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Cancer and Gene Therapy

Update, March 10: Bluebird has reported data that makes it much less likely that this even was due to their lentivirus vector. Good news, and I hope it holds up.

There’s news today that Bluebird has suspended its gene therapy work on sickle cell disease because of two cases of cancer in its treatment population. Another had been reported in 2018, so that takes us to two cases of myelodysplastic syndrome and one case of myeloid leukemia (which can be a sequel of MDS in some cases). This isn’t good. You’ll note that all of these are diseases of the bone marrow, and the marrow is where a good deal of the action in this sort of gene therapy takes place.

There are several companies working in this space, and it’s no coincidence. Sickle cell anemia is the absolute prototype of a genetically linked disorder, famously first identified in 1949 by Linus Pauling and co-workers. That paper termed it “a molecular disease”, and Pauling certainly deserves the credit he gets as a founder of molecular biology. Both sickle cell and the conceptually related beta-thalassemias are defects in the production of hemoglobin, and it has been obvious for decades that if you could somehow yank the defective gene out of the patients and replace it with a normal sequence that they simply wouldn’t have these conditions any more.

There are by now plenty of other genetic disorders that fall into the same category, but these blood-cell based ones have a unique feature that has put them into the forefront of actual attempts at gene therapy. In these cases, all the relevant cells come from the same tissue, the bone marrow. And we actually have ways to kill that off and to swap in new tissue of our choosing: a bone marrow transplant. It is a tough procedure to go through, for sure, but not as tough as living a life of acute sickle cell attacks (or being killed off early by rampaging leukemia, to pick another application).

Contrast that with so many other gene-linked disorders – take Huntington’s, for example. We know the gene for that one, and the protein it codes for, and it is equally obvious that if you could magically yank out that gene from a patient and insert the normal one for the Htt protein that they would no longer have the disease. But there is no analogous procedure for killing off the basal ganglia of the brain and replacing it with new neuronal tissue. Not quite. No, bone marrow based disorders are a unique opportunity, and that’s why so much effort has gone into this area.

It’s a similar situation to the way that therapeutic RNAs have been aimed at liver disorders. In that case, you’re not wiping out the old cell population but rather trying to overwhelm it in situ, and the liver is chosen because we don’t really know how to make i.v. dosed RNA species accumulate anywhere else. So we make do with what we have and turn the Liver Problem into the Liver Advantage. If we ever get to the point of treating Huntington’s at a genetic level, it’s surely going to be via a similar rework-things-in-situ method as well, but figuring out to do that in only the desired regions of the brain without causing trouble elsewhere is quite a challenge – you’ve lost the Liver Advantage.

Now, Bluebird. They have been using a lentivirus vector to rewrite the bone marrow transplant tissue, and there’s a solid reason for that. Lentiviruses (of which HIV is the most famous/infamous example) insert their genetic payloads into the host cell’s DNA. It’s their key step, and they can do it even on non-dividing cells. Now, when a person hears “viral vector” these days, the thought is immediately of vaccines, and that takes us to the worry that the vaccines aimed at the COVID-19 pandemic will do things to our DNA. But we’re not using lentiviruses for the viral-vector vaccines – we’re using adenoviruses, because those explicitly do not work by inserting genes into host DNA. That’s also a feature of the mRNA vaccines: messenger RNA is not incorporated into our DNA. Those two species are constantly working in close proximity in living cells and there’s a huge pile of optimized protein machinery to keep them from getting crossed in that fashion. Nor does a messenger RNA sequence get turned back into DNA and inserted that way. Every cell has hundreds of thousands of mRNA molecules in it at any given time, and things would come to a catastrophic halt if these started getting reversed back into DNA sequences. (Our cells do have some RNA-to-DNA machinery in them, but it doesn’t work like that).

But for gene therapy, the opposite considerations apply – you most certainly want to insert new genes into human DNA, and you want it done quickly, efficiently, and right where you tell it to go. That last part is always the worry with any gene-insertion technique, be it some variety of CRISPR, zinc-finger nucleases, lentivirus vectors or what have you. This is one of the main reasons the human-editing experiment in China was so amazingly irresponsible, because our control over such things in a human embryo is just not acceptable yet. Not even close.

