One of the World’s Most Hated Plants Is Becoming a Public Health Rock Star
The recent Ebola virus outbreak in the Democratic Republic of Congo has refocused attention on the vaccine and treatment prospects for the highly contagious and deadly disease. As of late May, more than 7,500 doses of an experimental vaccine made by Merck Pharmaceuticals had been shipped to the beleaguered African nation, according to a World Health Organization press release.
Research was focused on the production of antibodies and vaccines in a novel manufacturing system: the tobacco plant.
Meanwhile, Ebola treatments were also sent. One of these, ZMapp, was successfully used to treat two American missionaries in Liberia in 2014. Charles Arntzen, who helped develop the treatment, calls that moment the highlight of his career: "It started in a lab as a fanciful idea that needed to be validated. In ten years, it was being used and people went from almost dead to almost recovered."
His initial research was focused on the production of antibodies and vaccines in a novel manufacturing system. That system was the tobacco plant—not the smoking variety, or nicotiana tabacum. But rather, a distant cousin called nicotiana benthamiana, which is native to Australia, where it grows abundantly.
ZMapp is made from the plant, as are other therapeutics and vaccines. Indeed, the once-maligned plant family has turned its image upside down in the public health world, now holding promise to prevent and treat many conditions.
Cheap, easy and plentiful
Research on the tobacco plant's medicinal potential goes back a few decades. In the early 1990s, research on plants as vaccine production platforms was just beginning. "We wanted to make a lower-cost vaccine manufacturing system to be used in developing countries to broaden our manufacturing base in the developing world," said Arntzen, who is the founding director of the Biodesign Center for Immunotherapy, Vaccines and Virotherapy at Arizona State University. "There was and still is a shortage of vaccines in the poorest countries."
"I've got a list of about fifty vaccines that should be made in tobacco."
Initially, research focused on food plants: bananas, tomatoes, and potatoes. While these efforts were successful, they were stymied by the "anti-GMO food establishment," Arntzen said. "I didn't want to spend my time fighting." So, they switched to the tobacco plant.
"I've got a list of about fifty vaccines that should be made in tobacco," said Denis Murphy, professor of biotechnology at the University of South Wales. "We know a lot about how to express genes in tobacco and get it made."
Unlike egg-based vaccines, which require a clean, sterile laboratory to make, and can therefore be an expensive process, Murphy said, tobacco-based vaccines are relatively cheap to make. The process is simple: Three weeks after being planted, the plants are dipped into a liquid containing proteins from the given virus. The plants grow the proteins for another week and then are harvested and chopped up. The green liquid that results is the vaccine, which is purified and then bottled up in precise doses.
"The tobacco plant doesn't seem to mind making all this foreign protein," Murphy added. "The plants will stay alive and look okay, and they will be full of vaccine protein. If you did this with an animal, you'd probably kill it."
Still, there are certain challenges to producing tobacco-based vaccines, particularly in the developing world, said Murphy, who is also a biotech consultant for the Food and Agricultural Organization of the United Nations.
"The purification process of the vaccine protein from leaves is still something for which you need a specialized lab. You couldn't have that in the Congo," he said. Security is another concern. "Someone could steal the plant and grow it themselves as a pirate version."
Even birds could be the culprit for tobacco plant theft. "What if a bird came and started eating the leaves? You might want netting or greenhouse growing. That can be much more problematic in a developing country."
While the ZMapp treatment for Ebola is produced from tobacco, efforts to develop a vaccine this way have not proved fruitful so far. (Merck's Ebola vaccine is made from livestock.) "Our tobacco-based vaccine would require three doses for a full effect, while the vaccine made by Merck may only require a single dose," Arntzen said. "Having to give three doses, over about a month, makes the tobacco-made vaccine much more cumbersome and expensive to deliver." Yet a tobacco-derived vaccine for another newsworthy illness is in the works.
On the frontier of a flu vaccine
Quebec City-based biopharmaceutical company Medicago is using a novel technique to make a flu vaccine with tobacco. This offers several advantages over the current method of developing the vaccine from eggs.
First of all, the production is quicker: five to six weeks, versus four to six months, which means that researchers can wait to identify the circulating flu strain for the upcoming season, rather than guess and risk being wrong.
