An alarming rise in colorectal cancer rates among young adults is the subject of ongoing research by Washington University cancer epidemiologist Yin Cao, ScD, MPH, at Siteman Cancer Center. The Wall Street Journal highlighted her work to understand and remedy this troubling trend.
Read or listen to the article. Learn more about Cao’s research and a recent grant funding it.
Off-the-shelf CAR-natural killer cells could expand accessibility, reduce cost of cell-based cancer therapies
A new type of cell-based immunotherapy shows promise for B-cell lymphomas and — due to innovations in manufacturing — could make future cellular immunotherapies less expensive and more accessible to patients. A phase 1 clinical trial found one such immunotherapy to be safe for patients with several types of B-cell lymphoma, a type of blood cancer. Larger studies are needed to assess efficacy, but early data suggest this approach could offer a less toxic alternative to CAR-T cell therapies that are approved by the Food and Drug Administration to treat lymphoma.
The study, co-led by researchers at Washington University School of Medicine in St. Louis, was published Jan. 9 in The Lancet. The clinical trial was conducted at nine sites across the U.S. with Siteman Cancer Center, based at Barnes-Jewish Hospital and the School of Medicine, enrolling the highest number of participants.
Like CAR-T cell therapy, in which immune cells called T cells are harvested from the patient and genetically modified to attack cancer cells, this new approach engineers a different type of immune cell called a natural killer (NK) cell. For the new therapy, these cells are derived from stem cells that originated from healthy adult donor tissue — called induced pluripotent stem cells (iPSCs) — to make therapeutic CAR-NK cells. These new CAR-NK cells have features that allow them to be given to any patient without eliciting graft versus host diseases.
“The main difference between these CAR-NK cells and the FDA-approved CAR-T cell products lies in the ease of manufacturing,” said lead author Armin Ghobadi, MD, a professor of medicine and clinical director of the Center for Gene and Cellular Immunotherapy at the School of Medicine. “Currently, 10-20% of patients who need CAR-T cell therapy can’t access the treatment due to manufacturing failure or disease progression during manufacturing. Therapeutic CAR-NK cells produced from iPSCs address some of the key limitations of CAR-T cell therapies and could make cellular immunotherapy more accessible globally.”
In cell-based immunotherapies, harnessing NK cells also is an attractive alternative to T cells, in part, because other clinical trials have shown NK cells administered therapeutically tend to cause fewer serious side effects than CAR-T cells do.
The CAR-NK cell product studied in this trial — called FT596 — was developed by Fate Therapeutics, which funded the trial. Compared with traditional CAR-T cell products, FT596 has several differences in design and manufacturing that could reduce cost, accelerate production and make this type of cellular immunotherapy available to more patients worldwide.
FT596 has features that allow the CAR-NK cells to target the cancer in two different ways to avoid tumor resistance, compared with standard CAR-T cell therapy, which only targets the cancer cells in one way.
CAR-T cell products are made by harvesting T cells from donors or directly from the patient, shipping them to a manufacturing facility, genetically modifying them, expanding their numbers and then shipping them back to be administered to the patient in a process that takes three to five weeks. Induced pluripotent stem cell-derived CAR-NK cell products such as FT596 eliminate the harvesting, initial shipping, and patient-specific manufacturing as it is off-the-shelf and is available right away for broad patient access.
These therapeutic CAR-NK cells are made from induced pluripotent stem cells derived from healthy donor fibroblast cell lines with centralized manufacturing of a large number of doses per manufacturing run. These CAR-NK cells can be prepared ahead of time, stored and shipped to a patient’s doctor when needed or in advance. This is similar to off-the-shelf medicines in a pharmacy, potentially making iPSC-derived CAR-NK cell therapies more accessible to patients in places where health-care services don’t have the infrastructure to collect, freeze and ship donor cells, according to the investigators. The CAR-NK cell production process also avoids the variability seen in cell therapy products when the starting cells originate from a unique donor each time.
To assess the safety of off-the-shelf cellular immunotherapy, the study administered the CAR-NK cells to 86 patients with hard-to-treat B-cell lymphomas. On average, patients had already received four lines of therapy, including FDA-approved CAR-T cell therapy for 33 of the patients. Their cancers either had not responded to those treatments initially or had later returned. Patients with lymphoma whose disease has returned after several lines of therapy have a very poor prognosis, with most succumbing to the disease within a few months.
