More than 100 people had signed up to volunteer for a controversial clinical trial when staff at Guangzhou Fuda Cancer Hospital was forced to start turning people away, The Paper reported on February 13.
Some had arrived at the hospital after hearing news which, like many others fighting cancer across China, gave them hope
Chen Xiaoping, a researcher working with the Guangzhou Institutes of Biomedicine and Health under the China Academy of Sciences (CAS), along with his team, was testing cancer treatments that involved injections of plasmodium, a pathogen of malaria.
In the speech at the CAS Science, Education, Life and Future Forum (SELF) on January 23, Chen said that so far, two of his patients “might have been cured.”
Chen said his team had found that plasmodium can reactivate an immune system disabled by cancer cells while cutting off nutrition supplies to tumors by suppressing their blood vessel growth.
Chen said over the past two years they had treated 30 people. More importantly, he claimed that
tumors in two of them (diagnosed with terminal lung cancer and prostate cancer) had “shrunk.”
Video of Chen’s speech immediately went viral on social media, with some exclaiming China had found a cure for cancer. Medical experts and doctors in China, however, have criticized such remarks as “irresponsible hype.”
Some argued that Chen’s description of the treatment lacked sufficient scientific scrutiny and pointed out his conclusion was based only on individual cases. Given plasmodium can self-replicate and malaria is highly infectious, some critics expressed concern that the experiments posed unpredictable risks to patients and the public.
A graduate of Guangdong Medical University, Chen, now in his 60s, has been engaged in plasmodium-related biomedicine and immunology for nearly three decades. Chen said his idea for plasmodium treatment came from charts showing cancer and malaria rates he saw during an epidemiology class in 1985. When comparing the two charts, he found that regions with a higher rate of malaria saw a relatively lower rate of cancer. He hypothesized there was a negative correlation between malaria and cancer and dedicated himself to researching it.
Chen said he and his colleagues cross-referenced databases worldwide that confirmed the negative correlation. In 2017, Chen published his findings in the medical journal Infectious Agent and Cancer and began work on a plasmodium treatment.
Some in the field were skeptical from the start. Wang Liming, a neurobiology researcher at Zhejiang University’s Life Science Institute and Chen’s greatest critic, posted a long article questioning the plasmodium treatment and claimed the negative correlation was not enough to justify human trials.
“[According to Chen’s paper], when malaria rises by 100 percent, cancer [in the same region] only drops by 10 percent... And, it should be taken into consideration that studies show anti-malaria drugs may suppress cancer cells and strong evidence suggests that plasmodium may instead cause some types of cancers to grow,” he wrote in the article.
Wang’s argument echoed a study conducted by Ali Salanti, professor at the Immunology and Microbiology Institute, University of Copenhagen, and several other researchers from the Vancouver Prostate Center, showing no correlation between malaria and cancer. Salanti told NewsChina they also found that tumors would grow in some patients infected with the Ebola virus and malaria at the same time.Over the past five decades, researchers found that regions with high rates of malaria, such as in Africa, often suffer from high rates of Burkitt lymphoma, a form of non-Hodgkin’s lymphoma that was first detected in children in Africa.
In August 2015, Davide Robbiani of Rockefeller University and his colleagues claimed in a paper in medical journal Cell that their rat tests showed that some cells became more vulnerable to cancer during a long-term fight against virulent plasmodium. Although the plasmodium Chen injected into his trial patients was not virulent, he did not detail its side-effects or which types of cancer it would affect.
Chen’s second theory to support his plasmodium treatment – plasmodium can cut off the nutrition supply to the blood vessels of cancer cells – was also challenged. A paper published by researchers from Tokyo University in 2010 delivered contrary findings. Also, according to clinical experiments.gov, a database established by the US National Library of Medicine and US Food and Drug Administration (FDA), there have been more than 20 clinical experiments for malaria therapy drugs, which, as Wang said, helped weaken the relationship between plasmodium and cancer, if any.