Also, with tobacco, developers can use something called virus-like particles, instead of the actual flu virus.
"We hope to be on the market by the 2020/21 flu season."
"They have the structure of the flu virus, but not its full genetic code, so the virus doesn't replicate," said Anne Shiraishi, Medicago's communications manager. That's a big deal because the flu is a rapidly mutating virus, and traditional egg-based vaccines encourage those mutations – which wind up making the vaccines less effective.
This problem happens because the flu virus mutates a key protein to better attach to receptors in bird cells, but in humans, this mutation won't trigger an effective immune response, according to a Medicago fact sheet. That's why some people who have been vaccinated still get the flu. Indeed, the 2017 flu season had the lowest vaccine effectiveness record ever for H3N2 at 10 percent in the Southern Hemisphere, and 0 percent effective in the EU and UK in people over age 65. At least theoretically, their tobacco-derived flu vaccine could be far more successful, since no such mutations occur with the virus-like particles.
Last year, Medicago, which is 40 percent owned by cigarette company Philip Morris, began a phase 3 trial of the flu vaccine with 10,000 subjects in five countries: half are getting the vaccine, and half are getting a placebo. "We hope to announce really good results this fall," Shiraishi said. "We hope to be on the market by the 2020/21 flu season."
They're also preparing phase I trials for vaccines for the rotavirus and norovirus, two intractable gastro-intestinal viruses. They hope to roll those trials out in the next year or two.
Meanwhile, other research on antibodies is in their pipeline—all of it using tobacco, Shiraishi said. "We've taken something bad for public health and made it our mini factories."
A new type of cancer therapy is shrinking deadly brain tumors with just one treatment
Few cancers are deadlier than glioblastomas—aggressive and lethal tumors that originate in the brain or spinal cord. Five years after diagnosis, less than five percent of glioblastoma patients are still alive—and more often, glioblastoma patients live just 14 months on average after receiving a diagnosis.
But an ongoing clinical trial at Mass General Cancer Center is giving new hope to glioblastoma patients and their families. The trial, called INCIPIENT, is meant to evaluate the effects of a special type of immune cell, called CAR-T cells, on patients with recurrent glioblastoma.
How CAR-T cell therapy works
CAR-T cell therapy is a type of cancer treatment called immunotherapy, where doctors modify a patient’s own immune system specifically to find and destroy cancer cells. In CAR-T cell therapy, doctors extract the patient’s T-cells, which are immune system cells that help fight off disease—particularly cancer. These T-cells are harvested from the patient and then genetically modified in a lab to produce proteins on their surface called chimeric antigen receptors (thus becoming CAR-T cells), which makes them able to bind to a specific protein on the patient’s cancer cells. Once modified, these CAR-T cells are grown in the lab for several weeks so that they can multiply into an army of millions. When enough cells have been grown, these super-charged T-cells are infused back into the patient where they can then seek out cancer cells, bind to them, and destroy them. CAR-T cell therapies have been approved by the US Food and Drug Administration (FDA) to treat certain types of lymphomas and leukemias, as well as multiple myeloma, but haven’t been approved to treat glioblastomas—yet.
CAR-T cell therapies don’t always work against solid tumors, such as glioblastomas. Because solid tumors contain different kinds of cancer cells, some cells can evade the immune system’s detection even after CAR-T cell therapy, according to a press release from Massachusetts General Hospital. For the INCIPIENT trial, researchers modified the CAR-T cells even further in hopes of making them more effective against solid tumors. These second-generation CAR-T cells (called CARv3-TEAM-E T cells) contain special antibodies that attack EFGR, a protein expressed in the majority of glioblastoma tumors. Unlike other CAR-T cell therapies, these particular CAR-T cells were designed to be directly injected into the patient’s brain.
The INCIPIENT trial results
The INCIPIENT trial involved three patients who were enrolled in the study between March and July 2023. All three patients—a 72-year-old man, a 74-year-old man, and a 57-year-old woman—were treated with chemo and radiation and enrolled in the trial with CAR-T cells after their glioblastoma tumors came back.