The trial investigated escalating doses of the CAR-NK cells and found that patients tolerated even the highest dose given in this trial. The investigators tested these CAR-NK cells alone in 18 patients and for the remainder in combination with rituximab, a monoclonal antibody that helps further target the CAR-NK cells to lymphoma cells.
A total of 10 study participants experienced low-grade cytokine release syndrome, a side effect of immunotherapy that was managed with additional treatments. None of the patients experienced neurotoxicity, which can be a serious complication for some patients who receive CAR-T cell therapy. These results suggest CAR-NK cells could be safely administered in an outpatient setting.
Patients with follicular lymphoma, a slow-growing form of the blood cancer, responded most to the experimental therapy. All of them responded at least partially, and 85% experienced a complete response, meaning their cancer could no longer be detected after treatment with CAR-NK cells. This response continued for an average of almost 17 months after treatment. Among 20 patients with relapsed or progressed disease after standard CAR-T cell therapy who then received CAR-NK cell therapy plus rituximab, 45% responded with 30% achieving complete remission.
“In patients with follicular lymphoma, FT596 has shown comparable efficacy to the three FDA-approved CAR-T cell therapies, but with significantly reduced toxicity,” Ghobadi said. “For patients with large B-cell lymphoma who undergo FDA-approved CAR-T cell therapy, approximately 60% experience a relapse. These patients have very limited treatment options, and most survive only a few months. This study demonstrates that nearly half of these patients could achieve another complete or partial remission with FT596, representing a significant improvement.”
The apparent safety of the new approach also makes it appealing for investigating the potential of CAR-NK cells in treating solid tumors and autoimmune diseases.
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Ghobadi A, Bachanova V, Patel K, Park JH, Flinn I, Riedell PA, Bachier C, Diefenbach CS, Wong C, Bickers C, Wong L, Patel D, Goodridge J, Denholt M, Valamehr B, Elstrom RL, Strati P. Induced pluripotent stem-cell-derived CD19-directed chimeric antigen receptor natural killer cells in B-cell lymphoma: a phase 1, first-in-human trial. The Lancet. Jan. 9, 2025.
This work was funded by Fate Therapeutics, which developed and manufactured FT596. The funder had a role in study design, data collection, data analysis, interpretation and the writing of the report.
Fructose consumption has increased considerably over the past five decades, largely due to the widespread use of high-fructose corn syrup as a sweetener in beverages and ultra-processed foods. New research from Washington University in St. Louis shows that dietary fructose promotes tumor growth in animal models of melanoma, breast cancer and cervical cancer. However, fructose does not directly fuel tumors, according to the study published Dec. 4 in the journal Nature.
Instead, Washington University scientists discovered that the liver converts fructose into usable nutrients for cancer cells, a compelling finding that could open up new avenues for care and treatment of many different types of cancer.
“The idea that you can tackle cancer with diet is intriguing,” said Gary Patti, PhD, the Michael and Tana Powell Professor of Chemistry in Arts & Sciences and a professor of genetics and of medicine at the School of Medicine, all at Washington University. Patti also is a research member of Siteman Cancer Center, based at Barnes-Jewish Hospital and the School of Medicine.
“When we think about tumors, we tend to focus on what dietary components they consume directly. You put something in your body, and then you imagine that the tumor takes it up,” Patti said. “But humans are complex. What you put in your body can be consumed by healthy tissue and then converted into something else that tumors use.”
“Our initial expectation was that tumor cells metabolize fructose just like glucose, directly utilizing its atoms to build new cellular components such as DNA. We were surprised that fructose was barely metabolized in the tumor types we tested,” said the study’s first author, Ronald Fowle-Grider, PhD, a postdoctoral fellow in Patti’s lab. “We quickly learned that the tumor cells alone don’t tell the whole story. Equally important is the liver, which transforms fructose into nutrients that the tumors can use.”
