For more than two decades, Olivera Finn has tirelessly pursued one goal in her research: to develop a vaccine to prevent cancer. She has had this goal since 1989, when her research team discovered the first tumor antigen recognized by a type of immune cell that can kill cancer cells. That antigen—an abnormal version of a protein called MUC1—is produced by the cells of more than 80% of cancer types, including cancers of the breast, pancreas, colon, lung, and prostate.
Although she started her research career as an organ transplant immunologist, the discovery of MUC1 was a pivotal point in Olivera’s career trajectory. “Once we discovered tumor antigens,” she said, “I never looked back.” Olivera received her first NCI grant in 1991 and has been funded ever since to study the biology of tumor antigens and develop them as targets for cancer prevention.
Cancer can take many years—even decades—to develop. Some cancers arise from precursor growths that can be detected by current screening methods. For example, colorectal polyps called advanced adenomas, which can be detected by colonoscopy, can progress to colorectal cancer. These adenomas can be removed surgically, but in many patients, new ones continue to develop and some will become malignant. Olivera’s lab found that the cells of advanced adenomas and the precursors of pancreatic, lung, and many other types of cancer all produce abnormal MUC1 protein.
The presence of abnormal MUC1 on premalignant growths may make it a good target for a vaccine that would prevent their progression to cancer or the development of new precursors. To test this idea, Olivera’s group conducted the first ever clinical trial of a cancer prevention vaccine based on a tumor antigen in healthy people without cancer who were at increased risk of developing the disease.
In the NCI-funded trial, reported in 2013, individuals with a history of advanced adenomas were given an MUC1 vaccine. The vaccine was shown to be safe and to elicit a strong immune response and a long-lasting immune memory. NCI is currently sponsoring a phase II trial testing whether the vaccine will prevent the regrowth of colorectal polyps.
Looking forward, Olivera envisions, “If you are in your 60s and your doctor discovers you are at high risk for cancer, the idea would be to vaccinate to boost the immune system’s ability to keep any abnormal cells in check instead of waiting to see if cancer develops.”
Olivera says that funding from NCI is critical for her research and for cancer prevention research in general. Cancer prevention research is complex, and translating laboratory discoveries into new ways to prevent cancer requires sustained investments over many years—investments that the private sector is often reluctant to make. But “building the evidence that vaccines are an effective way of controlling cancer will go a long way toward getting companies interested,” she said.
The field of cancer immunology has expanded dramatically and has led to immunotherapies for the treatment of advanced cancers as well as vaccines against some viruses that cause cancer. Boosting the immune system to prevent cancers that are not caused by viruses may now be within reach. “The opportunities are amazing,” she added.
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Doctors and scientists are always looking for better ways to care for people with cancer. To do this, they create and study new drugs. They also look for new ways to use drugs that are already available.
A drug goes from being an idea in the lab to something that a doctor prescribes. To do this, it must go through a long development and approval process. During this process, researchers make sure the drug is safe for people to take and effectively treats cancer. This process often takes many years and significant resources. But the actual amount of time and money needed depends on the drug.
There are 3 main steps in finding and developing a new drug:
Preclinical research, which is when the drug is found and first tested
Clinical research, which is when the drug is tested in people
Post-clinical research, which takes place after the drug is approved
Drug discovery and initial testing
The discovery of new cancer drugs can happen in different ways:
Accidental discovery. In the early 1940s, an explosion exposed sailors to poisonous mustard gas. Doctors found that these sailors had low white blood cell counts. So they began using nitrogen mustard, or mechlorethamine (Mustargen) to treat Hodgkin lymphoma. This is a cancer of the lymphatic system involving the white blood cells. Nitrogen mustard is still a cancer treatment used today. But accidental discoveries such as this are rare.
Testing plants, fungi, and animals. Paclitaxel (Taxol) treats several types of cancer. This was first found in the bark of the Pacific yew tree. More recently, a primitive animal called a sea sponge was used to create the drug eribulin (Halaven). The National Cancer Institute (NCI) has samples of thousands of plants, marine organisms, bacteria, and fungi. These are collected from around the world in the hopes of finding new cancer treatments.
