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Vitamin C and Immuno-oncology

Linus Pauling was a fearsomely great scientist who is remembered by the general public for his advocacy of megadoses of Vitamin C, a favorite topic of his later in life. Infectious disease, cancer: Pauling advised gram amounts of ascorbic acid and had a lot of theorizing to offer about why that was beneficial. So while his scientific legacy is (among other things) his work on chemical bonding, on genetically-based disease and the concept of molecular biology in general, and plenty of lesser-known deeds such as encouraging the earliest NMR studies of organic compounds, his legacy in the wider world involves increased vitamin sales and the association of Vitamin C in particular with the treatment of disease.

Unfortunately, Pauling’s ideas about how Vitamin C would prevent and treat disease were wrong. Instead of having an antioxidant effect (which is one of the things he proposed and what most people associate with it), at very high doses ascorbic acid has a pro-oxidant mechanism of action (see below). This is almost entirely seen with i.v. dosing, and it’s worth noting that Pauling’s 1976 paper on prolongation of life in terminal cancer patients via ascorbate supplementation used a combination of oral and i.v. routes. Attempts to follow up on this observation (mostly with oral dosing) did not reproduce the effect, and it’s become clear that if you’re going to see anything, it’s via intravenous administration, and at even higher doses than Pauling thought.

Here’s a new paper from a team in Italy that suggests that these effects have to do with immuno-oncology, and that the combination of i.v. ascorbate and immunomodulators might be quite useful. Vitamin C only showed effects in mouse tumor models when the animals had a fully competent immune system. Narrowing down, its beneficial effects appear to depend on T-cell pathways: antibodies to CD4 or CD8, for example, took things back to baseline tumor development. But on the other hand, the combination of Vitamin C with anti-PD1 and/or anti-CTLA-4 antibodies was noticeably more effective. This appears to be independent of the pro-oxidative damage mechanism mentioned above, as well as of the reported effects of high-dose ascorbate on iron metabolism.

The big question is, does this apply to humans? It should be easy enough to find out, and such trials are the only way we’re going to know. Even in the mouse models, there were some tumor lines that responded strongly to this treatment, and some that were refractory. And as the authors note, they saw a benefit from Vitamin C alone in the mice, which is much harder to show in human patients and suggests that they could still be a disconnect. So the relevance to human therapy (as is so often the case in oncology) will only be made clear by treating actual humans. The authors suggest trials with escalating doses of ascorbate in the first few rounds of immune checkpoint therapy, across several different tumor types, with comparison to immuno-oncology standard of care. High-dose i.v. ascorbate treatment of this sort has been shown to be well tolerated; there should be few barriers to trying this out. If it works, it would be a low-cost way to increase the efficacy of several existing therapies – the results will be very interesting indeed. Good luck to those trying it, and to all of us by extension.

But if this work makes some headlines of the “Linus Pauling was right” sort, don’t believe them. Pauling was right about a lot of things, but like many bold scientific thinkers, when he was wrong he was wrong in grand fashion. And he was wrong about vitamin C and cancer. None of his hypotheses about any therapeutic effects have turned out to be correct, and the main mechanistic thing that does seem to be happening is the exact opposite of what he would have predicted. Huge doses of ascorbic acid are a precursor to hydrogen peroxide formation inside the cell, and at high enough levels this can overcome the natural antioxidant defenses. There are many lines of evidence for this, but if you’d tried to sell Pauling on the idea he might have kicked you down the stairs.

17 comments on “Vitamin C and Immuno-oncology”

  1. Lane Simonian says:

    Linus Pauling was indeed wrong about the mechanism. The combination of Vitamin C at high doses as a pro-oxidant along with an intact immune system may be the manner in which intravenous doses of Vitamin C may eventually become a treatment for some forms of cancer. Perhaps this provides a more targeted approach to cancer than chemotherapy and radiation therapy.

    However, maybe the baby should not be thrown out with the bath water. Some antioxidant treatments may help limit tumor escape and increase immuno-responses.

    https://www.ncbi.nlm.nih.gov/pubmed/22568930

    https://www.ncbi.nlm.nih.gov/pubmed/22568930

    1. Lane Simonian says:

      I accidentally duplicated the link. Here is the second article.

      https://www.jimmunol.org/content/162/6/3356

  2. RTW says:

    Good stuff – I posted about this in the Colon Talk colon cancer support forms the other day. We have had members attempt to use high dose IV Vitamin C infusions. I believe they were all late stage patients, that had run out of options, and were grasping at straws. Of course plenty of physicians willing to take advantage of that. I had a lot of respect for Professor Pauling being a chemist myself. Still although I have always been skeptical of Vitamin C, as a drug discovery chemist in Oncology I took the position it probably wouldn’t hurt. So any additional research in the area is always welcome. Seems in some situations at least in a mouse model this might prove to have some validity when combined with the currently available Immunotherapy treatments.

  3. paul oman says:

    Pauling died of prostate cancer at age 93. his large daily dose of C (reported to be 39 grams?) did not stop the cancer. However, Pauling thought that the C added 20 something years to his life. I assume that means he lived with prostate cancer for over 20 years.

  4. An Orange says:

    Wait! There’s more….