The results, which were published earlier this year in the New England Journal of Medicine (NEJM), were called “rapid” and “dramatic” by doctors involved in the trial. After just a single infusion of the CAR-T cells, each patient experienced a significant reduction in their tumor sizes. Just two days after receiving the infusion, the glioblastoma tumor of the 72-year-old man decreased by nearly twenty percent. Just two months later the tumor had shrunk by an astonishing 60 percent, and the change was maintained for more than six months. The most dramatic result was in the 57-year-old female patient, whose tumor shrank nearly completely after just one infusion of the CAR-T cells.
The results of the INCIPIENT trial were unexpected and astonishing—but unfortunately, they were also temporary. For all three patients, the tumors eventually began to grow back regardless of the CAR-T cell infusions. According to the press release from MGH, the medical team is now considering treating each patient with multiple infusions or prefacing each treatment with chemotherapy to prolong the response.
While there is still “more to do,” says co-author of the study neuro-oncologist Dr. Elizabeth Gerstner, the results are still promising. If nothing else, these second-generation CAR-T cell infusions may someday be able to give patients more time than traditional treatments would allow.
“These results are exciting but they are also just the beginning,” says Dr. Marcela Maus, a doctor and professor of medicine at Mass General who was involved in the clinical trial. “They tell us that we are on the right track in pursuing a therapy that has the potential to change the outlook for this intractable disease.”
Since the early 2000s, AI systems have eliminated more than 1.7 million jobs, and that number will only increase as AI improves. Some research estimates that by 2025, AI will eliminate more than 85 million jobs.
But for all the talk about job security, AI is also proving to be a powerful tool in healthcare—specifically, cancer detection. One recently published study has shown that, remarkably, artificial intelligence was able to detect 20 percent more cancers in imaging scans than radiologists alone.
Published in The Lancet Oncology, the study analyzed the scans of 80,000 Swedish women with a moderate hereditary risk of breast cancer who had undergone a mammogram between April 2021 and July 2022. Half of these scans were read by AI and then a radiologist to double-check the findings. The second group of scans was read by two researchers without the help of AI. (Currently, the standard of care across Europe is to have two radiologists analyze a scan before diagnosing a patient with breast cancer.)
The study showed that the AI group detected cancer in 6 out of every 1,000 scans, while the radiologists detected cancer in 5 per 1,000 scans. In other words, AI found 20 percent more cancers than the highly-trained radiologists.
Scientists have been using MRI images (like the ones pictured here) to train artificial intelligence to detect cancers earlier and with more accuracy. Here, MIT's AI system, MIRAI, looks for patterns in a patient's mammograms to detect breast cancer earlier than ever before. news.mit.edu
But even though the AI was better able to pinpoint cancer on an image, it doesn’t mean radiologists will soon be out of a job. Dr. Laura Heacock, a breast radiologist at NYU, said in an interview with CNN that radiologists do much more than simply screening mammograms, and that even well-trained technology can make errors. “These tools work best when paired with highly-trained radiologists who make the final call on your mammogram. Think of it as a tool like a stethoscope for a cardiologist.”
AI is still an emerging technology, but more and more doctors are using them to detect different cancers. For example, researchers at MIT have developed a program called MIRAI, which looks at patterns in patient mammograms across a series of scans and uses an algorithm to model a patient's risk of developing breast cancer over time. The program was "trained" with more than 200,000 breast imaging scans from Massachusetts General Hospital and has been tested on over 100,000 women in different hospitals across the world. According to MIT, MIRAI "has been shown to be more accurate in predicting the risk for developing breast cancer in the short term (over a 3-year period) compared to traditional tools." It has also been able to detect breast cancer up to five years before a patient receives a diagnosis.
The challenges for cancer-detecting AI tools now is not just accuracy. AI tools are also being challenged to perform consistently well across different ages, races, and breast density profiles, particularly given the increased risks that different women face. For example, Black women are 42 percent more likely than white women to die from breast cancer, despite having nearly the same rates of breast cancer as white women. Recently, an FDA-approved AI device for screening breast cancer has come under fire for wrongly detecting cancer in Black patients significantly more often than white patients.
As AI technology improves, radiologists will be able to accurately scan a more diverse set of patients at a larger volume than ever before, potentially saving more lives than ever.