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Improving breast cancer risk assessment for Black women

The National Cancer Institute, part of the National Institutes of Health (NIH), has awarded Washington University investigator Aimilia Gastounioti, PhD, at Siteman Cancer Center a five-year, $3 million grant to improve breast cancer risk assessments for Black women. Gastounioti is an assistant professor of radiology in the Computational Imaging Research Center in for Mallinckrodt Institute of Radiology (MIR) at Washington University School of Medicine in St. Louis. This is her first R01 grant.

The project aims to address an important need for a patient population that is not well served by current risk assessment tools. Black women are slightly less likely to develop breast cancer than white women are, but their mortality rates for the disease are strikingly higher — they are 40% more likely to die from the disease than white women. The risk models that are used to identify and plan treatments for patients who may develop the disease are not well suited, and historically have been less accurate, for Black women.

New tools that provide personalized risk assessments using artificial intelligence have shown enormous promise, but so far have largely been trained on data from digital mammography of white patients. Gastounioti, a principal investigator with MIR’s Computational Imaging Research Center, and her team will develop deep learning and medical imaging informatics tools on a database of more than 95,000 digital breast tomosynthesis (DBT) exams from Black women. The database is a collaboration of WashU, Emory University in Georgia, University of Pennsylvania and Columbia University Irving Medical Center in New York. Unlike standard digital mammography, DBT captures images of breast tissue from multiple angles, resulting in more-detailed tissue representations.

The goal is to develop and distribute an accurate screening tool specific to the patient population, which has the potential to drastically improve early breast cancer detection and prevention for Black women.

Drug in clinical trials for breast cancer could also treat some blood cancers

Researchers are working with industry toward a clinical trial for blood cancer patients

Two new studies led by Washington University researchers at Siteman Cancer Center have identified a possible way to block the progression of several forms of blood cancer using a drug already in clinical trials against breast cancer.

The studies — both conducted in patient samples and animal models — found that inhibiting a protein called RSK1 reduces inflammation and stops the progression of blood cancers called myeloproliferative neoplasms (MPNs) as well as an aggressive form of acute myeloid leukemia (AML). With the RSK1 inhibitor already in clinical testing, the path to expanded use as a treatment for blood cancers likely is accelerated.

One study appears Jan. 16 in Nature Communications. The second is available online in Blood Cancer Journal.

In humans, MPNs can be slow-growing blood cancers that simmer for years. Doctors can monitor the disease and treat symptoms, but there is no reliable way to cure it or slow progression. Patients with MPNs are at high risk of developing a secondary AML that is very aggressive with no effective treatment options.

“Patients with chronic MPNs can live with the disease sometimes for decades, but they’re at increased risk of developing secondary AML, which has a poor prognosis,” said senior author Stephen T. Oh, MD, PhD, an associate professor of medicine and co-director of the Division of Hematology at Washington University School of Medicine. “These patients have no effective medical therapies, so we hope this new drug will help fill that gap in clinical care. At minimum, we’re hopeful this drug can stop the chronic disease from progressing to AML. But the goal is to eliminate the disease and get patients into remission.”

According to Oh, researchers have long been seeking an inhibitor to block MPN progression because current therapies only reduce symptoms caused by the disease, including severe fatigue, night sweats, poor appetite, weight loss, and an enlarged spleen, but do not slow progression of the disease or reduce the risk of it evolving into acute leukemia.

In theory, using RSK1 inhibitors to treat patients with chronic MPNs may improve their health to a point where they could become eligible for a stem cell transplant, which is the preferred therapy for many blood cancers because it can potentially lead to long-term remission. Oh treats patients with MPNs and related blood cancers at Siteman Cancer Center, based at Barnes-Jewish Hospital and the School of Medicine.

In the Nature Communications study, inhibiting RSK1 helped reverse the progression of MPNs in mice, reducing fibrosis, or scar formation, in the bone marrow. Inhibiting RSK1 eliminated up to 96% of cancer in mice after four weeks. It also showed evidence of preventing the chronic disease from transforming into secondary AML.

In the Blood Cancer Journal study, blocking this protein treats a specific form of AML called FLT3-ITD AML that develops directly — without an MPN developing first. This type of AML can be treated with established drugs called FLT3 inhibitors, but the cancer often develops resistance to this treatment over time. Because the RSK1 inhibitor blocks a different pathway, Oh and his co-authors suggested, it could help address this resistance.

