Cutting the brake line on your killer immune cells so they can destroy tumours.
Translated from: Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells
As an ode to last year’s Nobel prize in Physiology and Medicine , let’s look a new cancer treatment developed using the same principles. Before we get into that, checkout my quick breakdown of the immunology behind the Nobel prize winning discovery. I’ll wait here….
Welcome back. In case you didn’t get to Nobel prize winning work here’s the TLDR version:
There are two main types of immune cells that can kill cancer cells. Cancer cells can prevent this by hitting the brakes on these killer immune cells. The Nobel prize winners discovered that if you block these stop buttons on one type of immune cell, killer T cells, they can go back to their job of killing cancers. This only works on certain types of cancers and is likely better if you block both at the same time.
Also, before you go any further, if you like mice don’t continue reading, a lot of mice were given cancer to make this new treatment possible.
Back to the research paper at hand.
Main finding: The researchers found that blocking a different stop button called NKG2A, boosts both types of killer immune cell responses to cancer cells. In addition, while on its own it does not seem to be super effective at clearing cancers, it looks like blocking NKG2A and PD-1 (one of the stop buttons from the Nobel Prize winning discovery) at the same time could be a new way to treat some types of cancer.
Why we care: One more step closer to curing some types of cancer. As I mentioned, there are two main types of killer immune cells that destroy cancer cells, these are natural killer cells and killer T cells (officially called CD8+ T cells). Both of the cancer treatments developed in the Nobel Prize winning discoveries block stop buttons for killer T cells. This new discovery lets loose both types of killer immune cells. This means that cancers that manage to escape the killer T cells, which will inevitably happen in some cases, can get killed by natural killer cells. Also, because natural killer cells have different ways of recognising and killing cancer cells, they might work well with other therapies that activate different parts of the immune system. The clinical trials (i.e. experiments involving people) are still in their early stages but it’s looking promising.
How they worked it out: The stop button NKG2A (this is its old name, it is also called Killer Cell Lectin Like Receptor C1 or KLRC1) and its presence on natural killer cells and some killer T cells has been known about since the 1990’s. The stop button is activated when NKG2A binds to its partner HLA-E (human leukocyte antigen E) which is found on normal cells. HLA-E is one of those flags that cells stick out to show off the proteins they are making to killer T cells.
The researchers who wrote this paper used tumour transplant models in mice to show that the stop signal (HLA-E binding to NKG2A on natural killer and killer T cells) promotes tumour growth. To do this they injected cancer cells into mice and measured the size of the tumours that grew (generally lumps at the site of the cancer cell injection). Cancer cells that had the stop button presser (HLA-E) grew into big tumours faster than cancer cells that didn’t have it. When they looked in the tumours, they found plenty of killer immune cells, but a lot of them had the stop button (NKG2A), this suggested that they could get into the cancer, but they couldn’t do anything once they got there.
When the researchers tried to grow tumours from cancer cells that couldn’t press the stop button (they didn’t have HLA-E), it only worked if they first neutralised the natural killer or killer T cells in the mice. This meant that the killer immune cells could kill the cancers if the stop button wasn’t being pressed.
The next step was to turn off the stop signal. Because the stop button presser (HLA-E) has other important jobs, they did this by blocking the stop button (NKG2A). They then went back to their tumour transplant model. What they found was…. blocking the stop button (NKG2A) DID NOT slow down tumour growth. Sad, I know, but scientists don’t give up so easily.
The researchers had noticed that half to all of the killer T cells in the tumours that had their stop button (NKG2A), also had one of the stop buttons discovered in the Nobel Prize awarded work, programmed death-1 (PD-1). So, they blocked both in their tumour transplant model and low and behold, half to three quarters of the mice had little to no tumour growth.
OFF TO HUMAN TRIALS!!
No! First the researchers showed that human cancers actually have lots of HLA-E, and that killer immune cells in these tumours have the stop button (NKG2A).
Okay, in humans tumours the killer immune cells and component for the stop signal (HLA-E and NKG2A) are there, OFF TO HUMAN TRIALS!
No! Just because the cells are there doesn’t mean they work or that the stop signal is supressing the killer immune cells.
The researches did some fancy experiments to cells in the lab (as opposed to in people or mice) to prove that blocking the stop button (the drug they made to do this in humans is called Monalizumab) boosted the activation and function of killer immune cells. Also, because in mice they needed to block two stop buttons (NKG2A and PD-1), they did these tests using both stop button blockers (Monalizumab blocks NKG2A and Cetuximab blocks PD-1).
So, in humans: the signal is there, the killer cells are there and blocking the stop button boosts killer immune cell responses to human cancers. Off to human trials?
Yes! The researchers did a small trial in patients with a type of cancer where they had found lots of the stop button presser (HLA-E). They treated the patients (for whom other cancer treatments had failed) with both stop button blockers. Three months later, nearly a third of patients had smaller tumours and the side effects were no greater than using the PD-1 blocker (already used as a cancer treatment) alone. This is very promising. The trial is still going so we will have to wait to find out how long it can stop the cancers for and if this combo treatment can cure, i.e. completely removes cancer in any of the patients.
Original publication Andrè P & friends in Cell, November 2018
https://doi.org/10.1016/j.cell.2018.10.014
