IO to reduce the
risk of recurrence in earlier-stage cancers.
Previously
In the previous 2 blogs we looked at IO for late stage
(“Bad”) cancers.
·
First, we looked at the Immune Checkpoint
Inhibitor breakthrough (blog 3)
·
and then the next wave, that of IO combination
treatment (blog 4).
We concluded blog 4 with Allison’s comment: “And I
believe that one day, immunotherapy is going to be a part of every successful
combination that’s used to treat cancer.”
A new area that is starting to take off now is IO for
earlier-stage cancers (what we have called “Intermediates”). In particular we
will look at the use of IO to reduce the risk of recurrence in the treatment of
“Intermediates”.
Intermediates and the risk of recurrence
We use the term “Intermediate” for a cancer that is
intermediate in stage (stage 1 to 3) as well as in grade (grade 2).
Importantly, it is a cancer that is localised and has not spread.
Being localised it can usually be treated conventionally
(surgery and/or radiation) and, importantly, treated with the objective of CURE
(“If caught early enough: just cut it out, game over”).
But there is always a risk of recurrence (“If just one
cancer cell escapes …”). Recurrence occurs when a cancer comes back after
treatment, usually after a period of time during which the cancer could not be
detected. The cancer may come back to the same place as the original (primary)
tumor or to another place in the body (i.e. either escape during surgery, or else
more distant micro-metastases which were unobservable before and during
treatment).
Recurrence rates after surgery for intermediate cancers are roughly
in the range 10 to 50%, depending on the cancer type and the stage of the
cancer[1].
Therefore, if there is any doubt, it is better to err on the
side of aggression … insurance. This usually takes the form of adjuvant treatment[2].
But IO is opening up an intriguing new option.
[2] The
NCI cancer dictionary defines adjuvant treatment as “additional cancer
treatment, given after the primary treatment, to lower the risk that the cancer
will come back”. And goes on to say “usually, these treatments include
chemotherapy, radiation therapy, and hormone therapy”.
Neoadjuvant
IO to reduce the risk of recurrence:
In discussing IO for risk reduction, we have to introduce
another new term – that of ‘neoadjuvant treatment’. The NCI cancer
dictionary defines neoadjuvant treatment as treatment “given as a first step to
shrink a tumor before the main treatment, which is usually surgery, is given”. But
IO has added a new dimension to neoadjuvant treatment. Using IO prior to
surgery can, in effect, kickstart an immune response against the cancer.
Here is the logic[1]:
Firstly, the cancer needs to be immunogenic; i.e.,
sufficiently “foreign” so that the immune system can see it (so it won’t work
for all cancers).
·
In this case, immune T-cells which can target
the tumor cells may well be present in the tumour prior to any treatment (though
obviously not in sufficient quantity to eliminate the tumour).
·
Under these circumstances, Immune Checkpoint
Therapy in the neoadjuvant setting has the potential to kickstart the immune
system, giving the existing immune response a massive jolt
·
And then, after the tumor is surgically removed,
those T cells can migrate into the circulation to go after any cancer cells
that still remain (and which could potentially cause recurrence).
·
Noting that Immune Checkpoint Therapy after
surgery (adjuvantly), cannot achieve the same result as there will be
insufficient T-cells left over to get the kickstart required.
Additionally, neoadjuvant IO could possibly even help avoid
surgery.
·
See for example: “Results from several clinical
trials suggest that, for some people with earlier-stage cancers, a short course
of treatment with immune checkpoint inhibitor may be all they need to eliminate
their cancer. More than half of these patients had no evidence of cancer in
the tissue removed during surgery, called a pathologic complete
response”[2].
[1] See e.g. Immune checkpoint therapy: Forging
ahead, P.Sharma and James P Allison, Science Translational Medicine, Nov 2022 (especially the
section: Testing ICT s Frontline Therapy), as well as Immunotherapy
before Surgery Appears Effective for Some with Melanoma, NCI, October 2022
[2] Immunotherapy and… Nothing Else?
Studies Test Potential Paradigm Shift in Cancer Treatment, National
Cancer Institute, Feb 2023
Current status
This is still an early technology, although there are
already some approvals: see, for example, the approval in March 2022 for neoadjuvant
therapy (followed by surgery) for an important class of early-stage lung cancers[1].
There are also a number of trials underway, especially for
the more immunogenic cancers. Here is a typical result from a trial in Melanoma:
“At 2 years, 72% of those in the neoadjuvant therapy group were still alive
without an event, compared with 49% in the adjuvant therapy group”.[2]
There are some issues, however
A potential concern with the neoadjuvant therapy approach is
that if the cancer doesn’t respond to IO and gets worse, there’s a risk that
surgery may no longer be an option. In the melanoma trial above, 42 people in
the neoadjuvant group had some evidence of progression of their cancer during
the neoadjuvant therapy period. However, in 30 of them, the progression was
limited and they were still able to undergo surgery (so 12 of them, then, had
to forgo surgery).
Furthermore, delay in surgery comes with increased anxiety. For
example: “When patients are diagnosed with lung cancer and they're told that
surgery offers the potential of cure and then hear that you're giving them a
treatment before surgery and that treatment may potentially delay surgery, that
is a huge source of anxiety”.
So, it is important to find out early if the neoadjuvant
therapy is going to work.
But there is an emerging opportunity in this regard.
Liquid biopsy to track response: an emerging opportunity
Liquid biopsy, which we covered in our book, is an important
and fast emerging technology. It is defined in the NCI Cancer Dictionary here.
It has multiple potential applications, which can include the
tracking of the early response of a cancer to neoadjuvant IO as well as testing
post-treatment to see if there is any sign of recurrence.
We are not going to get into this here, it is a subject for
a future blog. If you are interested, here are two papers you can look at:
Personalised
blood test could help predict which lung cancers might return, Cancer Research
UK, April 2022, and Liquid Biopsy Assay Can Predict
CRC Recurrence Early - Medscape - Apr 27, 2023.