The specific RSK1 inhibitor used in both studies, called PMD-026, is given as a pill and is currently in clinical trials as a treatment for breast cancer. Those ongoing studies seek to determine efficacy, and early testing showed trial subjects with metastatic breast cancer have tolerated the drug well with low-grade side effects.

Tracking the Path to MPN Development – and Stopping It


An earlier study by Oh’s group identified a signaling molecule called DUSP6 as an important protein driving the progression of MPNs. Further work identified the downstream signals triggered by DUSP6, and RSK1 stood out as the one they could potentially block with the RSK1 inhibitor already in clinical trials for breast cancer.

The investigational drug PMD-026 is a pan-RSK inhibitor in that it blocks all four versions of the protein — RSK1, RSK2, RSK3 and RSK4. In breast cancer, the evidence suggests that PMD-026 may work by blocking RSK2. If approved by the Food and Drug Administration to treat breast cancer, it would be the first drug on the market to inhibit the RSK family of proteins.

Oh and his team, including Tim Kong, first author of both studies and an MD-PhD student in Oh’s lab, became interested in working with the company that makes the drug — a biotech firm called Phoenix Molecular Designs — when they identified RSK1 as a key driver of several blood cancers and hypothesized that this drug potentially could block its activity as well. The company provided the drug for these studies.

“We are excited about these studies because they highlight RSK1 as a novel therapeutic target for MPNs and AML with a viable strategy for moving an investigational drug into clinical trials in the near future,” Oh said. “There are a few scenarios that we’re considering in designing a future clinical trial. It will most likely be for patients who are beyond the standard therapies that we use for the chronic phase of this disease but are not eligible for stem cell transplantation due to age or overall health.”

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Kong T, Laranjeira ABA, Letson CT, Yu L, He F, Jayanthan A, Los G, Dunn SE, Challen GA, Oh ST. RSK1 dependency in FLT3-ITD acute myeloid leukemia. Blood Cancer Journal. Nov. 26, 2024.

This work was supported by the National Institutes of Health (NIH), grant numbers R01HL134952 and R01HL147978; a Canadian Institutes of Health Research (CIHR) Doctoral Foreign Study Award; and the MPN Research Foundation. Additional support was provided by the Leukemia and Lymphoma Society Translational Research Program; When Everyone Survives Foundation; the Edward P. Evans Foundation; Gabrielle’s Angel Foundation; and a Leukemia and Lymphoma Society Scholarship.

On both papers, three co-authors are employees of Phoenix Molecular Designs, which provided PMD-026. Co-author Sandra E. Dunn, PhD, founder and CEO of Phoenix Molecular Designs, holds patents on using RSK inhibitors for treatment of cancer.

This content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Newsweek highlights whole genome sequencing work at Washington University

Pioneering work in genetic testing at Washington University School of Medicine and elsewhere has yielded invaluable – even lifesaving – information for cancer patients and physicians. Newsweek spotlights these groundbreaking advances, including WashU’s sequencing of the first cancer genome, as well as the development of ChromoSeq, the only whole genome sequencing test approved by Medicare, by Washington University pathologist Eric Duncavage, MD, at Siteman Cancer Center.

Read the article.

Learn more about ChromoSeq:

Siteman Cancer Center announces 2025 American Cancer Society-funded pilot projects

Washington University researchers will focus on Hodgkin lymphoma, myeloma and pancreatic and head and neck cancers

Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine is excited to announce the next cohort of pilot projects funded by the Institutional Research Grant from the American Cancer Society. The $360,000 grant will support 12 pilot projects from 2025–2027, including the four new projects described below.

Jason Weber Phd
Jason Weber, PhD

Under the leadership of Jason Weber, PhD, who has been the principal investigator of the grant since 2011, these awards support independent, self-directed investigators early in their careers and enable them to conduct research in areas of special interest to the American Cancer Society.

Washington University has funded early-career oncology researchers with this grant since 1958. Learn about projects initially supported in 2022, 2023 and 2024.




