編者按:

這是一篇來自英國Oundle School 14歲高一學生Golden Sheng的投稿，從他身上我們看到了醫療器械未來的新生力量，也了解到原來思宇醫械觀察的讀者群比我們預期的還小~頗感欣慰，特予刊發。

For almost a year, our world has been brought to a complete standstill due to an illness that has affected millions of people all across the globe. From India to the USA to Spain, COVID-19 has made it so that people can not enjoy the basic freedom of leaving their homes. I can guarantee you that everyone studying at Oundle School has been affected by this pandemic, some more prominently than others. Naturally, research teams and centres everywhere are scrambling to discover and distribute a vaccination for this highly virulent coronavirus. On the other hand, a condition that has affected humanity for much longer than COVID-19, is cancer. Just as COVID-19 has affected our school and us, cancer has affected all of us around the world more subtely than a pandemic like COVID-19, but with much more fatal results. Many doctors and research teams have spent decades trying to find the cure to cancer but none have succeeded so far. To specify, a cure would “eliminate all traces of cancer from the body and ensure it wouldn’t come back.” However, various treatments have been discovered with varying levels of success. One such promising treatment was discovered and employed by Dr. Patrick Soon-Shiong. This essay will explore Dr.Soon-Shiong, as well as his cancer treatment and how he plans to apply it in a potential vaccination for COVID-19.

（Figure 1- Patrick Soon-Shiong）

Before discussing his approach to cancer treatment and COVID-19, it is important to discuss Dr.Soon-Shion’s history and the journey that led the part-time Lakers (a basketball team in the NBA) owner to find a treatment for cancer. Patrick Soon-Shiong was born in Port Elizabeth, South Africa in 1952. Growing up in such a place made it so that he was no stranger to the intersection of the immune system, cancer and infectious disease. After graduating medical school at 22 years of age, he focused his early surgery career on transplants and cancer. He believed that crossing disciplines led him to look at the body as “a system, not a single cell. We are a biological system.” This interdisciplinary thinking is what allowed Soon-Shiong to create the medicine that made his fortune: Abraxane. This medicine took an existing chemotherapy medication, Toxol, but enclosed it in protein that made it easier to deliver it to tumors. Abraxane is now used to treat advanced cases of lung, breast and pancreatic cancer. In order to develop Abraxane, he purchased Fujisawa in 1998- a small, publiclytraded business that sold injectable generic drugs. The revenue from Fujisawa was used to boost Abraxane through the regulatory process. The FDA approved Abraxane in 2005 and in 2007?Soon-Shiong split the company in two and birthed a company called Abraxis, which focused on the cancer drug. Over the next 3 years, he sold both companies for about $4.5 billion each. He had multiple interrelated businesses organized in a complex corporate structure. His efforts against COVID come from the two companies that he founded that work on developing cancer immunotherapies: NantKwest, a publicly traded outfit based in San Diego, and the privately held ImmunityBio. Founded in 2002, Soon-Shiong’s company NantKwest focuses on developing so-called “natural killer” (NK) cells, which the immune system uses to destroy virally infected cells as well as early-stage tumors. The company has since been working to develop a line of “off-the-shelf” NK cells called NK-92, which can be used to treat certain cancers as well as viral infections.

Now that we have explored his history and how his life led him to developing cancer treatment, let’s discuss the cancer treatment itself. Cancer immunotherapy is based on the notion that the body’s own immune system can be stimulated to treat the disease. That idea dates to the 19th century, when scientists first observed tumors getting smaller after patients developed a type of skin infection. This led to some of the first experiments in which the immune system of cancer patients was stimulated. However, preliminary efforts proved complicated to reproduce, and the field got sidetracked by advances in chemotherapy and radiation. Interest spiked again in 1959, when a paper showed that the tuberculosis vaccine inhibited tumor growth in mice. After decades of intense research, the first cancer immunotherapy was approved by the FDA in 1986. Other types of immunotherapies followed, ranging from purified antibodies that attack cancer to drugs that turn off the chemical switches that let tumor cells hide from the immune system. The latest advances involve CAR-T cell therapy, which first gained FDA approval in 2017 and involves genetically engineering immune cells from patients so that they attack certain targets found in tumor cells. These advances are one of the reasons many have been persuaded to take Patrick Soon-Shiong seriously. Another reason is the physical cases that Soon-Shiong has dealt with to back up all his research. Harry Reid, who represented Nevada in the upper chamber from 1987 to 2017, was diagnosed with pancreatic cancer in 2018 and started chemotherapy that July. He didn’t respond well. Reid’s condition had deteriorated so far that they stopped chemotherapy in October of 2018. In July 2019, a scan of his liver showed that the cancer had spread which meant his only option was more chemotherapy. Around the same time, Joe Kiani, founder and CEO of Irvine, California–based health IT company Masimo, met?with?Soon-Shiong?to?discuss?acquiring?$50?million?worth?of?assets?from?NantHealth.?After?his?meeting,?Kiani?contacted?Harry?Reid?and?let?him?know?about?Soo-Shion’s?experience?with?immunotherapy.

