4. Immunotherapy:
The Next Wave of IO
Immunotherapy for cancer is currently somewhat of a “roll of the dice”, but it is still early in the learning curve
Immunotherapy for cancer, formally known
as Immuno-Oncology or IO, is the newest treatment modality
for the disease. In our previous blog we looked at immune checkpoint inhibitors,
the IO breakthrough which has put this modality on the map over the past decade.
Yet despite the promise shown by these treatments, including some cures of
advanced cancers, they are still somewhat of a “roll of the dice”, with around
a 1 in 5 chance of a substantive response.
This, however, is not entirely unexpected. The
immune system is extremely complex (and a long way from being fully understood);
while cancer is a large collection of extremely complex diseases, each instance
of which is unique. Putting two such complex systems in opposition to each
other is bound to raise issues. The new technology of IO is still early in its
learning curve[1],
with significant upside potential for improvement.
And things are moving fast. The checkpoint
inhibitor breakthrough led to an explosion in research, trials and new learnings.
We are now already in the early phases of the next wave of IO.[2]
The next wave in IO; pieces of the puzzle
So, what are these latest developments? The
puzzle is far from complete, but here are some of the more important pieces.
i.
The
immune response is a process, not an event.
The immune response builds over a sequence of steps, like an army
invading a castle.[3]
Are the soldiers armed and trained? Have they been transported to the scene of
the battle? Are they able to penetrate into the inner confines of the castle? Are
they able to kill the king? All of this has to happen for the mission to be
successful. A breakdown or blockage
at any stage in this process will cause the mission to fail.
ii.
The
tumour has to be hot for cancer killing to occur.
The soldiers of the immune system are called killer T-cells. If the
T-cells are armed and loaded (known as ‘primed’), and have penetrated into the tumour
environment (the castle grounds), then the tumour is said to be hot. If the
tumour isn’t hot, then armed T-cells are not present at the site of the cancer
and killing cannot occur.
iii.
But
many tumours are cold:
What can cause a tumour to be cold? There are a number of possible obstacles
along the path to a hot tumour. Examples of such obstacles include:
·
the
tumour may not be very ‘immunogenic’ – i.e., there may not be sufficient targets
on the cancer cells to enable the T-cells to recognize the cancer cells as
dangerous,
·
there
may be checkpoint defenses operating earlier in the immune process which
prevent the T-cells from priming (more on this below),
·
there
may be ‘bad actors’, cells and/or substances, sent out by the tumour to prevent
T-cells from getting close to the cancer cells[4].
iv.
Turning a cold tumour hot.
If a tumour is cold, then the first step is to identify the key blockage
(or blockages) in the immune process causing the cold ‘immune desert’. This is done
through a process called immune profiling and the outcome of this
process is particular to each cold tumour. Based on the results of the immune
profiling, a treatment or a set of companion immune treatments will be required
to remove the key blockages and thereby turn the tumour hot.
v.
But
even a hot tumour does not guarantee cancer killing.
A hot tumour is necessary, but not sufficient, for cancer killing to
occur. Cancer cells themselves can also develop a defense (checkpoints) to
cloak them against the immune system. The checkpoints directly on the cancer
cells are called the PD (programmed death) checkpoints (as described in our
previous blog). So, even if a tumour is hot, it may still require the
addition of a PD checkpoint inhibitor to enable the killing process to occur.
vi.
The
end result may well be a combination IO treatment.
·
If
the tumour is hot, then the treatment may just require a PD checkpoint
inhibitor. This was part of the first wave in IO as described in the
previous blog.
· But, If the tumour is cold,
then the PD checkpoint inhibitor must be supported by treatment(s) to remove
blockages, as determined by immune profiling. This is the next wave –
and is called combination IO treatment.
Combination IO treatment; two examples
A first example - combining two
checkpoint inhibitors:
Two different checkpoints were discovered in
the initial IO breakthrough. As we have just seen, the one that operates
closest to the killing zone, indeed directly at the interface between T-cells
and cancer cells, is called the Programmed Death (PD) checkpoint. One of the
best-known PD inhibitors is Nivolumab (often called Nivo). The application of Nivo
in a hot tumour is often effective.