Studying the biology of cancer cells. Most cancer researchers start by comparing both the genes found in DNA and growth patterns of cancer cells to healthy cells. This identifies important steps in the cancer growth process that a drug could fix.
For example, researchers learned that about 20% of all breast cancers have an abnormal amount of a certain protein. It is called HER2 and controls the growth and spread of cancer cells. Five drugs were created to target HER2: trastuzumab (Herceptin), lapatinib (Tykerb), pertuzumab (Perjeta), ado-trastuzumab emtansine (Kadcyla), and neratinib (Nerlynx). Now, a person with breast cancer has the tumor tested to check for HER2. It will show if these drugs can treat the cancer. Learn more about these targeted treatments.
Understanding the chemical structure of a drug target. Scientists may use computers to mimic how a potential drug interacts with its target. This is similar to fitting 2 puzzle pieces together. Researchers can then make chemical compounds that interact with the specific drug target.
After drugs are created, researchers test them on human tumor cells in the lab. They see if the drugs stop the growth of cancer cells. Next, they test the drug in animals to find out if it is still effective at treating cancer. Researchers test the drug in 2 or more animal species. They learn how the body uses the new drug. They also learn what side effects the drug may cause and what dose of the drug to test in people.
Drug developers and sponsors
The U.S. Food and Drug Administration (FDA) does not develop or test drugs. Instead, medical research universities, government agencies such as the NCI, and drug companies find and test new drugs. The sponsor is the group that develops a drug. It does the research needed for the FDA to approve the drug.
Drug developers are creating different types of biologic medicines to treat cancer. One kind of biologic medicine is called biosimilars.
Biosimilars are a variation of drugs already approved by the FDA. They offer a growing number of new treatment options for people. They also often cost less than similar drugs.
The FDA requires a biosimilar drug to be compared with an existing one. The existing drug is called a reference drug. The biosimilar must be highly similar in structure and function and have no large differences compared to the reference drug.
Biosimilars have to meet a strict approval process by the FDA to make sure it is a safe and effective treatment option. Talk with your health care team to find out if biosimilars could be a part of your treatment plan.
Before new drugs are tested in people, the sponsor must submit an Investigational New Drug (IND) application to the FDA. The IND provides information about past and future research plans, such as:
Preclinical studies done in the lab and in animals
Plans for clinical trials in people
How the new drug is made
The FDA approves potential drugs for testing in people under certain conditions:
The research shows that the drug is likely to work and be safe.
The proposed clinical trials must be designed correctly.
The drug can be made the same way every time.
Clinical trials are research studies involving volunteers. They are used to find out if a new drug is safe, effective, and better than the standard treatments. Each phase involves a larger number of people than the previous phase. It also provides more detail about the new drug’s safety and effectiveness.
Clinical trials may involve hundreds or thousands of people. They usually take years to complete. But sometimes, if a small clinical trial shows very promising results, the process may be sped up.
Early phases of clinical trials focus on safety, dosing, and how the body processes the drug. Later phases center on how well the drug works. Learn more about clinical trials.
Clinical review and FDA approval
If the clinical trials are successful, the drug sponsor submits a New Drug Application (NDA) to the FDA. The NDA requests approval for the drug to be prescribed by doctors. The request includes:
Results from the preclinical and clinical studies.
Details about how the drug will be made and labeled.
The drug’s possible side effects and any interactions with food or other drugs.
The FDA may approve the drug if the evidence shows it is effective and safe for use. No drug is completely safe or free from side effects. But a drug is approved if there are more benefits than risks.
After FDA approval
A drug is ready for the market when it receives FDA approval. This means it can be prescribed by doctors and sold to people. But the FDA may require that the sponsor conduct more clinical trials. These are called phase IV clinical trials.
Phase IV clinical trials look for other possible side effects or confirm the benefits of the treatment. They may study the drug in different doses, new combinations, or in different schedules. They may also study the treatment in new groups of people, such as older adults or children. Or they may assess the drug’s long-term effects.