However, these conclusions do not necessarily disprove Chen’s theories. What rankled critics most was that Chen jumped to a conclusion before completing a study with the data required for appraisal and judgment. Many have scolded Chen for casually using the word “cure.” Some argued the two patients were isolated cases and pointed out that Chen did not confirm whether they had previously received any other cancer treatments. Moreover, doctors generally consider cancer survivors as cured after living for at least five years in complete remission.
According to Wang Liming, Chen’s theory, if correct, merely provides more evidence of immunotherapy, a new therapy against cancer that involves recovering and activating the immune system.
In 2018, American physician James Allison and Japanese researcher Tasuku Honjo won the Nobel Prize in Medicine for discovering two molecules, CTLA-4 (cytotoxic lymphocyte-associated antigen-4) and PD-1 (programmed cell death protein 1), that suppress the reactivity of the immune cells. Current immunodrugs work by resisting CLTA-4 and PD-1.
But immunotherapy has even earlier origins. At the end of the 19th century, American physician William Coley injected inactive bacteria (called Coley Toxin) into his cancer patients after he accidentally found that the cancer tumor of a patient shrank following a bacterial infection. Over 40 years, Coley treated around 1,000 cancer patients with the Coley Toxin. Half of them reportedly went into near complete remission. However, quality and safety controls limited the treatment from widespread use. Radiotherapy and chemotherapy eventually took its place.
In the early 20th century, Austrian doctor Julius Wagner Jauregg found that plasmodium could be used to treat neurosyphilis. His discovery won the 1927 Nobel Prize in Medicine. However, to this day no one fully understands how the treatment worked. It was abandoned in the 1940s following the discovery of penicillin.
“In theory, any outer infectious source can activate the immune system thanks to the human body’s self-defense mechanism. For example, the influenza virus activates the immune system through fever,” Wang Yuedan, deputy director of the Immunology Department of Peking University Health Science Center told financial magazine China Business Network (CBN). She believes that plasmodium’s proposed ability to activate the immune system is not unique.
In his article, Wang Liming emphasized that it took a long time for immunotherapy to get from theory to clinical drug use. For example, Nivoluma, a monoclonal antibody drug that resists PD-1, did not hit the market until 2014 – two decades after the discovery of PD-1.
“Even if it’s proven that plasmodium can activate the immune system... researchers have to thoroughly explore the theories behind it, such as which immune cells it activates, how and which part of the activation is meaningful, which part is not specific and which should even be avoided... Based on those findings, researchers should develop a drug that could strengthen the cancer-fighting effects while limiting side-effects,” Wang said.
“As our current understanding of cancer is totally different compared to a century ago, it is wrong to simply copy Coley and directly inject toxins into humans,” he added.
This is not the first time malaria therapy triggered controversy. In the 1980s, American physician Henry Heimlich, inventor of the Heimlich maneuver, came under fire for his advocacy of malariotherapy to fight cancer. After the FDA and US Centers for Disease Control and Prevention discounted the theory, Heimlich turned his attention to human trials in Mexico. Four of the five
patients that received the treatment died within one year.
But Heimlich did not stop. Fueled by funding from movie stars and agents, he began treatment on people living with HIV and sought research partners in China. Chen Xiaoping was among them. According to a 2003 report in The New York Times, Heimlich and a Chinese team led by Chen injected plasmodium into eight people with HIV between 1993 and 1996. US authorities later investigated the American researchers involved.
The paper quoted medical experts who criticized Heimlich’s experiment in China, saying that it was unthinkable that such an experiment would be approved in the US.
“Chen’s team should not have launched the clinical trial so hastily before they could clearly weigh the cancer-fighting effects against the side-effects and conduct more animal tests for other types of cancers,” Wang wrote in his article.
Another concern is the spread of malaria. According to Chen, a major reason he chose Guangzhou as a venue is the city is free of the anopheles mosquito, a known vector to transmit malaria. But Wang Yuedan told CBN that the species exists in some rural areas of Guangzhou. Besides, given it takes malaria three months to two years to incubate in human hosts, medical experts expressed concerns that the trials could pose a potential risk to the public health if not controlled properly. Chen did not mention whether his team is continuing to monitor people who had received injections in the study.