Project Title: Characterizing the Expression Profile of Hodgkin Lymphoma Using Single Nuclei RNA Sequencing 

Principal Investigator: Felicia Gomez, PhD

Project Summary:

Felicia Gomez Phd
Felicia Gomez, PhD

Although Hodgkin lymphoma is relatively uncommon, with about 7,000-7,500 new cases diagnosed annually in the U.S., it comprises about 10% of lymphomas in the Western world. The treatment is relatively successful. However, patients who relapse or are refractory to treatment have few secondary treatment options, and overall survival remains low in this patient population. Thus, a better understanding of the pathobiology of this disease remains an important clinical question. Current genomic technologies struggle with cancers defined by rare malignant cell populations, leaving some cancer types poorly described — Hodgkin lymphoma is one such cancer. This project will address these shortfalls by using newly developed technologies and diverse sources of DNA and RNA to describe somatic variation and patterns of gene expression. Researchers will comprehensively investigate the biology of this disease to understand its etiology, with the goal of creating data that will inform new treatment strategies. Specifically, the data produced here will investigate the cells that are responsible for this disease. We will also investigate the immune environment that supports the proliferation of malignant cells. These data will provide foundational knowledge that will support our understanding of the biological processes that underlie this disease, which has the potential to create new and innovative treatment options.




Project Title: CAR T-cell Therapy with Radiation-Based Lymphodepletion for Patients with Myeloma and Advanced Chronic Kidney Disease

Principal Investigator: Michael Slade, MD, MSCI

Project Summary:

Michael Slade Md Msci
Michael Slade, MD, MSCI

Multiple myeloma remains an incurable cancer, but recent advances in treatment have helped patients live longer after diagnosis. Cellular immunotherapy with genetically modified chimeric antigen receptor T cells (CAR T) has been shown in large studies to be better than standard therapies in patients whose myeloma has come back after treatment. The effectiveness of CAR T treatment depends, in part, on giving preparative, or “lymphodepleting,” chemotherapy (LDC) prior to CAR T infusion. However, patients with poor kidney function often cannot receive standard LDC, making them unable to receive CAR T therapy. In addition, poor kidney function is very common (30% to 40%) in patients with multiple myeloma and particularly in Black patients, leading to inequitable access to this lifesaving therapy. Therefore, researchers are studying new methods of LDC that are safer in patients with poor kidney function. Radiation treatment has been used as preparative treatment in stem cell transplant for decades but has not been used as LDC with CAR T. Work by the research team in the lab has shown that replacing fludarabine with total body irradiation in LDC leads to similar CAR T anti-cancer activity without causing low blood counts, suggesting this approach can be safe and effective in humans. This study proposes using radiation as part of LDC for patients with multiple myeloma and poor kidney function who would otherwise be ineligible for CAR T therapy or would be at increased risk of unacceptable side effects from standard LDC. Researchers plan to collect patient samples to better understand the changes in the myeloma and CAR T cells after using radiation in LDC. If this pilot study is successful, it will help improve access to CAR T therapy, including for patients with poor kidney function and for members of historically underrepresented groups.





Project Title: Investigating Inflammatory Crosstalk in the Pancreatic Cancer Tumor Microenvironment

Principal Investigator: Max Wattenberg, MD

Project Summary:

Max Wattenberg Md
Max Wattenberg, MD

Pancreatic cancer is a deadly disease for which few effective treatments are available. It is well-established that pancreatic tumors are comprised of both cancer cells and noncancerous cells that interact with one another to influence patient outcomes. This project focuses on defining how noncancerous cells contribute to cancer cell growth and resistance to treatment in pancreatic cancer. Preliminary work shows a key role for inflammatory proteins produced by noncancerous cells in supporting cancer cell growth. Using sophisticated techniques including mouse modeling of cancer and engineering of tumor cells, researchers will investigate how cellular interactions in pancreatic tumors drive cancer growth and treatment resistance. The findings from this work are anticipated to open the door to new treatments for pancreatic cancer to improve outcomes for patients.





Project Title: NRF2 as a Therapeutic Target in Head and Neck Squamous Cell Carcinoma

Principal Investigator: Paul Zolkind, MD

Project Summary:

