Immune Checkpoint Inhibitors
https://teachim.org/teaching_material/immune-checkpoint-inhibitors-2/
Objective(s)
1. Develop a visual model for how the immune system interacts with
tumor cells.
2. Describe the most common types of immune checkpoint inhibitors
and their indications.
3. Identify the most common side effects of immune checkpoint
inhibitors and initial steps in management.
4. Utilize the NCCN guidelines to initiate treatment of common and
severe immune checkpoint complications.
Teaching Instructions
Plan to spend at least 20-30 minutes preparing for this talk by using the
Interactive Board for Learning/Preparing and clicking through the graphics
animations to become familiar with the flow and content of the talk.
The anticipated time to deliver this talk is about 10-15 min without
cases and 20-25 min with cases. It can also be divided into two
separate talks.
The talk can be presented in two ways:
1. Project the “Interactive Board for Presentation” OR
2. Reproduce your own drawing of the presentation on a whiteboard.
With either method, we recommend printing out copies of the Learner’s
Summary Handout which has the cases so they may have this for
reference after the discussion.
Begin with reviewing the ‘why do we care’ section, objectives and
clickable elements for the session. We recommend progressing in order,
as each concept builds upon the prior concept. All clickable elements are
indicated by a cursor icon.
Why do we care?
We recommend framing the talk with ‘why should you care?’ given the
granularity of the subject matter and to improve buy in from your learners.
Here are some bullet points to drive home the importance of this
discussion.
~40% of cancer patients will be treated with an immune checkpoint
inhibitor1
You may see complications/side effects of these medications on
wards or in ICU
These side effects can occur at any point during treatment or even
months after1
Immune system basics
Suggested prompt: Does anyone remember how your adaptive
immune system recognizes infected cells or cancer cells?
Cancer cells differ from regular cells in that they have undergone
mutations in various proteins to allow them to grow in an unregulated
manner. On the surface of all cells is a molecule called major
histocompatibility complex or MHC for short. This MHC molecule displays
pieces of the proteins that cells express to show the immune system
whether it is a healthy cell, an infected cell, or a cancerous cell. T cells,
part of the adaptive immune system, can recognize cancerous cells that
are expressing pieces of these mutated proteins on the MHC molecule
which binds to the T cell receptor (TCR). When T cells ‘see’ a cancerous
cell through this TCR-MHC interaction, they kill the cancer cell by secreting
toxic granules. The immune system is constantly surveying our bodies for
cancerous cells and in most cases, successfully destroys these cells before
they develop into tumors. When cancer cells figure out a way to ‘hide’
from these T cells, then tumors can develop
How tumors ‘hide’:
Tumor cells can ‘hide’ from the adaptive immune system through various
mechanisms.
One of these mechanisms it by expressing a molecule
called Programmed Death Ligand 1 (PD-L1) which can bind to programed
death 1 (PD-1) on T cells. This interaction ‘puts the breaks’ on the T cells
and effectively prevents this T cell from killing the tumor cell. Similarly,
tumor cells can express various ligands that bind to cytotoxic T-
lymphocyte-associated protein 4 (CTLA-4) on T cells which again ‘puts the
breaks’ on the T cell and prevents it from killing the cancer cell.
Immune checkpoints:
This mechanism of ‘putting the breaks’ on the adaptive immune response
is a mechanism that tumors have hijacked from our regular cells. Our
normal tissue, expresses these molecules (PD-L1 and ligands for CTLA-4)
which are collectively called immune checkpoints. Immune checkpoints
help prevent the adaptive immune system from destroying your normal
tissue which would lead to autoimmune diseases
Immune checkpoint inhibitors:
Suggested prompt: What do you think would happen then if we
blocked these immune checkpoints?
In order to ‘take off the breaks’ and allow T cells to recognize cancer cells,
numerous immune checkpoint inhibitors (ICIs) have been developed.
These drugs are monoclonal antibodies that can bind to these immune
checkpoint proteins, thereby allowing the T cells to remain active and kill
cancer cells. The drugs listed on the slide represent the current FDA
approved agents as of November 2021. Many more are in development
and are likely to be approved in the coming years.
When do we use ICIs?
Suggested prompt: Has anyone seen a patient on an immune
checkpoint inhibitor? If so what cancer(s) were they treating?
In order to understand when these agents are helpful, we need to go back
to the concept that our immune system recognizes tumor cells and ‘bad
cells’ because of the mutated proteins they express. This is the major way
that our immune system can distinguish normal cells from cancerous cells.
