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More Than Was Asked For

Via AndyBiotech on Twitter, here’s an interesting report from the New England Journal of Medicine. It describes a patient diagnosed with follicular lymphoma who also was positive for hepatitis C. They went through a course of Gilead’s sofosbuvir with ribavirin, and that (as it usually does) cleared the Hep C infection. What’s interesting is that at the end of the treatment the lymphoma was in complete remission as well.

The patient received a 24-week course of sofosbuvir (at a dose of 400 mg once daily) and ribavirin (1200 mg once daily) from March through September 2014. Within 4 weeks, the level of HCV RNA was undetectable. Twelve weeks after treatment ended, the HCV RNA level remained undetectable, with a normal alanine aminotransferase level and FibroScan results consistent with a high rate of sustained virologic response.

In December 2014, findings on computed tomography (CT) of the chest, abdomen, and pelvis were consistent with a very good partial response of the follicular lymphoma. Positron-emission tomography and CT in June 2015 showed normal-sized mesenteric nodes with no 18F-fluorodeoxyglucose–avid disease (Figure 1B and 1D). Immunohistochemical and flow-cytometric tests showed that the bone marrow was lymphoma-free. As of September 2016, the patient remained well, with no clinical evidence of disease recurrence.

This is probably not a coincidence, as the paper points out, because B-cell lymphoma has been associated with hepatitis C infection, and a few cases like this are actually in the literature with earlier therapies (such as interferon). But it still comes as a welcome surprise – I can certainly imagine some ways that a viral infection might lead to lymphoma, but after that happens, I’m surprised that curing the viral infection has any effect on the cancer. There’s clearly a tighter relationship between the two than my mental picture allows for, and I’ll bet that I’m not alone.

30 comments on “More Than Was Asked For”

  1. Me says:

    Works now!

  2. Curious Wavefunction says:

    Promising, although I think they need to do large-scale studies to distinguish correlation from causation.

  3. Me says:

    There are a few lymphomas related to viral infections from inconsequential viruses that are only a problem for immunosuppressed patients – post-transplant lymphoproliferative disorders. In that case it’s caused by Epstein-Barr Virus.

  4. b says:

    I don’t know enough about these subjects, any chance that the sofosbuvir/ribavirin were somehow responsible for the lymphoma remission through some sort of off-target mechanism? Or, did the lymphoma take long enough to clear out after treatment that this seems unlikely?

    1. AR says:

      An off target mechanism is incredibly unlikely

  5. Nile says:

    It’s easy to speculate that the pathological cell proliferation of this lymphoma is firing from the same trigger as the proliferation response these immune cells to hepatitis C infection.

    Easy to speculate, but much harder to pin down.

    If we ever do unravel the ‘winding-down’ phase of a B-Cell immune response, we might *just* discover drug targets for cancer suppression: and if we’ve got a cell line in vitro from this patient, we’ve got a useful tool for the second half of that, a decade or two into the future.

    1. Mark Thorson says:

      Wait a minute! Who owns these cells? If they came from my body, I’d certainly expect a piece of the action!

      1. Peter S. Shenkin says:

        Why wouldn’t getting better be enough for you? You’d have had nothing to do with the discovery….

        1. I’m not really sure if one, both or neither of Mark and Peter are being facetious, but I’ll take their comments at face value as an excuse to elaborate on the question of ownership of and compensation for biological research materials derived from humans.

          This is clearly an evolving area in bioethics. In this situation, as a patient under treatment I doubt there was any consent document signed which gave away rights to his/her cells should something interesting occur during the course of treatment. So right off the bat, deriving a cell line should involve asking the individual for permission and I think the individual is completely within their rights to ask for compensation as a condition for permission.

          Yes, the specific genetic/environmental combination you get is largely a matter of luck, and sometimes that leads to amazing things, from people who can run 100m in less than 10 seconds, to 10 year old chess prodigies and biomedical miracles. I think saying that one gets cured and that should be enough is akin to saying to an NCAA athlete, you get a full ride, that should be enough, never mind that the University and NCAA are making millions of dollars off of your work.

          In any case, the increased activism of patients’ groups means that for better and worse, the patients’ perspective, including the potential of meaningful compensation, is going to keep coming up, especially as we enter an age where the billions of PD1/PDL1 and similar trials all start recruiting from the same, very limited patient pool.

          1. Charles Hixson says:

            Have you read the EULA that hospitals ask you to sign? The one’s I’ve read generally give EVERYTHING to the hospital. And also say they can bill you whatever they like. I’m dubious about the legal enforceability of such a paper, especially as it’s generally on multiple pieces of paper that aren’t fastened together, and they generally only show you one and demand that you sign now. Sometimes on your way into the operating room after they’ve demanded that you remove your glasses. But the paper would generally permit them to do anything…and I don’t just mean things that are otherwise legal.

          2. loupgarous says:

            Someone down the page beat me to Henrietta Lacks, the donor of the HeLa cancer cell line that at one time or another seems to have infected many of the ATCC’s other cell lines back in the 1980s, which tells me that “HeLa”-ness might have had a viral cause 0 or just that ATCC needed to clean up their act (literally). Seems wrong she died poor.

      2. KG says:

        Read “The Immortal Life of Henrietta Lacks” by Rebecca Skloot. Every HeLa cell assay is a reminder of shady bioethics.

  6. Calvin says:

    Well HCV is pretty amazing at evading the immune system and hijacking cellular machinery so I’m not surprised that having removed the virus that the immune system might be directed towards a tumor. We know that many of these viruses cause cancers (HCV does eventually) so I don’t think it’s a massive surprise. So this doesn’t provide some new magic treatment option except where the cancer is caused by the virus AND the immune response is being suppressed.