Paul Zolkind Md
Paul Zolkind, MD

The introduction of immunotherapy has transformed the treatment and outcomes for many cancers and provides a potentially curative option for many patients. However, recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) continues to be a devastating prognosis with limited treatment options. Despite success in similar cancers, response rates to immunotherapy in R/M HNSCC are less than 20%, with long-term control in fewer than 5% of patients. Despite much investigation, PD-L1 expression remains the only clinically utilized biomarker guiding patient treatment decisions. Retrospective human tumor studies, mouse models and the research team’s previous studies suggest that activation of the NRF2 oxidative stress pathway plays a central role in shaping the immune cells within the tumor and impairing the response to immunotherapies. In this study, the researchers will use human patient samples and their genetically engineered mouse models to explore how NRF2 pathway activation impacts the immune microenvironment and impacts immunotherapy response rates. They will also explore how a novel NRF2 inhibitor, WCDD115, enhances the efficacy of immunotherapy in mice models. They hypothesize that NRF2 drives an immune “cold” tumor with comparably fewer infiltrating cytotoxic lymphocytes and that treatment with WCDD115 will create a more immune-rich microenvironment capable of producing tumor regression when combined with anti-PD1 immunotherapy. The goal is to develop and validate a clinically useful NRF2 biomarker assay that can be translated into clinical practice to guide treatment decisions, including the use of combined immunotherapy and NRF2 inhibitors in patients with NRF2-active disease.

 

For Your Health — Ultra-Processed Foods: A Growing List of Possible Health Risks

Scc 2025 For Your Health Digital Banner

Ultra-processed foods. It’s not a term many of us heard 10, or even five, years ago. But that’s starting to change. We now see it in news stories and posts on social media. And there’s good reason for that.

Even as more ultra-processed foods fill grocery store shelves, we’re also learning more about their possible health risks.

So, what are these foods exactly? While a precise definition can vary a bit depending on who’s talking about them, there are a few simple ways to identify many ultra-processed foods.

“Put simply, if you don’t see a food’s main ingredients in their natural forms — like grain, vegetables and meat, it is highly likely to be an ultra-processed food,” said Yikyung Park, professor in the Division of Public Health Sciences at Washington University School of Medicine in St. Louis. “Ultra-processed foods are highly manipulated and contain many added ingredients and additives. In most cases, we cannot make ultra-processed foods at home.”

Examples include: soda (sugary and diet), lunch meat, instant noodles, instant soup, sausage, hot dogs, frozen meals (including pizza and burritos), many store-bought cakes and sweets, and even most breakfast cereals.

Eating higher amounts of ultra-processed foods is associated with a higher risk of several serious conditions, including obesity, diabetes, heart disease, stroke, poor sleep, poor mental health — including anxiety and depression — and premature death, Park continued.

How ultra-processed foods increase these risks likely relates to their collection of ingredients. They tend to be high in those ingredients we should limit in a healthy diet and low in those we should focus on.

They can be high in calories, salt, unhealthy fats and added sugar and sweeteners, which can cause long-term inflammation in the body, disrupt the normal function of our metabolism and impact the development and release of neurotransmitters that play roles in mood disorders, such as depression, Park said.

Ultra-processed foods also tend to be very low in fiber, another potential negative. Higher fiber diets help promote a healthy microbiome, which is the collection of bacteria and other microorganisms in our gut that helps keep many processes in the body working normally, Park said. Eating lower-fiber, ultra-processed foods can have the opposite effect.

Switching from pre-packaged or fast foods to less-processed choices is one easy way to cut back on ultra-processed foods. Instead of frozen French fries or chips, choose a bag of nuts or buy raw popcorn and pop it in a pan at home. Instead of a frozen bean burrito, buy some tortillas, beans and cheese and make your own. In place of breakfast cereals, which can have refined, processed grains and many other ingredients, choose oatmeal, which is a simple whole grain.

These switches may take some extra effort at first, but it gets easier the more we do it, and often we can find that the less-processed options taste just as good — maybe even better — than the more processed foods.

Start with a small goal of cutting back on a couple of ultra-processed foods. Then, build from there. Small changes have real health benefits and can also lead to bigger changes and improvements down the road.

Whether we’re new to cutting back on ultra-processed foods or have been doing it for a while, Park shared one quick way to identify the types of foods we should try to steer clear of to improve our overall health. And all it takes is a glance at the food label.

“If the ingredient list is very long and you don’t recognize those ingredients, it’s better not to eat that food,” Park concluded.

Steinberg family establishes fund for blood cancer research

Pledge will help advance treatments for acute myeloid leukemia and multiple myeloma

For Howard Steinberg, Washington University in St. Louis runs in the family. His father, Harold, and his uncle, Ben, both studied business at the university with assistance from the GI Bill. In 2013, he and his wife, Cynthia, became Washington University parents when their daughter, Halle Steinberg, arrived on campus from the family’s home in suburban Atlanta.

