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CAR-T Cells: Engineering Immune Cells to Treat Cancer

CAR T-cell therapy is a promising treatment for patients with many types of blood cancer, including leukemia and lymphomas. Cathleen Rowland, MSN, MPH, RN, OCN, BMTCN, guided a discussion about this highly-specialized therapy, covering both its promise and its challenges.

  • Promises and peril. Rowland introduced the panel and described advancements being made at the Dana-Farber/Brigham and Women’s Cancer Center. Brigham has been a leader in CAR-T research and is approved to administer CAR-T therapy for treating certain forms of cancer She also notes that while the treatment is exciting, toxicity is a major challenge.
  • Amped up. Alexandra Lynch, PA-C, explains to her patients that T cells are supposed to recognize something foreign and attack it. CAR-T cells are like regular T cells but amped up and designed to recognize lymphoma and attract the immune system.
  • Toxicity risks. Lauren Spendley, MSN, NP, described a patient’s CAR-T timeline. This is still a very new therapy for us, she said, we follow our patients for 15 years. But the first week is when patients are at the highest risk for the toxic side effects of multiple organ failure due to cytokine release syndrome and  neurotoxic effects.
“These are patients who had no other effective treatment options. They were headed to clinical trials or to hospice. With CAR-T, we’re curing 40-50 percent of these patients. This is a revolution in oncology.” -Caron Jacobson, MD
  • But many questions remain. What about the other 50 to 60 percent of patients? What about resistance? What about cancers beyond leukemia/lymphoma? And what about unsustainable costs? And what about toxicity and its enormous burden on patients and providers? Research is underway to address all of these fronts.

‘A Second Chance at Life’ | Dana-Farber/Brigham and Women’s Cancer Center

Clinical Translation of Discoveries Generated in Engineering in Medicine

What is engineering in medicine? Some of the most familiar interventions have only been made possible because of biomedical engineering achievements such as cardiac stents, EKGs, LASIK surgery, and prosthetics. Every step in the health care journey is supported and advanced by engineering in medicine. As new technologies develop, engineering in medicine is starting to evolve and have a much deeper meaning. Engineering in medicine not only confronts ever-changing medical needs, but it also alters the way health care is delivered. A couple of examples of engineering in medicine are using Artificial Intelligence (AI) to improve radiology workflows and using AI to help assign diagnostics to patient images and inform treatment. During this session, researchers and entrepreneurs from the Brigham discussed their experiences in this transformative discipline and how their developments have transitioned from ideas that sprouted in a lab to interventions that have bloomed and are changing patient care as we know it.

  • Inspired by nature. Jeff Karp, PhD, spoke about several projects he and his colleagues have been working on throughout the years to advance and accelerate medical innovation, including engineering a degradable, liquid adhesive tissue glue, that, when activated by light, is strong and elastic enough to bind tissue together. In the future, Karp’s team plans to use the glue to repair cardiac defects without the need for open heart surgery, as well as repair defects in blood vessels, bone and intestinal tissue. In 2016, the glue was successfully used to treat a bulldog suffering from a nasal cavity defect.
  • Predicting the microbiome’s behavior. Georg Gerber, MD, PhD, MPH, associate pathologist, Center for Advanced Molecular Diagnostics, and co-director of the Massachusetts Host-Microbiome Center at the Brigham, spoke about how he and his colleagues developed a set of algorithms that can predict the microbiome’s behavior. Gerber designs sophisticated AI models to understand how the microbiota in the gut — beneficial microbes that colonize our bodies — may enable or thwart Clostridioides difficile (C. difficile of C. Diff) bacterium infections in patients. C. diff is the most common hospital-acquired bacterium in the U.S. With these findings, he and his colleagues will develop new diagnostic tests and treatments

Division of Engineering in Medicine

Transforming Medicine Through Preventive Genomics

Patients and experts took the stage to discuss how the power of DNA is changing and enhancing health care. Robert Green, MD, MPH, and Joel Krier, MD, MMSC, FACMG, from Division of Genetics, were joined by media moderator Megan Thielking and pharmacist Roseann Gammal, PHARMD, to discuss genomic testing currently available at the Brigham.

  • A brief history of genomics. The first genome cost $3B to sequence. That cost has plummeted dramatically! Each individual has a unique DNA sequence but many of those differences are inconsequential. But some are responsible for the traits that make us different from one another. Green notes that If you’ve done direct-to-consumer tests, that’s not sequencing. That’s genotyping. It’s the equivalent of looking at specific words on specific pages of the book of your genome. Sequencing–offered at the Preventive Genomics Clinic–is very different (more about the Brigham’s Preventive Genomics Clinic here)
  • A foundation of research. Genomes2People is research program at the Brigham addressing key questions about how people respond when receiving information about their genome to accelerate the evidence-based use of genomics in medicine. Projects include the REVEAL research study, which found that people do not get more anxious or depressed when they learn about their risk of Alzheimer’s Disease through APOE genotyping. But they do want to do something about it.
  • Incidental findings. Would you want to know? Lots of thought has been put into what incidental findings from genome sequencing should be returned to participants and a set of recommendations has been put together. There are now 59 genes considered “actionable.” At the Brigham, through the Partners Biobank, G2P has found 300 instances of mutations in these 59 genes. Now, genetic counselors are calling these patients and giving them the option of finding out about these results.
  • A comprehensive look. What if, instead of 59 genes, we look at all disease-associated genes?  How do we measure if this is a good thing or a bad thing? That’s what was studied in MedSeq. This project found that 1 in 5 people had a Mendelian disease risk variant; 92 percent were carriers. In babies, through the BabySeq Project, the team has found very much the same thing as in adults.
  • A family shares their experience. Laura Stetson, whose daughter Cora was enrolled in the BabySeq Project, described how the project helped detect a condition known as partial biotinidase deficiency. Now, Cora is healthy and takes medicine daily.
“Our daughter would have slipped through the cracks with what is in place today for standard newborn screening.” -Laura Stetson