In fact, it’s tricky enough just in the stem cells pulled out of bone marrow. That’s one possibility for what Bluebird is seeing – that when they treated the patient’s extracted cells with their lentivirus vector, that some of the hemoglobin genetic data got mishandled and plopped into the wrong stretch of DNA, demolishing some other important gene’s function in the process. You can be sure that they’re sequencing the abnormal blood cells from these patients now to see if this shows up. The MDS patient from 2018 turned out not to have this problem, so it’s possible that these two just reported don’t, either. So what’s the problem, if not that?

Well, as mentioned, bone marrow transplantation is a grueling process no matter what. The process of (either mostly or completely) wiping out a person’s bone marrow stem cells involves severe treatments mixing chemotherapy with radiation, and one of the compounds used (and used by Bluebird) is called busulfan. The organic chemists in the crowd will find that one interesting: it’s the bis-mesylate of 1,4-butanediol, nothing more and nothing less, and if the thought of taking a reactive small molecule like that intravenously gives you the shivers, well, welcome to chemotherapy and get ready for some stuff that’s even worse. The thing is, busulfan itself is a Class I carcinogen (as one would expect from its structure). Many older chemotherapy agents are. They are destructive to cells, and the only way you would take any of them is if you have a population of cells that you actually want to see destroyed, and you are willing to take your chances that you can bear up under the collateral damage of doing that. So it’s certainly possible that the leukemia seen in Bluebird’s patients is at least partly driven by the bone marrow transplantation procedure rather than the gene alteration part. In case you’re wondering, this could well be happening with some bone marrow transplant patients who undergo this whole procedure to treat leukemia itself, in which case it lands silently in the “relapsed” category. No, you only do bone marrow transplants when there’s no alternative.

As that first link in today’s post (Adam Feuerstein at STAT) mentions, though, there’s ongoing research to make that part of the process less risky. Survival rates for bone marrow transplants in general have steadily improved over the years, and everyone knows that one of the rough parts is the pre-treatment. But that problem might or might not get solved in time to help out Bluebird (or to quell the worries that other gene-therapy outfits might have who are also targeting that hematopoietic tissue). If indeed it’s the problem in the first place. . .

18 comments on “Cancer and Gene Therapy”

  1. PastTense says:

    What’s the current thought about Linus Pauling’s beliefs about Vitamin C? Totally discredited?

    1. Pedwards says:

      Mega doses of vitamin C are great if you want to have expensive urine. They aren’t particularly useful for anything else

    2. Derek Lowe says:

      Yep. It’s too bad that that’s what he’s mostly known for among the general public, because the guy was an absolutely fearsome scientist in his day. But none of the vitamin-C-megadose stuff has held up. If there’s any benefit, it’s at doses large enough to actually have an *oxidizing* effect, which is not what he had in mind: https://blogs.sciencemag.org/pipeline/archives/2020/03/02/vitamin-c-and-immuno-oncology

  2. Marko says:

    “Now, when a person hears “viral vector” these days, the thought is immediately of vaccines, and that takes us to the worry that the vaccines aimed at the COVID-19 pandemic will do things to our DNA. But we’re not using lentiviruses for the viral-vector vaccines – we’re using adenoviruses, because those explicitly do not work by inserting genes into host DNA. ”

    True, but the CDC shouldn’t mislead people by saying that the adenoviral vector DNA does not enter the nucleus. It most surely does, and it has to for the vaccine to work. The NYT, to their credit, has been transparent about this in their various pieces about the adenoviral vector vaccines, e.g. :

    https://www.nytimes.com/interactive/2020/health/johnson-johnson-covid-19-vaccine.html

    1. Marko says:

      A tip of the hat to commenter Josh B, who contacted the CDC about this error which has now been corrected.

      Progress!

  3. sgcox says:

    Telomerase is not the only source of RT. There is also LINE-1. It is usually repressed but get reactivated in cancer and some say even as we age. I vaguely remember there was a paper where cell line was made to express LINE-1 and even get Sars-Cov2 integrated. Nothing to do with the real life, more like curiosity.

  4. Anon3 says:

    HIV is, to the best of my knowledge, not linked to increased risk of cancer – or is it? Do we know how / where the HI virus inserts its natural genetic payload into human DNA?

    1. Ben says:

      It is in fact linked to an increased risk of several cancers (Kaposi Sarcoma, Primary CNS Lymphoma, Cervical Cancers, for example). But, it was my understanding that this link was due to the immunosuppressive effects, not due to mutations caused by integration.

  5. A Nonny Mouse says:

    Didn’t one of the people “cured,” of HIV by a bone marrow transplant recently did of cancer?