The Steinbergs’ recent gift to the university, however, has roots in another family history: blood cancer. At the end of his junior year at Washington University, Steinberg lost his father to a brain aneurysm triggered by medications used to treat multiple myeloma. About a decade later, his younger brother, John, was diagnosed with acute myeloid leukemia (AML) and underwent two bone marrow transplants. Howard served as the donor for both procedures. In 1994, John died at just 32 years old.

Now, Howard and Cynthia are helping advance research into these cancers by creating the Steinberg Family Cancer Research Fund through their family foundation, which includes their children, Halle, and John, who is named after Howard’s late brother. The spendable funding to Washington University School of Medicine will support research led by Todd Fehniger, MD, PhD, a professor of medicine in the Division of Oncology and an investigator at the Alvin J. Siteman Cancer Center, based at Barnes-Jewish Hospital and Washington University School of Medicine. The research fund provides Fehniger and his lab with minimum of $250,000 over five years. The first payment was received in March. The Steinbergs also made an additional gift of $50,000 to bolster Fehniger’s work, which focuses on understanding and treating AML and multiple myeloma.

“It is incredibly motivating to receive support from families like the Steinbergs who have firsthand experience with these difficult diseases,” Fehniger says. “Often, our ability to advance research is limited by our resources. Every dollar helps push us further toward curing more patients in the future. I am truly thankful for the Steinbergs’ generous gift to support research into developing new treatments for these diseases.”

A Promising Start

Over the years, the Steinberg family has supported cancer research at Seattle’s Fred Hutchinson Cancer Center, where Steinberg’s brother received treatment, and other institutions. But despite his connection to the university, Howard was less familiar with Siteman’s innovative approaches to treating blood cancers. That is until December 2021, when he came across an article about an encouraging new immunotherapy that leverages the immune system’s own natural killer (NK) cells to address recurrent AML in children and young adults. Four of the eight patients participating in the phase 1 clinical trial conducted at the School of Medicine reached total remission after 28 days of therapy. Two of these patients stayed in remission for more than three months — one remains in remission over four years later.

These results built upon earlier findings in adult patients made by Fehniger’s lab. In their original study from 2016, Fehniger and his team devised a method to enhance a patient’s NK cells by exposing them to a specific protein cocktail. The researchers observed that exposure to this mixture activated a “memory-like” quality in the NK cells, which increased their ability to attack cancers such as AML in adults.

Intrigued by their discovery, Steinberg arranged a call with Fehniger in early 2022 and was impressed by their interaction. “I just thought he was an absolute rock star,” he says. “And I wanted to help make his work more successful.”

The Business of Research

When Steinberg entered Washington University in 1978, he was on a path toward medical school. But like legions of premedical students before him, he hit a wall with organic chemistry. “I still have nightmares about ‘Benny the benzene ring,’” he jokes. Steinberg eventually pivoted to studying psychology and business and earned an MBA through Olin Business School’s 3-2 dual degree program.

In the 40-plus years since he graduated, Steinberg, along with his business partners, has built a thriving rental car and truck franchise in seven cities. A seasoned entrepreneur, Steinberg recognizes that moving the dial in cancer treatment is an enterprise that requires consistent capital. He sees his family’s new research fund as an angel, or early-stage, investment in Fehniger’s promising research. “Often when investing, you are betting as much on a person as you are on a concept,” Steinberg says. “That’s what our family is doing here. Dr. Fehniger does not have to write a paper or submit an application. The money is there for him to use at his discretion and support his efforts.”

Unrestricted funds like these provide critical fuel for scientific discovery, according to Fehniger. “There is a real gap in our current funding system,” he explains. “You need considerable preliminary data to compete for grants from the National Institutes of Health and many major nonprofits, which takes years to obtain. Multiyear support like this gives us much-needed flexibility to ask questions, explore different paths, and gather additional information. And that enables us secure larger grants and continue our research while making rapid progress.”

New Directions

Support from the Steinbergs is already helping propel Fehniger’s work with NK cells forward. He recently completed a clinical trial testing NK cell immunotherapy in children and young adults who had relapsed after undergoing allogeneic bone marrow transplants, which use stem cells from donors. Fehniger says the new study upheld results from the earlier clinical trials, and half of the participants achieved complete remission. Last year, his collaborator, Thomas Pfeiffer, MD, assistant professor of pediatrics, presented their findings at a meeting of the American Society of Transplantation and Cellular Therapy, and they are now preparing a manuscript for publication.