Using metabolomics — a method of profiling small molecules as they move through cells and across different tissues in the body — the researchers concluded that one way in which high levels of fructose consumption promote tumor growth is by increasing the availability of circulating lipids in the blood. These lipids are building blocks for the cell membrane, and cancer cells need them to grow.
“We looked at numerous different cancers in various tissues throughout the body, and they all followed the same mechanism,” Patti said.
Scientists have long recognized that cancer cells have a strong affinity for glucose, a simple sugar that is the body’s preferred carbohydrate-based energy source.
In terms of its chemical structure, fructose is similar to glucose. They are both common types of sugar, with the same chemical formula, but they differ in how the body metabolizes them. Glucose is processed throughout the whole body, while fructose is almost entirely metabolized by the small intestine and liver.
Both sugars are found naturally in fruits, vegetables, dairy products and grains. They are also added as sweeteners in many processed foods. Fructose, in particular, has penetrated the American diet over the last few decades. It is favored by the food industry because it is sweeter than glucose.
Prior to the 1960s, people consumed relatively little fructose compared with today’s numbers. A century ago, an average person consumed just 5-10 pounds of fructose per year. To put it in familiar terms, that is roughly equal to the weight of a gallon of milk. In the 21st century, that number has increased to be as high as the equivalent of 15 gallons of milk.
“If you go through your pantry and look for the items that contain high-fructose corn syrup, which is the most common form of fructose, it is pretty astonishing,” said Patti, who also is a research member of the Center for Human Nutrition at the School of Medicine. “Almost everything has it. It’s not just candy and cake, but also foods such as pasta sauce, salad dressing and ketchup,” he said. “Unless you actively seek to avoid it, it’s probably part of your diet.”
Given the rapid rise in the consumption of dietary fructose over recent decades, the Washington University researchers wanted to know more about how fructose impacts the growth of tumors.
Patti and Fowle-Grider began their investigation by feeding tumor-bearing animals a diet rich in fructose, then measuring how quickly their tumors grew. The researchers found that added fructose promoted tumor growth without changing body weight, fasting glucose or fasting insulin levels.
“We were surprised to see that it had a rather dramatic impact. In some cases, the growth rate of the tumors accelerated by two-fold or even higher,” Patti said. “Eating a lot of fructose was clearly very bad for the progression of these tumors.”
But the next step in their experiments initially stumped them. When Fowle-Grider attempted to repeat a version of this test by feeding fructose to cancer cells isolated in a dish, the cells did not respond. “In most cases they grew almost as slowly as if we gave them no sugar at all,” Patti said.
So, Patti and Fowle-Grider went back to looking at changes in the small molecules in the blood of animals fed high-fructose diets. Using metabolomics, they identified elevated levels of a variety of lipid species, including lysophosphatidylcholines (LPCs). Additional dish tests showed that liver cells that were fed fructose release LPCs.
“Interestingly, the cancer cells themselves were unable to use fructose readily as a nutrient because they do not express the right biochemical machinery,” Patti said. “Liver cells do. This allows them to convert fructose into LPCs, which they can secrete to feed tumors.”
A defining characteristic of cancer is uncontrolled proliferation of malignant cells. Each time a cell divides, it must replicate its contents, including membranes. This requires a substantial amount of lipids. While lipids can be synthesized from scratch, it is much easier for cancer cells to simply take lipids up from their surrounding environment.
“Over the past few years, it’s become clear that many cancer cells prefer to take up lipids rather than make them,” Patti noted. “The complication is that most lipids are insoluble in blood and require rather complex transport mechanisms. LPCs are unique. They might provide the most effective and efficient way to support tumor growth.”
Interestingly, over the same period of time when human fructose consumption has surged, a number of cancers have become increasingly more prevalent among people under the age of 50. This raises the question of whether the trends are linked. With $25 million in support from Cancer Grand Challenges, Patti recently teamed up with Yin Cao, ScD, MPH, an associate professor of surgery at the School of Medicine and a fellow Siteman research member, and other investigators from around the world, none of whom were involved in this study, to investigate possible connections.
“It will be exciting to better understand how dietary fructose influences cancer incidence. But one take-home message from this current study is that if you are unfortunate enough to have cancer, then you probably want to think about avoiding fructose. Sadly, that is easier said than done,” Patti said.