But the other checkpoint, the one discovered by
Allison[5],
acts earlier in the immune process. If this checkpoint is active then it puts a
brake on T-cell activation (priming), an earlier stage in the immune process. This
will then result in a cold tumour. The most common drug to inhibit this checkpoint
is Ipilimumab (often called Ipi).
This suggests that the combination of Ipi and
Nivo can increase treatment response in some cold tumours. And indeed, this is
the case, as was shown in a recent review of a 6+ year Melanoma trial[6].
Let’s build up the story:
·
10
years ago, before checkpoint inhibitors were introduced, only 1 in 20 people
survived advanced lung cancer for 5 years or more,
·
Ipi
was the first checkpoint inhibitor to be approved and that increased the
survival rate to 1 in 5
·
Nivo
(closer to the killing point) as a monotherapy, increased that to 2 in 5
…. but then, importantly ….
· Using Ipi and Nivo in combination
further increased the survival rate to 1 in 2.[7]
From 1 in 20, to 1 in 2 in 10 years; a major
transformation in a deadly disease.
A second example - IO plus radiation:
Now we add an additional piece of the puzzle. The
tumour must also not be too large, otherwise, it can exhaust the T-cell
response. For large tumours, additional treatment support is required to
help debulk it.
Conventional treatments such as chemotherapy
and radiation are good at dealing with bulk disease (but have difficulty eliminating
every last cell), while the immune system works best when eradicating small amounts
of residual disease. This suggests a combination treatment consisting of
conventional treatment, such as radiation, plus IO for larger tumours.
But there is more…..
Radiation can also stimulate the immune system
by generating antigen release from the dying tumour cells; effectively using
the resulting immunogenic cell death as a form of vaccine.
Let’s look at this again, slowly:
When
radiation kills cancer cells, it not only debulks the tumour but also creates cell
debris;
Some
of this debris can be recognized by the immune system as foreign antigen;
Which
then acts as a vaccine against the cancer, thereby priming the immune system.
Combined IO and radiation is a synergistic combination treatment. [8]
By now it should be clear that there isn’t an
‘off-the-shelf’ combination IO treatment. Each combination treatment needs to
be personalised to a particular cancer. So, what will combination
IO treatment look like in future? Here is a scenario, from an article by Padmanee
Sharma, M.D., PH.D.[9]
“If I were to imagine a patient
of the future, it starts with understanding their tumour. Perhaps we could get
a liquid biopsy from a blood sample to study the circulating tumour cells and
learn the unique features of their tumour’s microenvironment. If their tumour
has a particular mutation, we know that we can use a targeted therapy designed
for that mutation.
We can also learn, for example, if
their tumour has high numbers of myeloid cells[10], which can weaken an immune response. Then, we know that we need to
combine our targeted therapy with a drug to block myeloid cells. Perhaps we
then incorporate an immunotherapy to boost T cell activity and eliminate the
tumour.
The idea is to give these treatments
in synergy, with the right combination for an individual patient and the unique
features of their cancer. It’s not a treatment for breast cancer or for
prostate cancer, per se. It’s a treatment strategy for a specific tumour and
immune environment”.
The key thing to note here is just how highly
personalised this treatment is. It is hard to envisage best practice and
standards of care here, this is ‘tailored to fit’. But this is not unexpected.
Advanced cancers have high variety and so require a high variety treatment
response. Only variety absorbs variety.
And, of course, this is only a scenario. We are not there yet in practice. Nevertheless, I would choose a combination IO as my preferred option if I were to be diagnosed with an advanced cancer right now.
So, what would I do?
Combination IO is at the leading
edge of IO development; a place where there are a lot of ideas and theories,
but still a way to go in terms of hard science and, especially, clinical evidence.
A choice to pursue IO treatment right now, especially if the tumour is cold,
would be a risk - indeed, a ”trial”.
So rather than concluding with specific
guidelines and recommendations, I rather describe what I would do if I were
diagnosed with an advanced cancer.
i.
First and foremost, I would choose to explore IO as my primary treatment
option.
The
reason for this is that I would seek to pursue a cure. And, currently, IO
is the only modality that has shown potential to cure an advanced cancer[11].
It need not necessarily be only IO, but all treatments should, as far as
possible, be in support of the primary IO thrust.