Fehniger has also been able to experiment with chimeric antigen receptors (CAR), synthetic receptors that help identify and destroy cancer cells. With resources from the fund, he has generated several CARs, adding them to the NK cells to create modified CAR-NK cells. According to him, the CAR-NK cells can see and attack AML and multiple myeloma better than the NK cells alone.

Last year, the Leukemia & Lymphoma Society awarded a $5 million grant to Fehniger and a group of investigators at the medical school. He and fellow oncologist Brad Kahl, MD, professor of medicine, will use their portion of the grant to further study the effectiveness of genetically engineered NK cell immunotherapy in treating blood cancers. In addition, he and another colleague, Amanda Cashen, MD, professor of medicine, will explore NK cell immunotherapy through one of four projects funded by a recent $10.8 million grant from the National Cancer Institute that renews the medical school’s Specialized Program of Research Excellence in leukemia led by principal investigator Dan Link, MD, deputy director of Siteman.

“Support from donors like the Steinbergs has really allowed us to test new approaches, including these modified CAR-NK cells, and get a better grasp on how different cells behave in patients,” Fehniger says. “And we have been able to leverage that information to pursue additional funding.”

For his part, Steinberg appreciates receiving regular progress updates from Fehniger, even if his communications require some translation. “I keep telling him, I’m a rental car guy,” he says. “You have to simplify it for me!”

Paying It Forward

Steinberg’s relationship with Fehniger marks yet another chapter in his family’s legacy of leadership and philanthropy at Washington University. He is a member and past chair of the Atlanta Regional Cabinet and sits on the national council of the Skandalaris Center for Interdisciplinary Innovation and Entrepreneurship. He previously served as a member and vice chair of the Alumni Board of Governors.

He and Cynthia are generous donors as well. In 1997, the couple established and later endowed the Regina Karmel Memorial Scholarship, named in honor of Howard’s grandmother, for undergraduates studying economics or business. In 2000, they created the Harold and John Steinberg Memorial Nursing Scholarship Fund for nurses and advanced practice nurses working in the Division of Oncology.

When daughter Halle joined the Bears softball team, the Steinbergs became steadfast supporters of Washington University athletics. They have also previously made gifts for internships at the Skandalaris Center and research at Siteman Cancer Center.

Their latest gift to the university is particularly special because it is the first made through their newly formed family foundation. “We’re so lucky to be able to give back to WashU,” Howard says. “It’s truly a blessing.”

Learn more about how you can support research and patient care at Washington University School of Medicine.

Using genetics to prevent lung cancer

Genetic information is often used to guide precision cancer treatments. In the future, genetics could guide personalized efforts to stop smoking and prevent lung cancer.

343,000+. That’s the number of cigarettes Chris Kneibert, 65, has probably smoked over his lifetime.

Chris Kneibert 2 Using Genetics To Prevent Lung Cancer

“I basically smoked a pack a day for 47 years,” he said. “And there are 20 cigarettes in a pack. I smoked when I woke up or when I got bored. I smoked in the mornings and socially. It seemed like the thing to do when I first went to college, and I never really stopped — or couldn’t.”

The Centers for Disease Control and Prevention estimates that 49.2 million people in the U.S. — one in five adults — use tobacco products. Add e-cigarettes/vaping, cigars and smokeless tobacco products, and the number rises. With today’s average cost of cigarettes at more than $8 per pack, that means Kneibert and other smokers dole out almost $3,000 annually to support a pack-a-day habit.

The bigger problem comes when individuals want to quit smoking. Tobacco products contain nicotine, a known addictive chemical. When people smoke, the nicotine absorbs into the bloodstream and increases dopamine levels in the brain. Smokers then start craving the “hit” of nicotine, ingesting it more and more, and rapidly become addicted. Trying to quit causes withdrawal symptoms, and about half the people who want to quit, can’t.

“I really thought I could quit on my own, but I enjoyed it too much,” said Kneibert. “Even when news came out that smoking was bad for you and could cause cancer or heart attacks and stroke, I didn’t stop. It really was an opportunity for me to step outside and smoke a cigarette and temporarily get out of whatever I was doing.”

In the 1980s, the U.S. Food and Drug Administration (FDA) approved a nicotine gum, Nicorette, as the first medication to help people quit. Over-the-counter sales of Nicorette were authorized in 1996. Along the way, a plethora of other treatments became available, including hypnosis and behavioral therapy as well as phone and web-based counseling services to support those who wanted to quit. Still, many people can’t stop smoking.

“I tried the nicotine gum and was successful for only one to two months, said Kneibert. “I was not optimistic I could succeed and stop smoking.”