Some drug makers may conduct their own phase IV clinical trials. They may do more research to get FDA approval to use the drug in a new way, such as for another type of cancer.
The FDA also monitors the safety of drugs currently on the market. They do this to make sure that drug makers report any new or serious side effects. The FDA may withdraw a drug from the market if new research shows it is not safe or effective.
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SARS-CoV-2 virus particles (orange) isolated from a patient at the NIAID Integrated Research Facility in Fort Detrick, Maryland. Credit: National Institutes of Health
In her spare time last year, Neelam Giri, M.D., joined an effort to test fellow NIH employees for SARS-CoV-2, the coronavirus that causes COVID-19. She administered the test to many employees with symptoms of COVID-19 in their cars outside the NIH Clinical Center in all kinds of weather.
“I’m honored to be part of this campaign to end the pandemic,” Dr. Giri said before receiving the vaccine at an event to kick off COVID-19 vaccinations among NIH employees. Her volunteer job illustrates one of the many ways that cancer researchers have been working against COVID-19.
Since the pandemic began, cancer researchers have also been contributing their expertise and resources to scientific investigations of the coronavirus. Their findings have been broad in scope, ranging from insights into how the virus enters cells to the identification of potential therapies.
As the pandemic continues, the results of these and other studies could inform the prevention and treatment of COVID-19 among individuals with and without cancer, according to cancer researchers who have investigated SARS-CoV-2.
“Many cancer researchers have been able to pivot portions of their research—either in the laboratory or in the clinic—to try to better understand COVID-19 and find ways to treat the disease,” said James Gulley, M.D., Ph.D., head of the immunotherapy section of NCI’s Center for Cancer Research (CCR).
Cancer researchers are well suited to investigate COVID-19 “because we are used to dealing with complex biological problems,” Dr. Gulley continued. And some of the tools used to study how the immune system interacts with tumors can be modified to study SARS-CoV-2, he added.
Testing Biomarkers for the Severity of COVID-19
Last spring, for example, several cancer researchers in New York City shifted their focus from studying immunotherapy—treatments that help the immune system to detect and kill cancer cells—to investigating the body’s response to the coronavirus.
The results suggested that these cytokines could potentially guide decisions about the type of care that people with COVID-19 should receive, Dr. Gnjatic said. “Such biomarkers could be evaluated in future clinical trials,” he added.
About 10% of the patients with COVID-19 in the study also had cancer. “We are still analyzing the data to see whether there are certain factors that make these patients more likely to develop severe COVID-19 than other patients,” said Dr. Gnjatic.
He brought to the project his experience leading an NCI-sponsored initiative to develop biomarkers that doctors could use to identify patients with cancer who are likely to respond to immunotherapy drugs.
“We are interested in the interplay between tumors and the immune system,” said Dr. Gnjatic. “When COVID-19 hit, we were primed to use our research methods to investigate the pathology of the disease.”
Starting in March, Dr. Gnjatic co-led a team of researchers at Mount Sinai Hospital that created a COVID-19 research biobank. In just two months, the biobank collected blood samples from 500 patients hospitalized with COVID-19. Since then, the biobank has added samples from nearly 300 hospitalized patients, and all of these patients have been followed over time.
“We now have at least 6 months of follow-up data,” Dr. Gnjatic said. “The biobank will allow us to analyze many more biomarkers, predict patient outcomes, assess the impact of treatment, and hopefully contribute to better clinical care of patients with COVID-19.”
“The prior therapies that patients with cancer have had may make them more likely to get sick from COVID-19,” said Nirali Shah, M.D., of CCR, who co-led a clinical trial testing the drug tocilizumab (Actemra) in patients with cancer and COVID-19. Cancer and certain treatments for cancer, she noted, can weaken the immune system.
Patients with cancer also tend to be older and may have risk factors linked to aggressive forms of COVID-19, noted Ziad Bakouny, M.D., of the Dana-Farber Cancer Institute, who coauthored a recent overview of cancer and COVID-19. These risk factors include certain underlying health conditions, such as diabetes and a heart condition.