Aside from dietary intervention, the study authors said that this research could help us develop a way to prevent fructose from driving tumor growth therapeutically, using drugs.
“An implication of these findings is that we do not have to limit ourselves to therapeutics that only target disease cells,” Patti said. “Rather, we can think about targeting the metabolism of healthy cells to treat cancer. This has worked with mice in our study, but we would like to take advantage of our observations and try to improve the lives of patients.”
The study authors are working with clinical partners at Washington University School of Medicine to explore a clinical trial related to fructose in the diet.
A new study from Washington University School of Medicine in St. Louis describes an innovative method of analyzing mammograms that significantly improves the accuracy of predicting the risk of breast cancer development over the following five years. Using up to three years of previous mammograms, the new method identified individuals at high risk of developing breast cancer 2.3 times more accurately than the standard method, which is based on questionnaires assessing clinical risk factors alone, such as age, race and family history of breast cancer.
The study is published Dec. 5 in JCO Clinical Cancer Informatics.
“We are seeking ways to improve early detection, since that increases the chances of successful treatment,” said senior author Graham A. Colditz, MD, DrPH, associate director, prevention and control, of Siteman Cancer Center, based at Barnes-Jewish Hospital and the School of Medicine, and the Niess-Gain Professor of Surgery. “This improved prediction of risk also may help research surrounding prevention, so that we can find better ways for women who fall into the high-risk category to lower their five-year risk of developing breast cancer.”
This risk-prediction method builds on past research led by Colditz and lead author Shu (Joy) Jiang, PhD, a statistician, data scientist and associate professor of surgery in the Division of Public Health Sciences at the School of Medicine. The researchers showed that prior mammograms hold a wealth of information on early signs of breast cancer development that can’t be perceived even by a well-trained human eye. This information includes subtle changes over time in breast density, which is a measure of the relative amounts of fibrous versus fatty tissue in the breasts.
For the new study, the team built an algorithm based on artificial intelligence that can discern subtle differences in mammograms and help identify those women at highest risk of developing a new breast tumor over a specific timeframe. In addition to breast density, their machine-learning tool considers changes in other patterns in the images, including in texture, calcification and asymmetry within the breasts.
“Our new method is able to detect subtle changes over time in repeated mammogram images that are not visible to the eye,” said Jiang, yet these changes hold rich information that can help identify high-risk individuals.
At the moment, risk-reduction options are limited and can include drugs such as tamoxifen that lower risk but may have unwanted side effects. Most of the time, women at high risk are offered more frequent screening or the option of adding another imaging method, such as an MRI, to try to identify cancer as early as possible.
“Today, we don’t have a way to know who is likely to develop breast cancer in the future based on their mammogram images,” said co-author Debbie L. Bennett, MD, an associate professor of radiology and chief of breast imaging for the Mallinckrodt Institute of Radiology at the School of Medicine. “What’s so exciting about this research is that it indicates that it is possible to glean this information from current and prior mammograms using this algorithm. The prediction is never going to be perfect, but this study suggests the new algorithm is much better than our current methods.”
The researchers trained their machine-learning algorithm on the mammograms of more than 10,000 women who received breast cancer screenings through Siteman Cancer Center from 2008 – 2012. These individuals were followed through 2020, and in that time 478 were diagnosed with breast cancer.
The researchers then applied their method to predict breast cancer risk in a separate set of patients — more than 18,000 women who received mammograms through Emory University in the Atlanta area from 2013 – 2020. Subsequently, 332 women were diagnosed with breast cancer during the follow-up period, which ended in 2020.
According to the new prediction model, women in the high-risk group were 21 times more likely to be diagnosed with breast cancer over the following five years than were those in the lowest-risk group. In the high-risk group, 53 out of every 1,000 women screened developed breast cancer over the next five years. In contrast, in the low-risk group, 2.6 women per 1,000 screened developed breast cancer over the following five years. Under the old questionnaire-based methods, only 23 women per 1,000 screened were correctly classified in the high-risk group, providing evidence that the old method, in this case, missed 30 breast cancer cases that the new method found.
