Advanced cancers are very difficult to treat.
The cure of advanced cancers is not very common. Indeed, in his classic textbook, Weinberg states[1]: “Since truly effective treatments of most kinds of metastases are not available at present, this raises the question whether tumours of the [highly aggressive] class are worth treating, as they will become lethal no matter what therapies are attempted.”
And it is not only because they are metastatic. They are also genetically unstable, heterogeneous and evolving. To use a concept which we introduced in the book, these cancers have high ‘variety’[2].
The unfortunate experience with conventional, and even targeted treatments, for advanced cancers is an initial response followed by resistance and recurrence. These treatments do not have the ‘requisite variety’ to control an advanced cancer.
The immune system, on the other hand, is different. It is also complex, diverse and, hence, does indeed have high variety. The immune system does then potentially have the requisite variety to control advanced cancers[3].
Weinberg’s book was published in 2014, around about the time
that the first immunotherapy drug for cancer was approved. Subsequent
developments in cancer immunotherapy have injected significant new hope for
those diagnosed with such cancers.
A century of disappointment, and then a breakthrough
Cancer Immunotherapy is not the ‘new kid in the block’. Indeed, it goes all the
way back to the late 19th century. But it has a history of “flattering only to
deceive”, hype followed by disappointment, boom and bust.[4]
Until everything changed.
In the 1990’s two researchers working independently, Drs
James Allison and Tasuku Honjo, discovered defenses that cancers use to avoid the
attention of the immune system. More particularly, they discovered cellular
features (called receptors) that enabled cancers to switch off immune cells
which were targeting them.
These defenses, called immune checkpoints, are a part of the
body’s normal controls against the excesses of the immune system (such as
chronic inflammation and autoimmunity). However, cancers often ‘hijack’ these
controls to protect themselves from the immune system. Allison and Honjo found
two important mechanisms which cancers use to do this.
These breakthrough discoveries revealed the missing link,
the thing that had overshadowed all the attempts in cancer immunotherapy for
over a hundred years. It also led to the development of drugs called checkpoint
inhibitors to break down these defenses; and it led to the awarding to the
Nobel Prize in Medicine in 2017 jointly to Allison and Honjo.
The timeline since these discoveries has been quite remarkable.
The first Immuno-Oncology (IO) [5] drug was approved in 2011. It was called Ipilumumab (commonly called Ippy or Ipi) and it targeted the checkpoint discovered by Allison.
In 2013 cancer immunotherapy was announced the Science magazine breakthrough of the year.
And by early 2020 Allison was able to say[6]:
“And the treatment works! More than 20% of the metastatic melanoma patients who get it achieve a long-lasting response. It used to be that with metastatic melanoma, the average time between diagnosis and death was something like four months. We're seeing some melanoma patients living 10, 20 years after being diagnosed. There's a woman who was in on the very beginning of the phase 1 trials with Ippy. She's 19 years out now. After the trials were expanded, thousands of others received it, and a lot of them have lived 10-15 years so far, with no reoccurrence”.
Sharon Belvin's Melanoma Journey
The melanoma patient referred to by Allison in his quote is Sharon Belvin. Here is her story:[7]
“In 2004, at only 22 years old, Sharon Belvin was diagnosed with stage 4[8] melanoma. She was just completing graduate school in elementary education and preparing for her upcoming wedding when she received the life-altering news.
Her treatment started with chemotherapy and soon traversed nearly all available cancer treatments. The debilitating side effects left her feeling dejected.
Running out of options, her oncologist, Dr. Jedd Wolchok of
Memorial Sloan Kettering Cancer Center, informed her of a new type of cancer
treatment called checkpoint blockade immunotherapy that was in early stages of
testing. Without any hesitation, she enrolled in a clinical trial of
ipilimumab, a CTLA-4 checkpoint inhibitor. After only four rounds of treatment,
she was declared cancer-free one year later.
Sharon was one of the first patients to be treated successfully with ipilimumab, which received landmark FDA approval in 2011.
She credits herself as playing a part in her remission.
"It was empowering to know that it was my immune system that did the
job," she confessed. Today, Sharon is a mother to two children, a personal
trainer.”
And it’s not just melanoma.
Checkpoint inhibitors have now transformed the treatment of advanced melanomas. But it is not only melanoma that has been impacted by checkpoint inhibitors.
For instance, there have been big strides in advanced lung cancer as well. In an article, Is It Premature to Utter the Word 'Cure' in Advanced Lung Cancer? - Medscape - Nov 16, 2021, Dr Jack West states: “I would argue that we should consider a subset of patients with metastatic non–small cell lung cancer[9] effectively cured. I have a few patients with metastatic lung cancer who have had no evidence of disease longer than I would have ever thought feasible.”
Indeed, today checkpoint inhibitors have been approved for
more than ten types of cancer[10], and the list
is growing.
However, it is still a bit of a “throw of the dice”.
But checkpoint inhibitors do not work for all types of cancer (including, not in the important cases of most breast and prostate cancers) and even in cancers where they do work, the response rate has been restricted and unpredictable.
This led to the following conclusion in our book (chapter 6):
“However, IO is still early in its development phase and there is still a lot to be learnt. So currently IO is only an option in some (but growing) types of cancers, is a bit of a “roll of the dice” (only works in about 1 in 5 cases), and there is no knowing in advance who will be responsive and who not.
Furthermore, it is very expensive and may not have support
from your health insurance. So, it is definitely worth looking at as an option
for advanced, aggressive cancer, but there are no guarantees.”
Though this too is already changing, as will be seen when we cover combination IO in the next blog.
[1]
Robert A Weinberg, The Biology of Cancer (see the references page). Weinberg
does, however, then go on to temper this by stating: “The proviso here is that
existing treatments may ameliorate symptoms over an extended period of time and
may even forestall the inevitable, thereby extending the patients’ life spans
significantly.”
[2] Variety
is the number of states of a system, which in advanced cancers is high. A rule
of systems control is that “only variety absorbs variety”. Thus, the controller
(in this case the treatment) must have the ‘requisite variety’ to control the
system (in this case the cancer).
[3] This
is most eloquently, though somewhat technically, stated by Prof Mel Greaves: “A
major challenge in cancer is the extensive intra-clonal genetic diversity in
cancers which, combined with changing phenotypes, can lead to therapeutic resistance
and escape. The immune system is distinguished by its almost unlimited
repertoire of antigen epitope recognition or functional diversity. To
encourage a confrontation between one diversity-rich system and another
is therefore an intriguing game plan”, Cancer
versus immunological diversity, the Darwin
Cancer Blog, March 2016.
[4]
See e.g. Cancer
and the Immune System: The Vital Connection, a free eBook on the history of
cancer immunotherapy, from the Cancer Research Institute (CRI).
[5] Cancer immunotherapy has come to be
called IO (Immuno-Oncology).
[6] The Contrarian Who Cures Cancers, Quanta Magazine, February 2020.
[7] Melanoma Patient Miracle: Sharon
Belvin's Immunotherapy Story, Cancer Research Institute, July 2021
[8] Stage 4 is the most advanced,
metastatic stage.
[9] Non-small cell lung cancer (NSCLC)
is the most prevalent form of lung cancer, comprising around 85% of all lung
cancers. Checkpoint inhibition is primarily successful in the highly mutated
NSCLC found in smokers.
[10]
See, for example, Immune
Checkpoint Inhibitors, National Cancer Institute