As a result, cancers that have more mutations are more susceptible to
immune destruction because there are more targets for the immune
system to see. The dot plot shown at the top of the slide, stratifies cancer
types across the X axis based on the number of somatic mutations
identified using next generation sequencing along the Y axis. Cancers that
arise from exposure to classic mutagens such as UV light causing
melanoma and tobacco causing lung and bladder cancer have higher
numbers of mutations and are more ‘immunogenic’ or recognizable to the
immune system. Therefore, the cancers listed to the right of this graphic
are more likely to respond to immune checkpoint inhibitors. At the bottom
of the slide are listed all of the cancer types that ICIs are FDA approved to
treat.
Could tie this concept back into whatever cancer type(s) the audience
member stated that they saw being treated with one of these agents.
Side effects of ICIs
Suggested prompt: Based on how these agents work, what types
of side effects would you expect these drugs to cause? Has
anyone seen a patient(s) who had a side effect from an immune
checkpoint inhibitor?
Intuitively, since immune checkpoint inhibitors ‘take the breaks’ off of T
cells in a non-specific manner, these drugs can cause autoimmune
disease. Essentially any organ can be targeted as seen on the ‘All side
effects’ slide. The most commonly effected organs are GI/liver, lungs, skin,
thyroid and pituitary. The frequency and severity of these side effects
depends upon the immune checkpoint inhibitor used. Notably, while the
vast majority of these side effects are reversible with steroids and/or other
immunosuppressive agents, there are a few that are irreversible.
Specifically, myocarditis, adrenal insufficiency and type 1 diabetes (listed
in dark red) are almost always irreversible. Hypo/hyperthyroidism,
hypophysitis and hypopituitarism (listed in orange) can be reversible in
some cases but, irreversible cases have been reported. Again, while most
side effects respond well to immunosuppressive treatment, there are
several side effects that have a high mortality, the most significant of
which is myocarditis which is fatal ~40% of the time that it develops
(though thankfully this side effect is very rare). Is it therefore important to
note that these agents can cause a myriad of autoimmune side effects
ranging from mild to life threatening. Lastly, these side effects can
develop any time during the course of treatment with these agents and
even for many months after treatment has stopped, therefore it is
important to keep these etiologies on your differential if you see patients
who have been treated with ICIs.
Cases – After the completion of the talk, review the practice cases.
Start the cases by introducing the audience to the NCCN guidelines. These
are national guidelines that have been developed by experts and research
in the field to guide management for most cancer types and to toxicity
from common cancer treatment. There is a QR code provided to an
interactive PDF that is used to guide management specifically of immune
checkpoint inhibitor toxicity. Have the audience download this PDF to use
during the case discussion.
Next review the basic framework for how to treat ICI toxicity. The basic
premise is to rule out other causes of their chief complaint (infection,
medication induced etc). Next, if there is high suspicion that this could be
related to ICI treatment, stop the checkpoint inhibitor. Grade the severity
of the toxicity using the NCCN guidelines. Next start prednisone to
suppress the over-active immune response. Finally, if symptoms are not
improving within a few days, refer to the NCCN guidelines to additional
immune suppressive agents that can be used.
Case 1: Metastatic melanoma treated with combination therapy nivolumab
(anti-PD-1) and ipilimumab (anti-CTLA-4) resulting in colitis/diarrhea (most
common side effect). Using the previously discussed frame work, remind
the audience to rule out other causes of diarrhea (namely infection).
Grade the severity of this patient’s colitis using the NCCN guidelines
(should come out to grade 2). Then discuss treatment listed on the slide.
Case 2: Metastatic NSCLC treated with pembrolizumab (anti-PD-1) causing
pneumonitis. This is another common side effect and is often challenging
to differentiate from underlying lung disease such as COPD or infection.
Evaluate for infectious causes. CT imaging can show a wide range of
patterns, but the most common pattern is multifocal peripheral and
subpleural mid- and lower-lung airspace consolidations shown on the slide.
Treatment is listed and can be found again in the NCCN guidelines.
Take Home Point
1. Tumors can ‘put the breaks’ on the immune system by expressing
‘immune checkpoints’.
2. Immune checkpoint inhibitors take ‘off the breaks’ and turn the
immune system on.
3. Immune checkpoint inhibitors are best used for treating cancers with
a lot of mutations (skin, lung etc).
4. Immune checkpoint inhibitors cause autoimmune side effects that
generally respond to steroids.
5. NCCN guidelines are the ‘go to’ resource for guiding management of
toxicities.
References
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Wright JJ, Powers AC, Johnson DB. Endocrine toxicities of immune
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