Using Genetics to Quit Smoking

Last year, Kneibert was told about a new clinical trial underway at Washington University School of Medicine in St. Louis. The study focuses on gathering genetic information from individuals identified as smokers to better understand the mechanisms behind their smoking addiction as a tool for identifying optimal treatment options.

“I am very interested in how we can motivate people to have healthy behaviors,” said Washington University psychiatrist and physician scientist Li-Shiun Chen, MD, MPH, ScD, director of the Tobacco Treatment Program at Siteman Cancer Center at Barnes-Jewish Hospital and the School of Medicine. “Precision medicine is used in cancer treatment but not used in cancer prevention. We wanted to know if we could use precision medicine to affect behavior and lower the risk of health problems stemming from smoking. We, therefore, could shift the paradigm from cancer treatment to potentially cancer prevention using genetics and targeted therapies.”

Two years ago, Chen, along with organizational psychologist Alex Ramsey, PhD, and their colleagues in Washington University’s Precision Prevention and Treatment Lab received grants from the National Institutes of Health to see if individualized counseling along with a personalized genetics report highlighting the percentage of cancer risk would result in more effective treatment and smoking cessation rates. The first trial, PRECISE, focused on identifying the level of risk for lung cancer and counseling on the benefits of lung cancer screening for each study participant. In the second trial, MOTIVATE, researchers added information related to genetic markers that identified optimal smoking cessation treatments for each participant.

“Like an ACT test for college, a genetics ‘score’ can tell you your own individual lung cancer risk and, significantly, how difficult it may be to actually quit smoking,” Chen said. “We analyzed DNA and created a report that not only showed the benefits of quitting smoking but, significantly, also showed which smoking cessation products might be better for a person to try based upon their own genetic profile.”

In the MOTIVATE trial, the team analyzed more than 50,000 biomarkers linked to elevated cancer risk in 100 study participants. A report then was shared with both primary care physicians and patients to see if it would motivate individuals to stop smoking.

The report identified genetic markers and noted whether a person had a high or low nicotine metabolism level. “If you have a slow metabolism, you could use an other-the-counter nicotine patch to help you quit,” Chen explained. “But if you have a fast metabolism, nicotine patches or gum are less likely to work. In those cases, individuals would be more successful if they used a prescription medication.”

See an example of a personalized report here.

For Kneibert, an early participant in the MOTIVATE trial, he had a genetic marker that pointed toward a fast metabolism. His report also showed that he had a very high risk for developing lung cancer. “It was in the red zone, which was bad,” he recalled. He agreed to try Varenicline, one of seven FDA-approved prescription medications to help adults quit smoking. To his surprise, it worked.

“I started with one pill a day and still smoked,” he said. “But when I got to two pills a day, the medicine stopped my nicotine receptors from working. I would smoke and think to myself, ‘That was very unappealing.’ I quit about a month later and I’ve been smoke-free ever since.”

Chen and her colleagues still have a long way to go before they say their research will make a huge impact in the field of cancer prevention. The MOTIVATE trial is still underway, and they plan to recruit 800 participants to continue testing whether the genetics report motivates people to change behavior, stop smoking and get regular screenings for lung cancer. Still, publication last year of their early research is gaining attention.

“I believe we are at the forefront of innovation, and Siteman Cancer Center is really leading the country by using genetics for cancer prevention,” stressed Chen. “Patients and their doctors are more motivated when we can offer evidence-based risk assessments and smoking cessation treatment suggestions. I predict that we can move the needle on effective addiction treatment and, therefore, prevent some cancers because of our work.”

Kneibert now steps outside often to enjoy nature instead of smoking a cigarette. He also got a lung cancer screening, testing negative for any cancer. “I’m glad I found out why the nicotine patch didn’t work before,” he said. “That report was eye-opening and made me want to try to quit again because it really wasn’t my lack of willpower that caused me to fail.”

“I’m proud of myself for quitting,” he added. “And my kids are proud of me, too.”

To learn more about the MOTIVATE trial call 314-273-3826.

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Chen, Tony et al. Genomic insights for personalised care in lung cancer and smoking cessation: motivating at-risk individuals toward evidence-based health practices. eBioMedicine. December 2024.

New cellular immunotherapy approach shows promise for B-cell lymphoma

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.”

Off-the-Shelf Immunotherapy

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.

Promising Results of CAR-NK Immunotherapy

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.