My name is Dr. Keri Reynolds.

I'm the Clinical Director of Inpatient Oncology at the Massachusetts General Hospital, and I direct the Severe Immunotherapy Complications Service and Program at the Massachusetts General Hospital Cancer Center.

Today, I will cover cancer immune checkpoint inhibitors, drug overview, and mechanism of action.

Immune checkpoint inhibitors have truly revolutionized the treatment of cancer.

The key takeaways for today's video are, describe the mechanism of action of immune checkpoint inhibitors, review the impact of immune checkpoint inhibitors on metastatic patient survival rates, and recognize the applications for immune checkpoint inhibitors for early lines of therapy.

So taking a step back, Immunology 101.

Many times a day, an antigen, the small blue round circle at the top, is presented on an antigen-presenting cell by way of an MHC molecule, a major histocompatibility complex molecule.

It's presented to the TCR, the T-cell receptor, on that bluish-purplish cell, the T-cell.

And that is signal one.

But in order to get immune activation, there has to be a co-stimulatory, a second signal.

That is shown in the red CD80 or CD86, binds with CD28.

And then the T-cell can be off to the races.

It can proliferate, secrete cytokines, and start to migrate to tissue in order to recognize that antigen.

But soon, because we don't want overwhelming activation, soon, there has to be a break or checkpoints on the system to be able to control that immune activation.

And the checkpoints, you can see CTLA-4, it comes to the cell surface.

And then CTLA-4 can out-compete that co-stimulatory signal to get negative regulation as a checkpoint.

Similarly, that T-cell traffics out to the periphery, but soon, it expresses PD-1, programmed cell death one.

In addition, the tissue has ligands.

Both of these checkpoints are negative regulators to decrease immune activation.

Cancer has a way of co-opting the immune system and evading it.

And so in order to have adaptive immune system activation to recognize cancers, drugs have been developed against PD-L1, the ligand, and against PD-1 on the T-cell, and against CTLA-4.

And if we take a step back and look at all of the FDA-approved immune checkpoint inhibitors, there are now nine.

And what has this done for the field of oncology?

It is a true breakthrough therapy.

You will not be able to read every box on this slide, but it's just to show you the FDA approvals over the last decade.

It started in 2011 with ipilimumab for metastatic melanoma.

In addition, PD-1 in 2014 for metastatic melanoma.

At the time in 2011, before we had these drugs, the average overall survival for metastatic melanoma was about a year.

And we had the carbazine chemotherapy that worked about 5% to 20% for a response rate, depending on the literature you read.

And it only worked for a few months.

Now we have patients over 30% up to over 50% living out years and years with melanoma because of checkpoint.

It's a true breakthrough therapy.

And since that time, now there are over 83 FDA-approved indications, as you can see here, in over 17 types of cancer.

Importantly, the boxes, the light blue just show single agent immune checkpoint inhibitor approvals, but the dark blue show combinations.

So we are starting to combine an immune checkpoint inhibitor and an immune checkpoint inhibitor, or immune checkpoint inhibitor and chemo, or immune checkpoint inhibitor and targeted therapy.

So combinations are truly the way forward.

In addition, we're starting to see it in earlier lines of therapy, meaning it's no longer just in metastatic disease.

But in over 17 cancer types, it is approved.

And it's approved earlier in melanoma in lung.

In 2021, it's earlier in esophageal, triple negative breast cancer, bladder, and renal cell.

So new checkpoints are coming down the pipeline.

In fact, there are over 2,000 clinical trials in development with checkpoints.

So this was a document from 2020 that showed that we are estimated to treat over 230,000 patients with checkpoint on standard of care therapy in 2020.

There have been multiple approvals, so that number is higher.

And about 10% to 30% have immune-related adverse events, serious immune-related adverse events.

So that is anywhere from 23,000 to 69,000 individuals with serious immune-related adverse events.

Please see our next video for immune-related adverse events.

But as a summary, we know that immune checkpoint inhibitors are now standard of care, that a subset of patients experience these durable long-term responses.

So this is a good news story.

The success of single-agent checkpoint has led to combination approvals.

And we're moving those therapies to earlier lines of therapy called the adjuvant space.

Thank you so much for watching.

I hope you found this video educational.

And I'll see you in the next video.