This is a rather unexpected article that suggests that some mRNA vaccines can potentiate the actions of some immune-checkpoint therapies used in oncology. Specifically, the authors find that the mRNA coronavirus vaccines significantly increased overall survival rates in those patients who were getting anti-PD-1 antibodies as immune checkpoint inhibitor therapy (!)
In a welcome reverse of the usual way we end up studying cancer therapies, this effect could be replicated in mice. There was a strong synergistic effect of mRNA lipid nanoparticle vaccination and anti-PD-1 monoclonal antibody treatment in mouse cancer models, well beyond what either could achieve on their own. And this seems to be driven through Type 1 interferon pathways (which may remind you of the cancer vaccine work that I blogged about here the other day).
It wasn’t the spike-protein mRNA that did this specifically - the authors replaced that with mRNA against a cytomegalovirus antigen and this vaccination had the same effect. So it’s the immune-potentiating effect of the mRNA dose itself that’s helping, not anything to do with the specific antigen that’s it’s aimed at. The authors went to some trouble to try to figure out the mechanism behind this. They rigorously purified out any remaining double-stranded RNA that might have been in the vaccine doses, but that had no effect. On the other hand, changing the lipid nanoparticle formulation did wipe out the benefits - coupling that with other literature reports, they hypothesize that the LNPs form higher-molecular-weight secondary RNA structures that activate some of the innate immune receptors (like MDA5) that are watching for double-stranded RNA as a sign of viral infection.
They were able to demonstrate strong immune activation in the mice after these doses through multiple interferon-driven pathways, but (interestingly) could only partially replicate it by dosing them with interferon-alpha itself. Both innate and adaptive immune responses kicked into gear. So there’s a lot going on in there, and it’s safe to assume that we don’t know the whole story yet, but what seems clear is that the RNA-LNP vaccination primes the immune system for activation, presentation, and recognition of many tumor-associated antigen proteins, and that these effects are strongly potentiated if you’re simultaneously being treated with immune checkpoint inhibitors like the anti-PD1 monoclonal antibodies.
Another interesting effect was that in human volunteers the cytokine response to the vaccines was stronger with the Moderna shot (mRNA-1273) than it was with the Pfizer-BioNTech one (BNT162b2), and this appears to be a sheer effect of the former vaccine having more total mRNA in it (!) The mRNA vaccines seem to amplify tumor PD-L1 across a wide range of tumor types, and this effect even seems to extend to immunologically “cold” tumors that would otherwise have been considered not to be responding to treatment.
This is really, really good news, and it immediately suggests that patients who are eligible for immune-checkpoint therapy (things like Keytruda, Opdivo, Tecentriq, Bavencio, Imfinzi, etc.) should be dosed with some sort of LNP-mRNA shot right along with it. And it also suggests that there are patients who might not be thought to benefit from such ICI treatment who should be given a crack at it with this protocol, since the enhancement seems so robust. There’s obviously a lot more to be worked out as far as doses of mRNA, timing, formulations, tumor types and all sorts of other factors, but the survival curves in this paper argue against waiting for patients who are being treated right now. The benefits seem to be very real, and the risks - particularly compared to the underlying cancers - seem to be very low. Go for it!
I made this point the other day, and I want to make it again, because it cannot be overemphasized: there is still so much that we don’t know about immunology. We literally don’t know when something great like this will pop up, so we have to keep banging away in these areas and discovering as we go along. And while I’m at it, there is another thing that cannot be overemphasized: if you are spreading doubts and fears about vaccines and about mRNA research, you are killing people who could benefit. Killing them by not protecting them from the diseases being vaccinated against. Killing them by making them suspicious of advances in medical science in general. Killing them by driving them away from things like this new work that could fight completely unrelated diseases like cancer.
That’s you, Robert F. Kennedy, Jr. That’s you, Jay Bhattacharya. That’s you, Marty Makary. And all the rest of your minions and gofers and toadies. You have chosen the side of death and human suffering, and in a better world than this one you would be disgraced and shunned for it.