    1. BioRugby says:

      You mean the Berlin patient? He died of a relapse of the Hodgkin lymphoma that prompted the very same bone marrow transplantation procedure that cure the HIV infection. https://en.wikipedia.org/wiki/Timothy_Ray_Brown

    2. sgcox says:

      Patient had a late stage cancer. That is why marrow bone transplant. Alas, it it is not 100% cure and he relapsed. The fact that he also had HIV was just coincidence which is expected to happen eventually. He had been cured of HIV but unfortunately it did not effect final outcome 🙁

  6. Anon Investigator says:

    Derek, you wrote –

    “So it’s certainly possible that the leukemia seen in Bluebird’s patients is at least partly driven by the bone marrow transplantation procedure rather than the gene alteration part. In case you’re wondering, this could well be happening with some bone marrow transplant patients who undergo this whole procedure to treat leukemia itself, in which case it lands silently in the “relapsed” category. No, you only do bone marrow transplants when there’s no alternative.”

    It might be possible, but it’s not the reason most transplant patients relapse. It’s also detectable through sequencing of the AML blasts, as the mutations that result from chemical mutagens usually rise to a recognizable signature and karyotype in the cells that cause MDS and AML. Most transplant patients seem to relapse because of 1) insufficient eradication of the diseased clone prior to transplant or 2) outgrowth of a new clone. Sometimes giving healthy cells to diseased patients can cause the new healthy cells to turn malignant since the receiving patient’s’ vasculature and bone marrow can play a role in driving the acquisition of new somatic mutations. The disease isn’t just in the stem cells.

    There is another possibility with regard to Bluebird’s therapy. All of us go around developing somatic clones in our hematopoietic stem cells, the more so as we age. The condition is called clonal hematopoiesis and is predisposing to both myeloid diseases, like MDS and AML, as well as the usual culprits associated with aging (CV etc.) We all start to exhibit somatic clones in our hematopoietic stem cells after about 40 years of age. It all depends on how deep you look, but this is really noticeable in the later decades of life. An active area of research is why some people with these mutations develop disease and others don’t. Vascular aging, of which inflammation is a part, seems to play a key role. There are clinical trials underway to see if intervention is possible.

    There is the possibility that the lentiviral engineering accelerated this process in the patient’s cells through an inflammatory component associated with the cellular manipulation. This would be disastrous, but not unprecedented. Sequencing the hematopoietic stem and progenitor cells from the patients might not be possible, but it might be highly informative.

    1. Derek Lowe says:

      Absolutely – I’m sure that the bulk of the relapses are just as you describe. But if there are some brought on by the treatment, they’re pretty much invisible, whereas in the sickle cell population we can see them.

  7. Barry says:

    An adenovirus (not a lentivirus) was reportedly used in Jesse Gelsinger’s gene therapy for ornithine transcarbamylase deficiency. It did not insert itself into his DNA, but did provoke a lethal immune response. His death in 1999 sent a lot of early gene-therapy approaches to the scrap-heap.

  8. Relativ Fiktiv says:

    Wikipedia claims otherwise, but it seems adenovirus vectors can cause chromosomal integration:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC112682/

    The frequency is low though. Still, given the huge numbers of patients, I wonder if it may occur as a rare side effect of certain vaccines.

  9. Yuri K. says:

    There are better alternatives to busulfan. CD117, CD45 and CD52 toxin-conjugated antibodies work great (in mice).

    https://pubmed.ncbi.nlm.nih.gov/30728354
    2019. “Here we show that a single dose of a CD117-antibody-toxin conjugate (CD117-saporin) leads to >99% depletion of host HSCs, enabling rapid and efficient donor hematopoietic cell engraftment. Importantly, CD117-ADC selectively targets hematopoietic stem cells yet does not cause clinically significant side-effects. Blood counts and immune cell function are preserved following CD117-ADC treatment, with effective responses by recipients to both viral and fungal challenges. CD117 pre-treatment might be especially suited to GENE THERAPY in which preservation of immunity is desired.”

    https://pubmed.ncbi.nlm.nih.gov/27272386
    https://pubmed.ncbi.nlm.nih.gov/33484750
    https://pubmed.ncbi.nlm.nih.gov/32226796

    The unusual stability of saporin toxin
    https://pubmed.ncbi.nlm.nih.gov/9168975

  10. Gene says:

    > This is one of the main reasons the human-editing experiment in China was so amazingly irresponsible, because our control over such things in a human embryo is just not acceptable yet. Not even close.

    Thanks for explaining that. I personally never understood that nuance.

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