According to Chen, it took his team three years to receive approval for the latest clinical test. But critics argued that China’s loose ethics approval system is vulnerable to misuse. According to Chinese regulations, researchers can conduct clinical trials on humans with approval from an internal ethics committee formed by the hospital hosting the experiment.
Documentation from the First Affiliated Hospital of Guangzhou Medical University, one of the three hospitals that reportedly conducted Chen’s experiments, showed its committee consisted of 11 members, nine of whom worked at the hospital. Information about the remaining two was not released.
This only reinforced previous doubts about the ethics approval process, especially when it comes to challenging or controversial experiments. “Few people are familiar with [such] issues, so I think ethics committee members should be strictly selected and receive very professional training,” Wu Yilong, director of the Guangzhou Lung Cancer Institute and tenured director of Guangdong Provincial People’s Hospital, told NewsChina.
Zhai Xiaomei, director of the Humanities and Social Sciences Institutes, Peking Union Medical College Hospital, believes that an ethics committee should appraise both the ethics and the scientific value. “An ethics committee should prioritize the actual value of a project... If a project has many scientific problems, the ethics committee should be skeptical of its value,” she told NewsChina.
NewsChina attempted to contact the ethics committee members of the three involved hospitals numerous times for an interview, but received no response as of press time.
During investigations into Chen and his treatment, journalists found that besides the three hospitals involved, biotechnology company CAS LAMVAC Biotech also supported the experiments. Chen Xiaoping is its founder and CEO. The company possesses four initiative core technologies related to plasmodium, according to its official website.
In October 2018, Ke Zhonggui, CAS LAMVAC’s largest stakeholder, told media that the company is working hard to turn its plasmodium-based treatments into a unicorn in the immunotherapy field and is planning a Hong Kong IPO within two years. This led some to voice suspicions that Chen’s hasty push of the plasmodium treatment was done in preparation to go public.
Neither Chen nor the company confirmed the allegations. Instead, rebuttals came from Chen’s supporters on social media, who suggested that the producers and sellers of cancer drugs were behind the criticism.
Some supporters argued that Chen’s 30 years of commitment to malaria therapy research proves his motives go beyond the monetary. The treatment provides an alternative to radiotherapy and chemotherapy, which have serious side-effects, supporters said.
NewsChina found the comment sections of nearly all news reports on Chen and his treatment were filled with questions about how to participate.
According to media reports, Chen’s team has recruited around 160 volunteers for the second round of clinical trials. No further details were reported.
“For those diagnosed with terminal cancer, plasmodium [treatment] offers a last ray of hope. They are grasping at straws,” one supporter commented on the NewsChina Chinese edition Sina blog.
In the now famous SELF forum speech, Chen also described his previous patients as those willing to gamble on plasmodium because no other treatment was helping.
Critics, however, see this as taking advantage of people desperate for a cure.
“We scientists and doctors are professionals and we have the responsibility to protect patients rather than exploit their vulnerability and urgent need for treatment,” Zhai Xiaomei at Peking Union Medical College Hospital told NewsChina. “If we lead patients to believe a treatment is effective and reliable but it turns out to not be… they may lose their trust in scientists,” she added.
“Medical progress is not achieved by marketing ‘hopes,’ but by high standards of transparency and professional appraisal,” Zhu Yao, oncologist and deputy-director physician at Fudan University Shanghai Cancer Center, told NewsChina.
While Chen has refused all interviews amid the controversy, Zhong Nanshan, one of Chen’s partners and an academic with the Chinese Academy of Engineering renowned for his studies of SARS, has stepped into the media spotlight.
In an interview with China Central Television on February 7, Zhong claimed the treatment is still in its experimental phase and that current evidence and cases are not sufficient proof that the treatment works. “We can say that the treatment has shown some promise, but it is too early to make a conclusion,” he said.
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