How Covid Vaccines Might Help Fight Cancer

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Researchers have discovered that Covid-19 mRNA vaccines may be able to improve the responsiveness of tumours to certain cancer drugs, even though the mRNA these vaccines carry has nothing to do with cancer. This means these already widely available vaccines could potentially make existing cancer treatments more effective at relatively little cost. But what’s going on here, and how did researchers reach this conclusion?

The Problem: How Cancers Trick The Immune System

‘Immune checkpoints’ are regulatory molecules found on the surface of immune cells. These can either activate or inhibit an immune response upon interacting with molecules on the surface of their potential targets. Immune checkpoints that inhibit the immune response are important for ensuring that the immune system doesn’t attack the body’s own cells and tissues unless they are infected by pathogens. Unfortunately, cancer cells can use this to their advantage by activating inhibitory immune checkpoints, thereby preventing immune cells from attacking the tumour.

Immune checkpoint inhibitors (ICIs) are anti-cancer drugs that work by blocking these inhibitory immune checkpoints, essentially “taking the brakes off” the immune system and allowing the body’s own T cells to attack cancer cells. ICIs were a significant breakthrough in cancer therapy when they were first developed, but they only work well in patients whose immune systems are ‘trying’ to eliminate the cancer – their immune cells have infiltrated the site of the tumour but are simply unable to do much. By contrast, some patients don’t mount much of an immune response to begin with, either because the cancer hasn’t mutated enough to be recognised as a problem, or because it has developed other ways of keeping immune cells away.

Vaccines to the Rescue?

One strategy for sensitising such tumours to ICIs is to ‘vaccinate’ patients against their own cancer. This would involve finding molecules that are produced by their cancer cells (but not healthy cells), creating mRNA that encodes those molecules and delivering it in the form of an mRNA vaccine. This is the same technique used to produce some Covid-19 vaccines – by delivering mRNA encoding the spike protein. However, since everyone’s cancer mutates differently, a personalised vaccine would need to be created for each individual patient – a challenging and costly endeavour. Treating everyone with the same mRNA wouldn’t work – or would it?

Kicking The Immune System Into Gear

While Covid vaccines may not have been designed with cancer in mind, researchers knew that these vaccines triggered a strong immune response. They also knew of anecdotal reports of patients’ tumours unexpectedly shrinking after they received mRNA Covid vaccines. Combined with some of their previous research, this was enough for them to suspect that these mRNA vaccines, while not specifically designed to target cancer cells, might produce sufficient immune activation to make a difference anyway.

Researchers first looked at observational data, and found that receiving an mRNA-based COVID-19 vaccine within 100 days of starting ICIs was associated with a remarkable doubling in survival rates after three years compared to those who did not receive a Covid vaccine or who received a non-mRNA Covid vaccine. The strongest benefits were seen in patients with tumours that are usually resistant to ICIs, who showed a 5-fold increase in survival rates. Though this analysis controlled for confounding factors, correlation isn’t causation, so the researchers conducted a controlled experiment in mice. They gave mRNA vaccines or a control treatment to mice carrying various types of tumour that are typically resistant to ICIs. As hoped, they found that ICIs were more effective at helping the immune system to reject the tumours when they were combined with commercial Covid mRNA vaccines.

The researchers then returned to human data to see if they could find molecular evidence for these effects. They conducted a retrospective analysis of over 2315 cases of non-small cell lung cancer and looked at the expression of PD-L1 in cancer biopsies. PD-L1 is a molecule that cancer cells express in order to activate an inhibitory immune checkpoint on T cells (PD-1), telling the T cells to stand down. PD-1 is the target of several ICIs. The researchers found that patients who had received a Covid mRNA vaccine less than 100 days before the biopsy had significantly higher levels of PD-L1 than those vaccinated earlier or who were unvaccinated. While this might sound like a bad thing, it’s actually a good sign, because it shows that the cancers were having to respond to an attack by T cells and could therefore be susceptible to ICIs.

In an attempt to gain some insight into the underlying mechanisms in humans, blood and plasma samples were collected from five healthy volunteers after receiving the mRNA-1273 vaccine and 11 volunteers after receiving the BNT162b2 vaccine (both of which are mRNA Covid vaccines). The researchers observed a dramatic, short-lived surge in inflammatory cytokines (signaling proteins of the immune system), particularly one called IFNα at 24 hours post-vaccination. This was accompanied by widespread activation of all parts of the immune system, including activation of T cells.

What’s Special About These Vaccines?

It seemed as though these Covid vaccines were particularly effective in activating the immune system in a way that promoted an anti-tumour response, but why? The researchers asked if the Covid-19 spike protein could be responsible. They replaced the spike protein mRNA with mRNA encoding an antigen from another virus, but found that there was no significant difference in the anti-tumour response with this new mRNA. This suggested that the specific protein encoded by the mRNA was not important. Rather, the mRNA molecule itself and its delivery system (the lipid nanoparticle) appeared to be the main drivers of the immune reaction.

The researchers found that they could significantly increase the effect of the vaccine by swapping one type of nucleoside (the molecules that form both the ‘backbone’ and code of the RNA strand) with an alternative version that triggers a stronger immune response, but has the same genetic ‘meaning’. They also found that the mRNA + lipid nanoparticle combination was able to activate a sensor (called MDA5) that is usually triggered by double stranded DNA. This led to the production of an antiviral molecule (type I interferon) that activates immune cells, including T cells. When this molecule was blocked, the effects seen previously in mice were completely gone.

The Implications

This research could be highly significant, as it suggests that readily available mRNA vaccines may activate the immune system enough to transform “cold” tumours into “hot” ones, making them responsive to ICIs. If it turns out that we can achieve this using “off-the-shelf” vaccines, rather than complex personalized ones, cancer therapy could suddenly become a lot more effective for a large number of people.

This is not to say that personalised vaccines against cancer-specific antigens won’t still be useful. Rather than simply triggering a broad activation of the immune system, such vaccines should further enhance the immune system’s ability to recognise and destroy cancer cells regardless of whether the tumour is ‘hot or cold’. Yet since mRNA Covid vaccines are already approved in humans, they could reach the clinic a lot sooner.