and spread of cancer. The “C” word is not an outside force invading our body (though some cancers are indeed caused by viruses); rather, cancer is what happens when, through the accumulation of changes in their DNA sequence, a local mass of our own cells starts to grow out of control.

Can our immune system detect the cancer? Not in the early stages, since cancer cells still look like our cells. But as they mutate, these cells start to display molecules that are not normal, like a ship slowly raising more and more pirate flags, which should in theory attract the attention of our immunological home guard. Unfortunately for us, a tumour creates an environment around itself which effectively puts our soldiers to sleep.

Immunotherapy is an attempt on the part of medical researchers to wake up our home guard so that they see the tumour and destroy it.

Failure, failure, failure, … win?

While its concept is marvellous, cancer immunotherapy has a long history of simply not working out. For example, cancer vaccines were made throughout the years against a variety of antigens (the pirate flags on the surface of cancer cells). As a new antigen was discovered, a vaccine was made and tested; however, none of them succeeded in waking up the home guard. Cancer research, as it turns out, is more complicated than spotting pirate ships.

Then, in 2010, an interesting baby step was made: a product called sipuleucel-T was approved by the U.S. Food and Drug Administration (FDA) to treat an advanced form of prostate cancer. Sipuleucel-T is an interesting treatment: many of the patient’s immune cells are taken out of the blood and are put into contact with a prostate cancer cell “pirate flag” in the laboratory, before being infused back into the patient in a bid to wake up the patient’s own soldiers. While initially touting an increase in survival of 4 months, sipuleucel-T subsequently failed to show much in the way of tumour shrinkage.

A year after the approval of sipuleucel-T, the FDA approved a different sort of immunotherapy, ipilimumab (or “ipi” for short). At the time, I was studying the genetics of melanoma, a particularly aggressive form of skin cancer, and I remember that the news of this drug being available for late-stage melanoma was received with jubilation. I was told, “Before ipi, patients with advanced melanoma were informed that there was nothing we could do for them. Now, there’s ipi.”

Since then, a number of immunotherapies have been tested, as well as combinations of them, in order to figure out what works best at eliciting a response from the patient’s otherwise dormant immune cells.

If all this sounds too good to be true, it’s because that’s not the full story.

What the media often sweep under the rug

In the enchantment over empowering cancer immunotherapies, the media often fail to mention a number of important caveats.

By tinkering with the immune system, there’s a risk of triggering an autoimmune condition. Autoimmunity is when our immune system improperly responds to something that belongs to us. Rheumatoid arthritis is a good example, in which the immune system starts attacking the joints. Some patients given cancer immunotherapy develop “severe colitis and widespread arthritis”, and that’s something that shouldn’t be ignored when choosing a treatment or when reporting on how cancer patients do on these protocols.

Immunotherapy also tends to be very expensive. As Joy Victory pointed out in an article entitled “Six tips for writing accurately about cancer immunotherapy drugs”, a year-long treatment course can cost USD 250,000, leading to some patients using up all of their life savings to pay for these newfangled drugs.

When ipi came out, a single dose cost CAD 24,360, the price of a car. Why so expensive? It should be pointed out that ipi doesn’t grow on trees. In order to obtain this drug (which is actually an antibody, much like the ones your body creates to fight off an infection), scientists had to create a mouse that would produce the right kind of antibody. First, the mouse had to express human antibodies, which means that the genes that code for these antibodies had to be inserted into the mouse. Then the mouse had to be exposed to one of the molecules preventing the immune system from fighting off cancer, in order to produce a human antibody against it… and the cell producing this antibody had to be harvested and fused with another cell that grows continually. That, in a nutshell, is ipi.

Other immunotherapies, like the one Judy Perkins undertook, are even more complicated and personalized, involving the sequencing of tens of thousands of genes of the patient’s tumour cells. Does this costly research and development really justify the price tag? Even though only a small percentage of drugs ever make it to market and companies need to pay for the research that went into the duds, it has been argued that greed plays an important part in the dramatic increase in pricing.

It’s worth emphasizing that this pricing problem is not unique to immunotherapy: indeed, it is part of a larger trend of new cancer drugs that do not significantly improve survival but cost the patient an arm and a leg.

Judy Perkins, exceptional responder

I am truly happy that Judy Perkins’ course of immunotherapy cleared her body of metastatic breast cancer and allowed her to subsequently paddle 1,200 miles as part of a five-week kayak race in Florida. Hers is a success story.

But the trial she enrolled in aimed to recruit 332 patients. And the research team in charge of the trial wrote a paper about 1 of these 332 patients.

Even though the first attempt at waking up the body’s home guard dates back to the Victorian era, it’s still early days for cancer immunotherapy. In our desire to shine a light on its promises and its few unquestionable successes, we would be wise to also highlight its price tag, its side effects, and its frequent failures.

[For those who want to delve deeper into "exceptional responders", click here].

 

Judy Perkins seems to be an “exceptional responder”, a patient who, for reasons that are still not fully understood, experiences a dramatic response to their treatment. These patients make for impressive scientific articles, which get boosted by effusive public relations releases, which themselves are repackaged as awe-inspiring news stories.

These accounts may make us think that the drugs that delivered these exceptional patients from their cancer are incredibly potent, but that may not be the case. First, there’s the fact that a certain number of patients have “spontaneous regressions”, meaning their cancer goes away. On its own. No one knows why.

Second, a review of exceptional responders was recently released in the European Journal of Cancer which showed that many of them “had already experienced a response to prior therapy that was far better than average”. The authors wonder if these patients simply had tumours that were sensitive to any drug or that were simply slow growing, and speculate that there may not be any “super drug”.

The media may amplify these success stories, but medical researchers are also guilty of promoting this narrative. That same review paper calculated that only 14% of scientific articles reporting on exceptional responders actually mentioned how many patients got the same treatment but didn’t respond exceptionally! Indeed, the article detailing Judy Perkins’ response to her immunotherapy makes no mention of all the other patients who underwent the same treatment. That information can only be gained by accessing the ClinicalTrials.gov page for the trial she was enrolled in. If medical doctors are to make the most educated treatment decision, this withholding of selective information needs to stop


@CrackedScience

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