    Vitamin C Infusion for the Treatment of Severe 2019-nCoV Infected Pneumonia
    https://clinicaltrials.gov/ct2/show/NCT04264533

    1. loupgarous says:

      From “study description” in https://clinicaltrials.gov/ct2/show/NCT04264533:

      Vitamin C, also known as ascorbic acid, has antioxidant properties. When sepsis happens, the cytokine surge caused by sepsis is activated, and neutrophils in the lungs accumulate in the lungs, destroying alveolar capillaries. Early clinical studies have shown that vitamin C can effectively prevent this process. In addition, vitamin C can help to eliminate alveolar fluid by preventing the activation and accumulation of neutrophils, and reducing alveolar epithelial water channel damage. At the same time, vitamin C can prevent the formation of neutrophil extracellular traps, which is a biological event of vascular injury caused by neutrophil activation. Vitamins can effectively shorten the duration of the common cold. In extreme conditions (athletes, skiers, art workers, military exercises), it can effectively prevent the common cold. And whether vitamin C also has a certain protective effect on influenza patients, only few studies have shown that vitamin C deficiency is related to the increased risk and severity of influenza infections. In a controlled but non-randomized trial, 85% of the 252 students treated experienced a reduction in symptoms in the high-dose vitamin C group (1g / h at the beginning of symptoms for 6h, followed by 3 * 1g / day). Among patients with sepsis and ARDS, patients in the high-dose vitamin group did not show a better prognosis and other clinical outcomes. There are still some confounding factors in the existing research, and the conclusions are different. Therefore, during the current epidemic of SARI, it is necessary to study the clinical efficacy and safety of vitamin C for viral pneumonia through randomized controlled trials.

      My wife beat me to the conclusion that barnyard byproducts are being thrown against the wall here in hopes some of them stick.

      The speculation about neutrophil activity is interesting. Sections 8 and 9 of https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827506/ and https://www.atsjournals.org/doi/full/10.1165/rcmb.2013-0200OC discuss the potential usefulness of Syk inhibitors. Given that steroid therapy doesn’t help once COVID-19 patients develop pneumonia, IV vitamin C can’t hurt very much, but could Syk inhibitors be more effective in keeping patient airways open?

      1. loupgarous says:

        Robert Neighbors’ suggestion of using nebulized NAC once COVID-19 infection progresses to pneumonia sounds very sensible – if the idea is to keep weakened patients breathing until they rebound.

  5. Barry says:

    fascinating that effects were seen only in fully immune-competent mice. So much of onco research relies on immune incompetent mice xenografts and trusts that they behave like immune-competent humans.

    1. johnnyboy says:

      No one using human xenografts in immunodeficient mice “trusts that they behave like immune-competent humans”. Biologists are well aware of the limitations of these models, and they are used to answer specific questions about tumour biology, not as a predictor of immune response. There are plenty of syngeneic tumour models used in immune-competent mice which are used to generate data on immune response to tumour, data which may be a better predictor of the human immune response, though there are also clear differences in mouse vs human immune systems.

  6. Arthur Weisser says:

    I had 5 patients in my practice who were told to go home nothing more could be done by their oncologists. All 5 lived 3 to 5 years longer with a good quality of lifI never charged them anything. One was a 3 year old girl with liver cancer. She died at age 7. She had a great quality of life her hair grew back %0 grams of Vitc nothing else

    1. Rick says:

      Are you saying she had no Vitamin C, or was that typo?

    2. Michael Kos says:

      Why did you not charge them??

      Thank you

  7. A non-rodent mammal says:

    Why study this in mice, though? I thought a significant factor in the questions of Vitamin C dosing was how humans are unusual for not producing their own metabolically. Obviously we have more data to compare to in mice rather than guinea pigs, but that seems like a major enough difference to consider.

  8. Robert Neighbors says:

    They really should be trialing nebulized N acetyl cysteine for those with pneumonia from the coronavirus (in a solution with proper osmolarity) – – get NAC into the lungs effectively, cysteine is lacking where viruses ravage the lungs.

    Also NAC liquefies mucus by opening the disulfide bonds in the mucoproteins.

    1. Greta Quintin says:

      Can you get meaningful quantities into the lungs via blood if you take NAC orally?

  9. milkshake says:

    Linus Pauling was promoting his unorthodox theories about panacea of ascorbic megadoses when he was old. We know that his short term memory was very poor in his later years, he had to write down everything, so it is also possible that his way of thinking got cyclical – one famous professor of synthetic chemistry (and he was very far from being dulled by age when I interacted with him) made a habit of listening to his students and postdocs and then forgetting/disregarding opinions and data that did not fit with his preconceived ideas. Over the years, he asked several his students to look into project “that just had to work”, all the evidence notwithstanding

  10. Alexander Michels says:

    Vitamin C taken by oral routes is completely different from vitamin C administered intravenously. Oral dosing of vitamin C does lead to levels in plasma, cells, and tissues that bolster antioxidant protection – but that’s only part of what it does in the cell (see: enzymatic functions of vitamin C). Some studies on oral dosing of ascorbic acid have shown effects on T- & B-cell maturation. How does this work? We’re not sure.

    Intravenous dosing of ascorbate is a way of bypassing the tight control of vitamin C absorption in the intestine. The results of reaching millimolar quantities of ascorbate in plasma can be pro-oxidant… but it depends on the circumstances. Pauling didn’t know this – most of his recommendations were for oral dosing of vitamin C. They only turned to intravenous when oral turned out to be challenging.

    Looking back at Pauling’s recommendations through the lens of time is hard – he had some good ideas but also some not-so-good ones. At least he pushed vitamin C hard enough and long enough for us to do quality studies on it… even if it was 25+ years after his death.

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