Science Fiction Medicine: Immune Checkpoint Inhibition

I love the practice of medicine, but it puzzles me why I chose Oncology.

PD-1

It was a long time ago, when there was virtually no treatment for malignant disease, apart from surgery and radiation. Chemotherapy was rudimentary, and only for leukemia, lymphoma and other blood disorders. People were trying things for solid tumors (things that typically produce lumps and metastases, like lung and colon and breast).

There was no program in solid tumor work, so some of us in that era took Hematology as a discipline and extrapolated into oncology, using our experience of treating blood disorders to try to extend the treatment of solid tumors. The understanding of the underlying biology of cancer was very superficial, and the standard of treatment at the time was limited to breast cancer for partially successful intervention, lung and colon for hoping.

Indeed, some of what we tried to do was ultimately proven to be counterproductive, a risk that always exists in medicine, but rarely more so than in oncology where the treatments are often viewed by the patients to be worse than the disease.

We have come a long way since then, but along the way, the path to today was littered with wishful thinking and hoper-picking. And some science fiction, like believing that cancer could be treated by turning the body’s immune system on to the cancer that was present. We believed that cancers came and went all the time, but that our immune system would wipe them out before they became too big, long before we could detect them, long before we knew they were even there…unless somehow the immune system failed.

And when it failed, well, that’s when we got cancer. So all we had to do was turn on the immune system again.

It was science fiction, or so we thought.

Cancers are pretty amazing things. In 2001, Hanahan and Weinberg published their wonderful review article on the Hallmarks  Of Cancer. In it they summarized the needed characteristics that cells must have in order to become malignant. It is a must read article for all students of cancer, and in 2011, they upgraded the review. It is hard going. For several years I used to hold an afternoon seminar for our Medical Oncology residents, on the content of that one article, and that really was never enough time. The paper itself, only a couple of dozen pages long, invariably takes me 20 hours to read. It is difficult enough for physicians who are specializing in the field, and the complexities almost make you want to find a deity somewhere, to explain it all.

Basically, in 2001, cancer cells had to learn how to do six things, and the tendency to anthropomorphize the cancer cell is really difficult to resist. After all, the cells don’t really learn how to do this stuff. They don’t have a consciousness that leads their intent. It is all done by Darwinian selection.

Of course, by 2011, when Hanahan and Weinberg updated their review, cancer cells had a lot more to learn. One of those emerging characteristics was the ability to manipulate the immune destruction of the cancer by the host. The cancer had matriculated, and was doing graduate work on the direct counter-attack.

The squiggly diagram above is a cartoon of the PD-L1, the Programmed Death Ligand 1. Physicians call these types of diagrams ‘cartoons’ because doctors don’t get out much. It is a pictorial representation of a protein which is several thousand atoms (40 kDA) in size, in the order of 1/10,000,000,000 of a meter in size! Different shapes of sections of the protein represent different typical structures (tertiary) of the protein.

A ligand is another large molecule, usually also a protein, that grabs on to something; in this case, PD-L1 grabs on to the Programmed cell Death 1 (PD-1), a protein in the immune system that helps to cause the death of a cell. From the standpoint of the organism, the death is intentional, but since we don’t anthropomorphize, we call it ‘programmed.’

Organisms aren’t totally stupid (well, they are at a cellular level, really) and when a cell becomes defective, it is a simple matter just to get rid of it. Who’s going to miss it? You have about a gazillion (1,000,000,000,000) in your body, whatever you call that number. You’ll never miss one cell. So if one is identified to be defective, well, that’s where Programmed Cell Death comes into play. Rather than just replicating the mistake with abandon, the body triggers it into committing suicide, and being eaten by the immune system.

Some cancer cells evade immune destruction by developing signs that say “Don’t eat me,” like PD-L1. This is particularly true of lung cancer, and many others. If you can interfere with the “Don’t eat me” sign, the immune system takes care of the rest. This is, in essence, turning the immune system back on to attack the malignant cell. It is correcting that one defect that has resulted in the malignant cell surviving.

Back when I started medicine, forty-six years ago, this idea was science fiction. You see it sometimes in stories, or variations on the theme, as in nano-particles injected into the body to attack the cancer.

The fiction was perhaps the idea of sending in an agent, into the blood stream, which would go and put ‘Cancelled’ over the ‘Don’t eat me sign’ on the cancer cell surface. Remember, these cells are in the range of one millionth of a meter in size, and the ‘signs’ themselves are way too small to be seen with a light microscope…they are smaller than the usual wavelength of visible light.

But today, the hackneyed phrase applies, that ‘science fiction is becoming science fact.’ Drugs consisting of proteins that can attach themselves to the ‘Don’t eat me sign’ are being used in patients.

We have to back up seventy years, to appreciate how far we have come. Initial treatments of lung cancer date back to the 1940’s, some of the work actually being done by my father-in-law when he was a doctor in training, using derivatives of Mustard gas, Nitrogen Mustard, to treat the cancer in terminally ill patients. In fact, the recognition that this substance might have an effect on rapidly reproducing cells came from studies of soldiers gassed in the first world war, and resulted in some of the studies during the forty’s, in the USA, being restricted from publication under national security legislation, because of the weaponizing of the molecules.

