High amounts of injected vitamin C may delay the growth of many types of tumors and enhance the anticancer power of some types of immunotherapies, according to a new study in mice. The preclinical research is detailed in the February 26 issue of Science Translational Medicine.
The findings indicate that vitamin C — which has been investigated as a treatment for cancer in the past — should be tested as a supporting therapy for cancer patients receiving immunotherapies called checkpoint inhibitors, which are often ineffective due to treatment resistance.
The vitamin was injected in very high doses in the mice, at levels beyond what a human could get from supplements or food. For example, the study authors estimated that the required therapeutic dose for a patient with cancer would equate to over 2,000 oranges per day.
Vitamin C has attracted interest from cancer scientists since the 1970s, when initial research suggested that it could benefit some cancer patients. In that study, scientists found that administering high amounts of vitamin C both orally and intravenously extended survival times in 100 terminal cancer patients.
However, the results were controversial because subsequent studies failed to reproduce any therapeutic effects, according to Federica Di Nicolantonio, an associate professor at the University of Torino in Italy and a senior author of the new study.
The field of vitamin C in cancer was subsequently abandoned for some time. But researchers soon realized these follow-up studies had used oral vitamin C in the form of pills. A study in 2004 showed that vitamin C can’t be absorbed through the gut in high enough amounts to achieve anticancer effects, potentially explaining the failure to reproduce the original results.
Since then, a growing body of work has shown that intravenous vitamin C can bring some therapeutic benefits and can kill cancer cells, according to the authors of the new study. It remains unclear how the vitamin props up anticancer immune responses on the biological level, but scientists do know that immune cells become weak in humans with low levels of vitamin C.
“That gave us an idea, that perhaps the immune system was also relevant in controlling tumor growth in the presence or absence of vitamin C,” said Alberto Bardelli, a professor at the University of Torino in Italy and a senior author of the new study.
To understand how vitamin C affects immunity and interacts with cancer cells, Alessandro Magrì, a researcher at the University of Torino in Italy and lead author of the new study, and colleagues gave the vitamin to mice with various types of cancer. Unlike previous studies, they conducted their work in mice with healthy immune systems, allowing them to discern how the vitamin modulates immune cells.
The team found that giving high doses of vitamin C through abdominal injections delayed the growth of colorectal, breast, melanoma and pancreatic cancers in the mice, primarily by ramping up the activity of anticancer T cells.
Having studied the vitamin alone, the authors then decided to combine it with anti-CTLA-4 and anti-PD-1 checkpoint antibodies, which have been approved to treat some types of cancers. Although checkpoint antibodies are promising cancer therapies, they have toxic side effects and fail to bring durable benefits to many patients.
The injections of vitamin C substantially improved the effectiveness of the checkpoint antibodies in the mice, to the point where many animals with breast cancer experienced total regression of their tumors. The study also showed that the triple therapy was well-tolerated by the mice and didn’t cause any autoimmune reactions that have previously been linked to anti-CTLA-4 antibodies.
Taking it a step further, the scientists tested their strategy in mice with mismatch repair deficient tumors, which lack a critical DNA repair mechanism. As before, the combination of checkpoint inhibitors and vitamin C wiped out the tumors, which were otherwise resistant to checkpoint inhibitors.
The major hurdle in translating the findings from mice to humans is the dose of vitamin C that needs to be given to achieve these anticancer effects, said Di Nicolantonio and Bardelli. Any treatment based on vitamin C would therefore have to be administered intravenously, they added.
The authors are planning a clinical trial where they will give escalating doses of intravenous vitamin C to cancer patients receiving checkpoint inhibitors. By ramping up the doses in this manner, they hope to pinpoint the ideal dose of the vitamin for combating tumors, as well as the optimal length of treatment.