    There have also been rumors that some patients on HCV therapy have a significant immune response once the virus is eliminated and this has to be carefully managed. It’s clearly pretty complex in some cases.

    I do have a suspicion that viruses, bug and fungi play a much bigger role in disease than we realize and that removing such infections could have a more significant disease altering effects than you’d currently expect. It’s going to be quite a task unraveling that if it’s true

    1. Phil says:

      Not a biologist, so excuse me if what follows is completely off-base.

      This is a single data point, so could it be that this particular patient’s immune system would have fought off the lymphoma were it not for the HCV infection? In this case, there would be causality; however, it would be indirect and not general for anyone else with lymphoma.

      1. tangent says:

        Yeah, I wondered the same, but I’m also not a biologist.

        Are there examples of immunosuppressed patients who develop a lymphoma, are then able to stop the immunosuppressant, and subsequently clear the lymphoma?

  7. Sam says:

    Perhaps patients with follicular lymphoma will first need to be HCV infected and then (after some time) treated with sofosbuvir.

    1. dave w says:

      Hmmm…. thinking further along such lines: specialized synthetic “viruses” for therapeutic purposes?

      1. b says:

        Such a good idea that the field has existed for many years.

        1. Barry says:

          classic virotherapy relies on boosting the immune response indiscriminately by infecting the patient with a pathogen that provokes a strong immune response (i.e. a good candidate for a vaccine). What is hinted here is the converse; that one may be able to disinhibit the T-cell response by wiping out a pathogen that is barely immunogenic (because it may be actively lulling the host’s immune system)

        2. Design Monkey says:

          Virotherapy articles in Wikipedia earlier were heavily spammed by Rigvir charlatans self promotions. By now they are somewhat cleaned up, but not yet enough.

      2. Barry says:

        Frank McCormick’s group worked for years on a “oncolytic adenovirus” that could only infect/kill cells that are p53 defective. A related approach has been approved in China only

    2. pete says:

      well thought (truly)..but imagine that as an Oncologist suggesting such an approach, you might scare the wits out of your patients & their families

  8. Barry says:

    There’s a mass of evidence that sophisticated parasites lull the host’s immune system. Auto-immune diseases that are rare or unknown in the Third World where intestinal worms are ubiquitous are endemic in the West where they’ve been eliminated. And Crohn’s disease can be cured or controlled by the introduction of such worms to the gut (“helmintho-therapy”).
    It is reasonable (although unproven) that Hep. ‘C’ likewise lulls the host’s immune system. It’s a notoriously tough target for vaccine development. So it may indeed be that wiping out an infection with HCV would disinhibit T-Cells throughout the body,much like blocking PD-1 or CTLA4. How many such parallel (or interconnecting) brakes act on our immune system is still anyone’s guess

  9. Lymphoma is a complication of coeliac disease, and HCV infection can cause a sensitivity to gliadin which resolves on treatment (in my experience, having the disease for 20 years and being in support groups and so on, most people with Hep C who take an active interest in their health end up gluten-free).
    If the sensitivity to gliadin is due to an immune dysfunction, caused by the virus, that is similar to that which exists naturally in the coeliac cases, and if the immune reaction to gliadin (I’d assume to prolamine exorphin peptides) in these cases is suppressing some part of the immune response to cancer, that could provide a mechanism for improvement.
    Alternately, a reduction in immune surveillance after viral clearance could be the mechanism. Lymphoma affects immune cells, and their activation may upregulate oncogenes in these cases. See this report where relaxed immune surveillance is suggested as a cause for increases in liver cancer after treatment with DAAs.

    1. Handles says:

      Google “medscape 862041” to get past the paywall

  10. johnnyboy says:

    Many mechanistic possibilities and much speculation, so why don’t I add mine ? What I’d suggest is to not automatically accept the diagnosis of ‘follicular lymphoma’ at face value. Speaking as a pathologist, the distinction between abnormally proliferating lymphoid tissue and a true neoplastic lymphocytic process can be a lot fuzzier than people would assume. Just because something was called a follicular lymphoma by a pathologist doesn’t mean it’s necessarily a monoclonal population of cells proliferating out of control. The virus may have been inducing some sort of dysregulation of lymphocyte proliferation causing polyclonal lymphocyte populations to expand abnormally, but not neoplastically; get rid of the virus, the lymphoid tissue returns to normal. May sound far-fetched, but to me seems much more likely than a true lymphoma just disappearing by itself.

  11. PorkPieHat says:

    A hematologist I showed this paper to had the following to say:
    “Would be careful of the conclusion you draw here. What they show is once the hep c is controlled, a remission in the lymphoma occurs. [This is] something that has been seen in related lymphomas before but never in follicular. The prevailing thought is that the chronic antigen stimulation from the virus promotes the lymphoma, not that the antiviral agents worked on the lymphoma.”
    This seems consistent with Johnnyboy’s posit above.

    1. Barry says:

      “chronic antigen stimulation” from HCV infection? If HCV were so antigenic, it would be a better vaccine target. It’s a terrible vaccine target precisely because it does not provoke much of an immune response. And it’s possible (although unproven) that it provokes so little immune response because it’s tamping down T-cell activation. So–if I’m right–the lymphoma may mean that HCV sufferers are immune-compromised, the way Kaposi’s sarcoma reported immune defects in HIV.

  12. Arne says:

    Whats interesting is that we wasted tons of years assuming that viral infection has little to do with carcinogenisis. Another huge failure from the pfizer scientists of the world.

    1. Barry says:

      we’ve known about viral oncogenesis since Rous published in 1911 on Rous Sarcoma in chickens. The question remains how many cancers have a viral etiology. Other mechanisms (ionizing radiation, chemical carcinogens…) seem sufficient on their own. But I don’t know how to rule out participation by ancient viral material that we carry in our genomes.

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