The early cytotoxic (cell killing) chemotherapy had dreadful side effects that many know today: hair loss, nausea and vomiting, immune suppression with attendant infections, numbness and tingling, bleeding, mucositis (ulcers in the mouth) and a host of other less common symptoms, often with response rates for all this suffering which amounted to only a few months of additional life. Such drugs are still used today, such as Cyclophosphamide, and the more modern version of alkylating agents, Cisplatinum.

Today, we have better supporting medications which blunt the nausea and the immune suppression, ease the pain due to nerve damage, and treat the infections which accompany such aggressive treatments. But such supportive treatment was rudimentary or nonexistent when I started my career in oncology, and it was a very real question whether the treatment was worth it. In fact, for lung cancer, after more than a decade of trying Cyclophosphamide as a mainstay of treatment, we discovered we really were doing many patients more harm than good, and for a time in the nineties physicians stopped treating this disease.

Oncologists in the latter half of the last century were often viewed with skepticism and disbelief. There were very few of us, and our medical colleagues could not really believe we had chosen such a depressing specialty. A typical greeting with a cynical smile and a salutation of “What poisons are you using today?” spoke to the wide-held opinion that the work we were doing was worse than useless…it was detrimental. And all too often, they were right.

I remember, as recently as the 90’s, attending a meeting of Cancer Care Ontario where I served as a regional Vice-President. A senior executive of a public relations firm, who was going to pitch a campaign for fund-raising for us, referred to cancer treatments with the phrase, “slash, poison and burn.” He thought this was clever.

Such was the state of broad public opinion that he did not realize how insulting that was. You could hear a pin drop in the room, and if I recall correctly, he departed quickly.

In a word, systemic treatment of cancer, chemotherapy, was awful. Even today, systemic treatment of stage IV lung cancer still carries a grim prognosis, although we do a much, much better job of comforting our patients, and such suffering is unacceptable and quickly ameliorated now.

Lung cancer prognosis is still poor. The average patient who is diagnosed, before any treatment, with lung cancer that has spread beyond the chest, has about a ten per cent chance of living for one year without any intervention except best supportive care. For those who do get modern treatments, that number approach 35% for one year overall survival.

We can expect response rates of thirty percent, perhaps, to standard chemotherapy and median survival (the time that half the patients get past) to double from four months to eight months, with first line chemotherapy. Second line chemotherapy can improve symptoms, but clear improvement in survival is not forthcoming.

With this background knowledge, enter the science fiction. A drug is given to heavily pre-treated patients (lots of cycles of chemotherapy that has failed) with stage IV (metastatic) lung cancer. The drug has very little in the way of side effects. Nausea, vomiting, suppression of the white blood counts and infection are measured in single digit percentages and hard to differentiate from patient who get a placebo. Fatigue, poor appetite, generalized weakness are no greater than placebo, and in fact, probably a lot better in responding patients. Life can get back to very close to normal.

And what are the survival numbers?: 42%, 24% and 18% for one year, two years, and three years, in patients who were expected to live only a couple of months.

Three years! In someone who heretofore had only months left.

Monoclonal antibodies to the sign post, PD-L1, tell the immune system to go ahead and kill the cancer cell anyway, even though it holds the “Don’t kill me sign”. And the immune system does its job. I have not been able to treat a patient with this drug yet. It is new in Canada, and Canadian physicians, Canadian institutions, are cautious.

But some of my colleagues have. And I expect I will have the appropriate case soon. At our centre we are starting clinical trials to verify this good news.

Funding is a problem…these drugs are dreadfully expensive, but as the numbers of new drugs in this class increase, the price will come down.

Of course, there are a number of treatments for selected patients that are better than old style chemotherapy of the 90’s. I have many patients on the ‘lung cancer pill’ which helps about 12% of lung cancers, and they are doing well for long stretches, often a year or so. And I have several patients surviving over two years on maintenance chemotherapy with drugs that have become available in the last decade.

But the science fiction becoming science fact for the Immune Checkpoint Inhibition drugs like Nivolumab and Pembrolizumab is real, is the beginning of a new era of cancer treatment.

 

Carter

To highlight this improvement, the other day I saw President Carter on the tube. He announced he had been declared cancer free at 92. Now, this was not lung cancer: it was worse. He apparently had melanoma metastatic to brain and liver, a disease which killed my uncle so many yeas ago. He was treated with Pembolizumab, I believe, or so it is reported in the media, and the mechanism of action would be the same. The difference is that this disease, melanoma, is even less responsive to standard treatments than is lung cancer, making his recovery all the more note-worthy.

I would not dare to treat a 92 year old patient with the usual cytotoxic chemotherapy (and virtually every 92 year old I have seen in such a state has declined such treatment), believing full well they would be at risk of dying from the treatment, a ‘risk’ comparable to the chance of getting any benefit at all.

But, with this new treatment, Jimmy Carter is cancer free at 92 from a disease that was hopeless a few short years ago. Couldn’t happen to a nicer man, either.

 

 

 

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