The mammograms were conducted at academic medical centers and community clinics, demonstrating that the accuracy of the method holds up in diverse settings. Importantly, the algorithm was built with robust representation of Black women, who are usually underrepresented in development of breast cancer risk models. The accuracy for predicting risk held up across racial groups. Of the women screened through Siteman, most were white, and 27% were Black. Of those screened through Emory, 42% were Black.
In ongoing work, the researchers are testing the algorithm in women of diverse racial and ethnic backgrounds, including those of Asian, southeast Asian and Native American descent, to help ensure that the method is equally accurate for everyone.
The researchers are working with Washington University’s Office of Technology Management toward patents and licensing on the new method with the goal of making it broadly available anywhere screening mammograms are provided. Colditz and Jiang also are working toward founding a start-up company around this technology.
In recognition of a transformative commitment to Washington University School of Medicine in St. Louis from St. Louisan Richard Frimel and his late husband, Gary C. Werths, Siteman Cancer Center’s new building for outpatient care will be named the Gary C. Werths Building. The historic pledge will fund groundbreaking cancer research and medical student scholarships to support aspiring physicians.
The nine-story building opened in September on the Washington University Medical Campus and exemplifies the collaborative strength of BJC HealthCare and WashU Medicine in providing innovative cancer care. Patients receive the most advanced, lifesaving therapies informed by the latest research discoveries, many of them made by WashU Medicine faculty who are leaders in their fields.
“We are honored to name Siteman’s new building after Gary, forever linking his name with world-class, compassionate cancer care,” Chancellor Andrew D. Martin said. “Gary and Richard’s extraordinary commitment will advance WashU Medicine’s innovative cancer research and provide enduring scholarship support for future generations of physicians. Their philanthropy offers hope to cancer patients and their families and will help alleviate the financial burden of attending medical school for students aspiring to become physicians.”
The pledge is the largest single philanthropic investment in Siteman Cancer Center since Alvin J. and Ruth Siteman’s founding gift 25 years ago.
Siteman – based at Barnes-Jewish Hospital and WashU Medicine – is the only National Cancer Institute-designated Comprehensive Cancer Center in Missouri and southern Illinois and draws patients from across the U.S. and beyond who seek access to the latest treatments and technologies as well as innovative clinical trials.
“At WashU Medicine, we fully recognize that investing in pioneering research is essential to advancing cancer care and improving outcomes for patients,” said David H. Perlmutter, MD, the George and Carol Bauer Dean of WashU Medicine, executive vice chancellor for medical affairs and the Spencer T. and Ann W. Olin Distinguished Professor. “Gary Werths’ legacy will live on through the excellent patient care delivered every day in this beautiful new building and the scholarships that will change the future for generations of medical students.”
The Gary C. Werths Building is thoughtfully designed, with cancer patients’ needs at its core. An innovative model of care enables many patients to see a multidisciplinary team of WashU Medicine cancer specialists at Siteman and receive chemotherapy and other services in collaboration with BJC caregivers, all coordinated during a single visit. This patient-centered approach focuses on their comfort and convenience and reduces the need to return for multiple appointments.
Frimel and Werths’ commitment will advance discoveries by WashU Medicine researchers at Siteman that shape the future of cancer diagnostics and therapeutics and redefine excellence in cancer research and patient care. It will bolster efforts to better understand cancer, pioneer new therapies, conduct leading-edge clinical trials and enhance patient care.
Their pledge also will support medical student scholarships in perpetuity. Such support will enable WashU Medicine to attract the best and brightest students who can pursue their dreams of becoming physicians without having to take on overwhelming financial debt.
Additionally, the gift will benefit cancer patients in St. Louis and beyond.
“Much of our research and medical training emphasizes the importance of community outreach and cancer prevention,” said Timothy J. Eberlein, MD, director of Siteman Cancer Center, the Spencer T. and Ann W. Olin Distinguished Professor and senior associate dean for cancer programs at WashU Medicine and BJC HealthCare. “This transformational gift will help assure that Siteman continues to provide the most innovative and impactful treatments to our patients in the most supportive, compassionate environment possible.”