（ Figure 2- Harry Reid cancer-free）

?

Two weeks later, Soon-Shiong and a doctor from NantKwest named Leonard Sender were working with Reid, using treatments from NantKwest as well as Soon-Shiong’s ImmunityBio. Those treatments aren’t yet officially approved but were permitted under the FDA’s compassionate-use rules. Reid was treated with a combination of Abraxane, NantKwest’s natural killer cells and a drug from ImmunityBio called N-803, which stimulates the immune system to produce its own killer cells called T cells. T cells (also called T lymphocytes) are one of the major components of the adaptive immune system. Their roles include directly killing infected host cells, activating other immune cells, producing cytokines and regulating the immune response. Soon-Shiong compares it to the “triangle offense” often employed by the Lakers basketball team. In November 2019, Reid reported that his scans were completely clear, showing no signs of cancer.

?

（Figure 3- Shows boost of T cells after cancer immunotherapy was started in mouse with pancreatic cancer）

After his announcement, he made his admiration for Dr.Soon-Shiong well known- “both for what he’s done for me personally and what he’s done for the health-care delivery system in this country.” Reid’s is an extraordinary story, as pancreatic cancer remains one of the deadliest forms of the disease. Within five years of diagnosis, it kills some 90% of patients, accounting for 7% of cancer deaths globally. American game show host Alex Trebek, who also suffers from pancreatic cancer, has received the same treatment, as have two other unidentified patients. However, many caution against declaring this treatment a cure as it is too early to tell, and the cancer it aims to treat is a very nasty form of cancer. Due to this reason, NantKwest is now focusing its efforts on a new randomized clinical trial which is looking to recruit nearly 300 pancreatic cancer patients with advanced forms of the disease, who will be given a course of treatment similar to the one Harry Reid received.

?

The cancer immunotherapy that Harry Reid received and several hundred patients are currently receiving has various benefits such as:

?

●Bolstering other treatments: Other therapies, such as chemotherapy, may work better if applied in tandem with?immunotherapy.

●?Effective when other treatments aren’t: Certain cancers, such as skin cancer, don’t respond well to chemotherapy or radiation, but may respond well to?immunotherapy.

●?Fewer side effects: As it targets only your immune system, you may experience fewer side effects.

●?Cancer less likely to return: Your immune system learns to go after cancer cells if they return (immunomemory.)

?

While immunotherapy is a very promising cancer treatment, it does carry a few risks of its own. These include...

?

●?Side effects: Certain types of immunotherapy rev up your immune system, which can make you feel flu-like symptoms. You might also experience weight gain, stuffiness, diarrhea, and swelling.

●?Bad reaction: You might endure pain, itching, redness, swelling, or soreness in the area the medication is?applied.

●?Harm to Organs: Some immunotherapies can cause your immune system to attack your intestines, kidneys, heart, and other?organs.

●?Lengthy treatment: Immunotherapy can take longer to work than other?treatment options.

●?It may not work: Immunotherapy works for less than half of people who try?it.

●?It may stop working: Immunotherapy can stop having an?effect.

?

So how can this up and coming cancer treatment be applied to the pandemic that has plagued our world for almost a year now? It may seem counterintuitive, but advances in knowledge about the immune system, and how it might help kill cancer, have real applications for infectious diseases. An immunologist at Harvard Medical School named Dr.Wayne Marasca, who is currently researching COVID-19 treatments, referred to a cancer cell and a virus-infected cell as “one and the same.” The immune system, he adds, seems to think the same way. Since February, NantKwest and ImmunityBio have redirected a good portion of their attention toward the coronavirus pandemic, using a number of weapons in their collective arsenal. The first of which is a vaccine based on the system Soon-Shiong’s companies are developing for cancer, that has already shown positive results against COVID-19 in a?study involving mice. It’s also being studied in monkeys as a part of the federal government’s “Operation Warp Speed.” As for human trials, Soon-Shiong says he’s ready on that front and he simply needs the FDA to allow him to continue.This vaccine is delivered to the body in a common cold virus called an adenovirus that has been stripped of all the parts that can cause harm to people or

?