For
example, I would avoid long intensive chemo and/or radiation treatments; they
destroy the immune system. Though, if necessary, I would consider appropriate
use of these conventional modalities to reduce tumour burden in a way that as
far as possible would promote immunogenic cell death as a vaccine.
And when I say I will pursue IO, I am not just talking about checkpoint
inhibitors - I am talking about a personalized, holistic, adaptive, IO combination
strategy, if that should prove necessary.
ii.
But it would not be easy, especially if the tumour were found to be cold:
Clinical IO is a new technology. It requires knowledge
and experience which are not widely available. I
would also not expect to get enthusiastic support from my primary oncologist. Recommendations
would more than likely be driven by standard of care considerations (“do what
is known to work first, you can always try IO later”).
But
… the standard of care will not cure; it would also more than likely damage the
immune system. Furthermore, IO is more effective if used earlier rather than
later. The question I would be asking then is: “Why shouldn’t I use IO rather
than why should I?”
If
there were to be limited encouragement from the primary oncologist, I would
seek to find an alternative entry point into the IO world. Armed with Google,
that may not be as difficult as it sounds. My home country is South Africa; a
Google search quickly finds a good starting point.[12]
Health insurance support should always be a consideration, of course (IO
is far from cheap); although doing it through a clinical trial or a series of
clinical trials should help limit the financial burden. I would look to involving
my health insurance consultant in my planning team.
Then, working with my primary IO consultant, we could potentially open
up a world of expertise using based on selected video consultations.
I conclude with words from Dr Jim Allison.
“Immunotherapy
is really adaptable. The three pillars of cancer treatment are surgery,
radiation and chemotherapy. What’s unique about immunotherapy is that it can be
given in tandem with any or all of those. So, when I first started looking at
it, I anticipated there would be a lot of combinations tried. And I believe
that one day, immunotherapy is going to be a part of every successful
combination that’s used to treat cancer.”[13] [14]
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
[1] All
new technologies go through a learning curve (think, for example, of
information technology - from large mainframes in the 1960’s to the current hand-held
smartphones). The new technology of IO is no exception, still early in its
curve, in contrast to chemotherapy which is a mature technology with limited
further growth potential.
[2]
See, for example, Dr Jedd Wolchock in The Future of
Immunotherapy: Building on Checkpoint Blockade in
The ASCO Post, April 2019.
[3] This castle analogy is taken from an
excellent Roche website article Beyond the Immunity Cycle. The
article was written by Drs. Ira Mellman and Dan Chen, two of Roche’s most
prominent scientists.
[4]
Potential “bad actors” here include defensive cells mobilised by the tumour (we
will see so-called myeloid cells referred to later), as well as some tumour
induced “chemical warfare”.
[5] See the previous blog.
[6] Long-Term
Outcomes From CheckMate 067: Nivolumab/Ipilimumab, Nivolumab, or Ipilimumab in
Advanced Melanoma,
The ASCO Post, September 2021.
[7] Furthermore,
if one looks at the survival curves, they're really quite flat after 3 to 5
years, suggesting that the survival rates quoted would pretty much continue to
hold beyond the 5-year horizon.
[8] Provided
the radiation treatment is appropriately dosed - see e.g., In Era of Immunotherapy, Radiation
Therapy May Become Essential Component of Systemic Treatments of Cancer, The ASCO Post, February 2019.
[9] Dr
Sharma is the professor of Medical Oncology and the Scientific Director of the
recently formed James P. Allison Institute at MD Anderson. The article is What is the future of
immunotherapy?
[10] One of the “bad actors” mentioned
earlier.
[11]
Let me qualify that, though. Of course, I would want to work through the genetic
profiling as well – one needs to know one’s enemy thoroughly. If the genetic testing were to show
the presence of one of the better-known key driver-mutations then it would be
given strong consideration. See, for example, Janet’s story in Blog 1. But such
cases of ‘addiction’ in advanced cancer are relatively rare, though always
worth looking out for.
[12] Discovery Foundation supports oncologist’s passion.
[13] Nobel Prize-winning researcher: The future of immunotherapy for
cancer treatment - Jim Allison Ph.D., Cancerwise, MD
Anderson Cancer Centre, November 2019
[14] And
we are not just talking about advanced cancer. The use of IO for earlier
stage cancer is also moving very fast, a topic for a future blog.