Chemo Doesn't Turn 'Cold' Tumors 'Hot': Debunking a Myth

David J. Kerr, CBE, MD, DSc, FRCP, FMedSci


July 29, 2019

This transcript has been edited for clarity.

Hi. I'm David Kerr, professor of cancer medicine at the University of Oxford. I picked up an interesting article recently in Annals of Oncology written by an old pal of mine, Thomas Helleday.[1] Thomas spent quite a bit of time with us in Oxford; he's a good scout. For the title of his article, he's debunking, in a way, a myth about turning "cold" tumors "hot" for immunotherapy. I quite like that strapline. I guess "cold" implies that the tumors aren't sufficiently primed for immune recognition or activation, and turning them "hot" can in some way convert them from not being recognized by the immune system into something that is and therefore could become a prime target for immune checkpoint inhibitors.

He would argue that there is a myth suggesting that priming with conventional cytotoxic chemotherapy and causing DNA lesions leading to mutations should increase the neoantigen tumor burden (which, as we know, is one of the markers that tends to correlate with response to immune checkpoint inhibitors). The more neoantigens present at the tumor cell surface, the likelier the tumor is to respond to immunotherapy—turning it from "cold" to "hot."

He debunks the myth by saying that although there are known pathways whereby chemotherapy-induced DNA mutations can lead to neoantigens (such as the STING pathway, in which this is a recognized effect), it's unlikely to be relevant clinically for a number of reasons:

  1. Cytotoxic drugs are not very good [mutating agents]. They tend to be cytotoxic, and the majority of cells are killed rather than mutated and retained.

  2. The number of mutations formed is really altogether too small. If we think about the progression of mutations in a tumor cell that was mismatch repair-deficient, [resulting in] hundreds of thousands of neoantigens, there is no way a cytotoxic drug could come remotely close to generating that number of mutations, and therefore neoantigens.

  3. We know there is a lot of clonal variation in all tumors, but if we look at the proliferative rate in any tumor cell, only a tiny minority of cells are actively proliferating. The majority of tumor cells are nondividing, and nondividing cells cannot mutate in response to chemotherapy.

  4. The majority of responsive neoantigens are clonal. That is, they are mutations that have occurred early in the tumor's progression, early in the carcinogenesis. Whereas mutations induced by chemotherapy will be in a late stage, when the tumor is established.

It's a thoughtful paper. I think a much more likely way to turn "cold" tumors to "hot" is by using epigenetic regulators, such as histone deacetylase inhibitors (HDAC). A large and growing body of evidence suggests that these agents can actually switch on the machinery of antigen presentation. By doing so and influencing the tumor microenvironment, HDAC inhibitors reduce regulatory T cells and increase CD8 numbers. This would seem to me a much better means of turning a "cold" tumor "hot."

Have a look at the article and see what you think about this debunking of the myth that cytotoxic-induced mutations are potentially effective or synergistic partners with immune checkpoint inhibitors.

And as always, I'm happy to respond to any posted comments.

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