“In general, patients with cancer have more severe COVID-19 symptoms at diagnosis and, unfortunately, they also have worse outcomes than patients who don’t have cancer,” Dr. Bakouny said.
More research, he continued, is needed to understand “how the biology of cancer and COVID-19 may interact in individuals with both diseases.”
“We expect that the samples and data we are collecting will help researchers to better understand many aspects of how COVID-19 is affecting patients with cancer,” said Larissa Korde, M.D., of NCI’s Cancer Therapy Evaluation Program and a leader of the NCCAPS study.
The researchers have been enrolling children and adults at some 700 sites across the country, including sites that are part of the NCI Community Oncology Research Program (NCORP). NCORP reaches patients in underserved areas, many of which have been disproportionately affected by the pandemic.
Revealing Clues to Coronavirus Infections and Treatment Possibilities
Some cancer researchers, including DCEG’s Ludmila Prokunina-Olsson, Ph.D., have focused on the underlying biology of coronavirus infections.
Last fall, her team described a previously unknown form of ACE2, the receptor protein used by the coronavirus to bind to and infect cells. The newly identified molecule—now called deltaACE2 (dACE2)—is shorter than the other form of ACE2 and does not appear to bind to SARS-CoV-2, which means that it is unlikely to be a gateway for viruses to enter human cells, said Dr. Prokunina-Olsson.
The researchers also found that certain cells, including some tumor cells, produce dACE2 when exposed to interferons. The body makes interferons in response to viral infections; interferons are also synthetically produced as drugs to treat cancer, infections, and other diseases. In clinical trials, researchers have been testing interferons as possible treatments for COVID-19.
In their study, Dr. Prokunina-Olsson and her colleagues found that the full-length ACE2 protein did not appear to be produced by cells in response to exposure to interferons or viruses, as some previous studies had suggested.
Taken together, the new findings suggest that exposure to viruses or interferons used for treatment may lead to the expression of dACE2 rather than the full-length form of the ACE2 receptor—and would therefore not increase the risk of cells being infected by SARS-CoV-2.
Two other groups of researchers recently confirmed the existence of dACE2 in human cells. “We are conducting additional experiments to understand why and when dACE2 is produced by normal and tumor cells—and whether differences in the expression of ACE2 and dACE2 could be important for infection,” said Dr. Prokunina-Olsson.
Profiling T-Cell Responses to the Coronavirus
Cancer researchers have also been investigating the body’s response to SARS-CoV-2, including the role that immune cells called T cells may play in fighting the infection.
“T cells can identify cells that have been infected by the virus and kill those cells,” said Dr. Gulley. “We think that studying T cells will be important for understanding the immune system’s response to SARS-CoV-2 as well as the immune response to vaccines against the virus.”
In cancer immunotherapy research, investigators routinely monitor how T cells are turned on, or activated, in response to certain proteins (antigens) on tumor cells. “We can bring this experience to the fight against COVID-19,” said Dr. Gulley.
Some of Dr. Gulley’s colleagues in CCR have done just that. A team led by Jeffrey Schlom, Ph.D., and Renee Donahue, Ph.D., has adapted tests used to profile T-cell responses to tumor antigens for studies of the coronavirus.
“As COVID-19 emerged, we modified the tests so that we could specifically measure T-cell responses against certain parts of the coronavirus, such as the spike protein on the surface of the virus and the nuclear protein,” said Dr. Donahue, of the Laboratory of Tumor Immunology and Biology.
The new technology “offers a very sophisticated way of looking at T cells and determining how active they are against certain viral proteins,” said Dr. Gulley.
The tests could be used to study COVID-19 vaccines in patients with cancer who are receiving immunotherapy, noted Dr. Donahue. “We need to learn whether COVID-19 vaccines can generate effective immune responses in patients being treated for cancer,” she added.
Understanding Inflammatory “Storms”
In some patients with severe COVID-19, the immune system mounts an overly aggressive response to the virus. When this happens, the body may produce large numbers of cytokines. By stimulating the immune system, these proteins can damage vital organs, such as the lungs and the heart, leading to death. This hyperinflammatory state is sometimes called a cytokine storm.
