Immune Checkpoint Inhibitors

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.