Engineering a cancer-fighting immune super soldier
There are tens of millions of white blood cells in just one teaspoon of your blood. But this is just a tiny part of a vast and complex disease-fighting army that constantly patrols your body: your immune system.
Just like a real army, these troops fall into a variety of different roles – but perhaps its most powerful soldiers are called T-cells.
Your immune system has two main T-cell battalions. ‘Helper’ T-cells respond to problems by releasing signals that rally the other immune troops on the battlefield. And their comrades, ‘killer’ T-cells, deliver lethal injections directly into their enemies.
T-cells are very good at targeting infection, but when it comes to combating cancer, neither of these highly trained battalions seems to be able to tell the difference between a cancer cell and its healthy neighbor. As a result, tumors manage to hide – and grow – in plain sight.
So how can scientists unlock the power of T-cells to fight cancer?
Researchers have been trying lots of different strategies – some of which have had significant early victories.
And one of the most exciting and sophisticated approaches sounds like something taken straight from the plot of a Hollywood movie: researchers are turning T-cells into genetically engineered super soldiers, completely redesigning their targeting system, and allowing them to recognize cancer cells and wipe them out.
Let’s have a look at the promise – and challenges – of engineered T-cell therapy.
Identifying the enemy
When your body’s cells become damaged or infected, they alert the immune system by physically displaying signs of their internal problems on their surface. They do this with molecules called Major Histocompatibility Complex (MHC) proteins, which have a built-in groove that can hold a fragment of enemy protein up for inspection by passing T-cells.
T-cells wander through your body, scanning MHC molecules as they pass using their own specialist surface molecules, known as a ‘T-cell receptors’.
Amazingly, each of your millions of different T-cells has a slightly different T-cell receptor, and will only start to activate if it detects its exact foe.
Before it can attack, the T-cell has to wait for more orders from other immune cells – this helps prevent friendly fire. But once it receives these orders, it arms its weapons, and then starts to multiply furiously, producing an army of clones.
And then, everything in place, weapons armed… the clones attack.
But cancer cells are experts at hiding from the prying eyes of T-cell receptors. Researchers have identified a bewildering array of tricks and tactics they use to do this, from hiding their MHC molecules so that the T-cells cannot see what is going on, to producing other molecules that put the T-cells to sleep.
So what if we could keep them awake? Now, researchers believe they can offer T-cells an upgrade, turning them on the cancer cells so they can mount a proper attack.
And for inspiration, they’ve turned to a completely different type of immune cell, known as a B-cell.
While T-cells’ receptors can struggle to identify cancer cells, B-cells are able to release a completely different type of weapon: antibodies. These immune cell warheads are able to see through cancer’s disguises. And for many years, researchers have known how to engineer antibodies to stick to particular molecules found on cancer cells – a process that works entirely independently of the MHC display system T-cells use to spot and target problems.
In the clinic, these engineered antibodies are already being used to treat a number of different types of cancer.
The problem is that while antibodies can stick to cancer cells, they don’t have the killing power of T-cells. So what if the two weapons were combined? What if T-cells could be armed with antibodies’ detection capabilities?
That’s the goal of engineered T-cells.
Engineering a super T-cell
The fundamental idea behind engineered T-cells is the creation of a hybrid molecule, stuck to the T-cells’ surface, combining the cancer-homing power of antibodies with the deadly killing abilities of an army of T-cell clones.
And now, after more than three decades of testing, researchers are closing on exactly that: Chimaeric Antigen Receptor T-cells, or CAR T-cells.
These immune super soldiers are made using healthy T-cells taken from a patient’s blood. They are given the genetic instructions to make cancer-seeking antibodies in addition to their normal T cell receptor, and are forced to replicate to form an entire upgraded army. They are then injected back into the body to seek out cancer cells.
When these upgraded T-cells encounter cancer cells, they use their carefully designed hybrid warheads instead of the standard T-cell receptor, bypassing the cancer’s defenses and destroying the tumor cells.
But does this approach actually work?
Putting it into practice
Researchers really got excited about CAR T-cells back in 2011 when Professor Carl June and his team at Pennsylvania State University published the results of a small trial on three patients with lymphoma. Their modified immune soldiers were working.
All three patients responded to the treatment, two entered remission, and the CAR T-cells were estimated to have killed 1,000 cancer cells each. A really promising result.
But this was only a very small study, and there are still huge technical challenges to overcome. The immune system is a powerful weapon, and CAR T-cells are still in the very early stages of development. They need to be tweaked and modified to ensure that they don’t cause too much collateral damage.
Targeting is a critical part of the design process for an immune super soldier. Once their weapons are armed, T-cells will hunt their enemies relentlessly, so choosing the right molecular target is vital.
Most of the research so far has focused on blood cancers that develop from B-cells, including acute lymphoblastic leukemia, chronic lymphocytic leukemia and non-Hodgkin lymphoma.
Because these cancers all arise from B-cells, they have one important thing in common: they all make a molecule called CD19.
Researchers have produced CAR T-cells that will recognize CD19 and attack any cell that makes it, and in early phase trials these super T-cells have performed well. In a number of different early phase clinical trials, CAR T-cells have launched successful attacks on cancer cells, helping patients who had exhausted all other treatment options to enter lasting remission. But there’s a catch: CD19 is found on all B cells, not just the cancerous ones, and the CAR T-cells cannot tell the difference. As they fight the cancer cells, the healthy cells become caught up in the crossfire.
Patients can survive without B-cells, but they need lifelong drug treatment to compensate.
More work to do
While CAR T-cells targeting CD19 are showing promise in these forms of blood cancer, finding targets on other cancer types is proving a challenge.
If CAR T-cells recognize molecules found on healthy cells, they can do more than just attack them. In the heat of the battle, the entire battalion can whip itself into a frenzy, releasing huge quantities of powerful chemicals in a response known as a ‘cytokine storm’.
And, while CAR T-cells might be capable of chasing down cancer cells in the blood, solid tumors have extra layers of defense against immune attack, and breaching this barrier will be difficult.
There are some promising targets for types of brain cancer, head and neck cancer, and lung cancer, but early clinical trials have been much less successful.
To get around the potentially life threatening problem of friendly fire, some labs are trying to engineer a ‘kill switch’ to turn CAR T-cells off if they get out of hand, or once the cancer cells have been killed. Other labs, paradoxically, are experimenting with CAR T-cells that actually stick to their targets more weakly – and this is looking promising.
Our own scientists are also looking into how we can use CAR T-cells equipped with a kill-switch to treat solid tumors. And Professor John Anderson and his team at University College London and Great Ormond Street Hospital are now preparing their upgraded T-cells to be tested in early phase clinical trials.
The latest generations of CAR T-cells are now also being engineered to resist the inactivating influence of solid tumors, and some are even being trained to target the cells that shield the cancer from immune attack.
It’s still early days, and designing safe and effective CAR T-cells is going to take time, but the progress that has been made already is very encouraging.
We need to know that we can keep these super soldiers under control before we unleash their full potential in the clinic. But if we can get it right, the immune system could become a powerful weapon in the fight against cancer.