Uncontrolled immune responses involving cytokines can also occur in patients with cancer who receive immunotherapy drugs known as CAR T-cell therapies. In these patients, the phenomenon—called cytokine release syndrome—occurs when large amounts of cytokines are released into the blood all at once.
Such responses can be life-threatening, so patients receiving immunotherapy are routinely monitored for evidence of aggressive immune responses and treated as needed.
Although some of the same cytokines may be involved in responses to CAR T-cell therapy and to the coronavirus, the underlying biology of these responses is different, Dr. Shah explained.
“Fundamentally, what is happening with COVID-19 is that an infection leads to an inflammatory response,” said Dr. Shah.
“There may be direct or indirect injury to tissue as a result of COVID-19, and this could lead to very different immune responses,” she continued. “Also, for a host of reasons, some patients may have more of an inflammatory response than others.”
Understanding why people can have such different responses to infection with the coronavirus is the focus of ongoing investigations. For example, the NIH-led COVIDcode study is examining how genetic variants may contribute to the severity of COVID-19.
Testing Potential Treatments for COVID-19
Cancer researchers have also played a role in identifying and evaluating potential treatments for overactive immune responses associated with COVID-19. Several cancer drugs—or drugs being studied as cancer treatments—have been evaluated for this purpose.
“The results of these studies have been mixed, and more research is needed to determine which treatments may be effective,” said Dr. Bakouny, who noted that certain steroids have been shown in clinical trials to treat overactive immune responses associated with COVID-19.
One of the first cancer drugs to be evaluated for COVID-19 was acalabrutinib (Calquence). This treatment blocks the activity of a protein called Bruton’s tyrosine kinase (BTK), which plays an important role in the normal immune system.
Last March, a team led by Wyndham Wilson, M.D., and Louis Staudt, M.D., Ph.D., in CCR launched a small study to test acalabrutinib in 19 patients hospitalized with severe COVID-19.
“We took the knowledge we had about the drug from our cancer studies and tried to apply that to the treatment of patients with COVID-19 who had the most dramatic immune responses,” said NCI’s Mark Roschewski, M.D., who helped conduct the study.
In the study, some of the 19 patients seemed to benefit from the drug. But in a subsequent randomized clinical trial, the drug did not improve the number of patients who were alive and free of respiratory failure, according to the maker of acalabrutinib, AstraZeneca.
Nonetheless, the research on BTK inhibitors that began during the pandemic will continue through a study called RESPOND, which is led by the National Institute of Allergy and Infectious Diseases.
“What we learn may help us understand how these inhibitors could potentially be useful for the treatment of other common inflammatory and autoimmune conditions that afflict the general population,” said the study’s lead investigator, Michail Lionakis, M.D., Sc.D., who also collaborated on the NCI-led acalabrutinib research.
An Unprecedented Pace of Scientific Discovery
Researchers have been studying coronaviruses for decades, Dr. Gulley noted, so investigators “already have a head start on identifying important questions to explore.”
He added, “The more research tools we can bring to this fight—and the more different angles we can come at this virus—the better our chances of gaining insights that will help us to more effectively treat the virus and limit its spread.”
Dr. Prokunina-Olsson said that the pace of scientific discoveries related to COVID-19 has been “unprecedented.” She undertook her study of ACE2 in response to research that had been posted online for the scientific community early in the pandemic.
The practice of sharing scientific results almost in real time fuels new studies and raises additional research questions, Dr. Prokunina-Olsson stressed.
“This process has allowed the research community to conduct follow-up studies and to refine the messages of previous publications,” she said. “What could normally take several years happened in a matter of months.”
Understandably, many who are diagnosed with cancer are overwhelmed with fear for their health and for what the future may hold. However, understanding the fears around cancer research studies can help bring modern treatment approaches to high-need, high-risk groups in their own communities. In this short video, Raymond U. Osarogiagbon, M.D, principal investigator of the Baptist Memorial Health Care/Mid-South Minority Underserved NCORP, tells about reaching out and taking the time to help one cancer patient and her family understand why a clinical trial might be the best care option. Find more information about cancer clinical trials in your community HERE.
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