（Figure 4- Diagram of SARS-CoV-2 molecule）

trigger the body to attack it. That modified virus contains two individual segments of the COVID-19 coronavirus: the spike protein, the surface protein on the virus that triggers an antibody response; and a nucleocapsid protein, which is found in the center of the virus. Most of the more than 100 vaccines that are currently in clinical development for COVID-19 focus on the spike protein to generate an immune response. However, Soon-Shiong thinks that won’t be enough, which is why he’s including the nucleocapsid protein. He is concerned that the spike protein mutates and has already mutated.?Beyond potential mutations, another concern about merely eliciting an antibody response is that from the data seen so far, antibodies to the COVID-19 virus are not very lasting. Levels of antibodies in the blood greatly reduce after a few months, so it is uncertain how long immunity will remain after successful vaccination. Experts believe that using the nucleocapsid protein “couldn’t hurt” and it could elicit not only antibodies but virus-killing T-cells as well.

The second weapon is the application of NantKwest’s NK-92 and ImmunityBio’s N-803 against COVID-19. NK-92 is being adapted to directly attack virus-infected cells, while the N-803 stimulates the patient’s immune system to produce its own natural killer cells against the virus. The treatments might be used either together or separately depending on the particular patient. Human trials of these treatments have already begun. Immunology experts from John Hopkins Center for Health Security believe that the concept is great but whether the collected data supports the concept or not is yet to be seen.

The third weapon NantKwest and ImmunityBio are developing to combat COVID-19 involves the use of mesenchymal stem cells, which are derived from bone marrow. This type of stem cell has been investigated over the past decade for diseases such as COVID-19, that can cause the body’s immune system to go into overdrive and attack itself. This treatment would be for the most severely sick coronavirus patients, who are experiencing a “cytokine storm,” in which the immune system overreacts. Small-scale studies have suggested this might be an effective treatment, and several companies, including Melbourne, Australia–based Mesoblast, are already in late-stage clinical?trials for severe COVID-19 patients. Soon-Shiong’s companies are currently working with hospitals to recruit patients for human trials and further develop the treatment.

If Soon-Shiong’s approaches to Covid-19 bear fruit in clinical trials, the next step may prove harder still: getting those treatments to needy patients. This is especially so for the vaccine as at the moment, neither NantKwest nor ImmunityBio has the resources to scale up manufacturing.?Soon-Shiong states that he only has a million or 2 millions doses and there is no way he could achieve 2 million doses without support from the government. Billions of dollars are going to companies that have billions in revenues. This can be seen in the case of pharma giant Pfizer (2019 revenue: $51.8 billion) which received a $2 billion federal contract in July to manufacture a vaccine it’s developing. Despite these frustrations, the world needs people like Soon-Shiong to do their part in this war against the coronavirus. “This is the crisis of our time,” he says. “It’s almost existential.” The information presented in this essay leads me to conclude that cancer immunotherapy is a promising treatment for cancer, with pros that outweigh the cons in most cases. I can also conclude that Dr.Soon-Shiong’s efforts toward developing an effective vaccination for COVID-19 are also promising and necessary in our current situation. I believe that in times of crisis, we must come together as citizens and taxpayers in order for small companies such as NantKwest and ImmunityBio to be able to distribute their vaccines to people all over the world.. It is our responsibility to support Dr.Soon-Shiong and research groups all around the world in their research and development, and cleanse our world of COVID-19.

?

Bibliography:

?

●?Knapp, Alex. “The Inside Story Of Biotech's Barnum And His Covid Cures.” Forbes, Forbes Magazine,19 Oct.?2020,www.forbes.com/sites/alexknapp/2020/08/27/the-inside-story-of-biotechs-barnum-and-his-covid-cures/?utm_source=newsletter.

●?Media, Haymarket. “Immunotherapy: Side Effects, Risks & Benefits.” Cancer Therapy Advisor,23 Apr.2019,www.cancertherapyadvisor.com/home/tools/fact-sheets/immunotherapy-side-effects-risks-and-benefits/.

●?Pathak, Neha. “What Are the Pros and Cons of Immunotherapy?” WebMD,WebMD,23Jan.2019,?www.webmd.com/cancer/immunotherapy-risks-benefits.

●?HealthLeaders. “Dr. Patrick Soon-Shiong on Solving COVID-19: 'No Different From Cancer'.” HealthLeaders?Media,?www.healthleadersmedia.com/innovation/dr-patrick-soon-shiong-solving-covid-19-no-differe?nt-cancer.

●?“T Cells - Production of T Cells - Types of T Cells.” TeachMePhysiology, 26 May 2020, teachmephysiology.com/immune-system/cells-immune-system/t-cells/.