Werths died from Alzheimer’s disease in February 2021 at age 83. He achieved prominence within the St. Louis and international art communities as owner of Gary’s Antiques & Imports in the Central West End neighborhood that borders the Washington University Medical Campus. Werths and Frimel also were business partners, working to supply fine art to decorators, designers and architects throughout the Midwest. An avid art collector and travel enthusiast, Werths served as a trustee of the Saint Louis Art Museum, a charter member of the Central West End Savings & Loan and a board member of Harvest Bank in Dubuque, Iowa.
Through his estate, Werths previously made a gift to WashU that was designated for undergraduate scholarships and Alzheimer’s disease research.
“Gary referred to WashU Medicine and Barnes-Jewish Hospital as our best neighbors,” Frimel said. “He always had a fondness and deep respect for the physicians and caregivers on the Medical Campus. He believed in them and would be proud to support research to improve cancer care and treatment, and scholarships to support future physicians on their journeys to becoming doctors.”
Frimel noted that Werths would have loved the design of the new building named in his honor.
“It’s fabulous on many levels,” Frimel said. “It’s contemporary, and the layout is wonderful. The expanse of windows makes the building light and airy. From one direction, you look out at the whole Central West End, and from the other direction, you can see the Arch.”
Through his business, Werths provided art to decorate buildings and physician offices. Frimel said Werths believed art could have a positive effect and act as a source of comfort — a belief carried forward in the inspirational art in his namesake building. “The art is colorful, bright and cheerful,” Frimel said. “It’s just wonderful.”
A new Outpatient Cellular Therapy Center has opened at Siteman Cancer Center, based at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis.
With nine infusion beds and three infusion chairs, the center is on the eighth floor of Schoenberg Pavilion on the Washington University Medical Campus in the Central West End. The center is accessible through:
The new center offers outpatient therapies to certain patients diagnosed with lymphoma or multiple myeloma who receive one of three treatment options: CAR T-cell therapy, autologous stem cell transplant or immunotherapy with the use of bispecific T-cell engagers (BiTEs).
“These patients typically would be admitted to the hospital for two to four weeks,” said medical oncologist Amanda Cashen, MD, Washington University associate chief of hematologic malignancies and a stem cell transplant specialist at Siteman. “We’ve carefully planned this center for several years, because we wanted to offer a high standard of care in a safe setting. It complements our 96-bed inpatient stem cell and immunotherapy unit and is supported by our 24/7 cancer care clinic and a dedicated intensive care unit for emergencies or after-hours care.”
Medical oncologist Armin Ghobadi, MD, clinical director of the Center for Gene and Cellular Immunotherapy at Washington University, said patients often prefer outpatient treatment options over spending the night at the hospital. “We’ve set it up so that all of the patients undergoing BiTE immunotherapy will be outpatient,” he said. “For CAR T and autologous transplants, where the patient is his or her own donor, we believe up to 75% of our patients can have most of their treatment and monitoring in the outpatient setting, too.”
Short hospital stays still may be required but far fewer than was the case before the new center opened. Key to outpatient care, Ghobadi said, is the requirement that a caregiver remain with the patient while at home. “Some insurers don’t approve outpatient cellular or stem cell therapies without a dedicated caregiver,” he explained.
Kelly Terrell, MBA, BSN, RN, BMTCN, senior clinical program manager for hematologic malignancies, cellular therapy and transplantation at Siteman, said the care team educates patients and their caregivers so they understand the entire process and how to access any needed after-hours care. “But outpatient treatments for multiple myeloma and lymphoma are safe. Now patients can avoid long hospitalizations that previously were a deterrent to those who needed these therapies.”
The Outpatient Cellular Therapy Center includes the expertise of bone marrow transplant and cell therapy specialists, advanced nurse practitioners and infusion nurses, as well as case coordinators, a social worker and a pharmacist. Washington University physicians at Siteman perform more than 200 autologous stem cell transplants and 90 CAR T-cell procedures annually. The team also has treated more than 60 patients with BiTEs. “We envision ramping up the outpatient offerings rapidly,” Ghobadi said. “We already have six CAR T therapies that are FDA-approved, and more are in the pipeline.”
Cashen added: “As we see more treatment options become available, we can introduce new patient populations to outpatient care. I see this as a growing trend, because it is safe and convenient for patients.”