Preventive Genomics Clinic | Genetics & Genomic Medicine

Home Hospital and the Brigham Experience

David Levine, MD, MPH, MA, from the Division of General Internal Medicine and Primary Care, and panelists — including a previous patient — share details about how the Brigham is providing high-value, acute care to patients in their own homes.

  • Did you know the Brigham has a home hospital? When Levine asked the room, about half of attendees raised their hands. “We’re going for 100 percent,” said Levine. He argued that there’s an opportunity to involve digital technology in health.
  • Home Hospital beginnings. Home hospital at Brigham almost always starts in the emergency room. If you’re going to be admitted or observed, you may have the opportunity to enroll in home hospital. Home hospital began with a tiny pilot project in 2016. Read more here. “We are now one of the highest volume home hospitals in the country,” said Levine.
  • A patient’s story. Joanne Goldstein got sick with a kidney infection the day before her son’s wedding. “This angel appeared in my hospital room and said, ‘Hold on, I have an idea.’ Next thing I knew, Dr. Levine was there with an option for how I could go to my son’s wedding. I arrived at the hotel with an IV in my arm and a patch on my chest to monitor my vitals, and a doctor with me at the wedding. I didn’t have the shoes to match my dress, but that’s ok. I was able to be a part of the celebration and attend part of the wedding.” Going was critical to her physical health and mental health, Goldstein said. And as much as she love the Brigham, being at home was so much more nurturing in terms of getting better. All of the strains of being in a hospital are so much less. It made being sick so much better, she said.
“The gift this program gave me, of being able to go to my son’s wedding, is just unbelievable.” -Joanne Goldstein

Blood from Plants

Could a little-known plant from Central Africa transform medicine and agriculture as we know it? Wilfred Ngwa, PhD, a medical physicist in the Department of Radiation Oncology, explores the remarkable applications of an unidentified plant that produces vital blood components, including hemoglobin levels seven times greater than in humans.

  • Close to home. Ngwa first learned about the plant — believed to be a species of the Justicia genus — while visiting a village in Cameroon, his native country. He encountered a man consuming a bright red tea made from the plant following a recent accident, saying he drank it to restore his blood. After meeting more people from the area who made similar claims and insisted the tea was an effective treatment for anemia, Ngwa says his curiosity was piqued.
  • Looking for answers. As a scientist, he was skeptical but open-minded. He took a sample of the plant back to his lab upon returning to the States, only to discover that the plant contained 14 grams per deciliter (g/dl) of hemoglobin 1. Human blood contains 2 g/dl of the same substance. “That was unbelievable,” Ngwa recalled, noting he and his colleagues ran a battery of tests to confirm their findings. Not only did they verify their initial discovery, but they also found that tea made from the plant contained main of the same components found in blood plasma, including comparable levels of calcium, iron, magnesium, potassium, sodium and more. The concentration of heme iron, in particular, was greater in the plant compared to red meat.
  • Safe for consumption? In an initial study using an animal model of anemia, Ngwa and his colleagues were also astonished to find that animals treated with the plant extract recovered their hemoglobin faster compared to the standard treatment. Additional research showed the extract was not toxic, having the same effect on the kidneys as water.
  • Mystery plant. The plant itself has yet to be conclusively identified. It is believed to be a species of Justicia, but the Smithsonian Institute — with which Ngwa’s lab is collaborating — has tested its genetics and so far been unable to match it to a known species of plant. This means it’s possible the plant will be a newly identified species or an evolved version of a previously known one.
  • Potential applications. 
    • Transforming anemia treatment. The potential applications for the plant are far-reaching. In particular, Ngwa noted, it has the potential to change the way blood disorders such as anemia are treated, as the plant extract is better absorbed than traditional iron supplements. This is especially important for patients in limited-resource settings and vulnerable populations, including children, pregnant women and cancer patients.
    • Blood transfusions from plants? The most ambitious — and far off — vision for the plant is potentially using it to develop a universal blood substitute for transfusions, something that, if safe and successful, could have tremendous implications everywhere from the bedside to the battlefield, Ngwa said.
    • A better burger. Consumers are already embracing plant-based meat replacements, such as Impossible Burger and Beyond Burger products, which derive their meat-like flavor from heme obtained from soy. Ngwa explained that, compared to the plant he’s studying, soy naturally contains a very small concentration of heme. The Justicia plant has the potential to produce these types of food products far more efficiently and cost-effectively, he said.
  • Wakanda (and Brigham) forever. The story of this yet-to-be-identified plant and the Brigham researcher studying it have uncanny parallels to a film and pop culture figure that Ngwa says is close to his heart: Black Panther, the Marvel comic book hero from the fictional, technologically advanced African nation of Wakanda who gains his superpowers from consuming a plant native to the region. “In the world of the Black Panther, the best-quality health care is in Wakanda, and this reminds me of Brigham and Women’s,” said Ngwa, who wore a Black Panther T-shirt under a blazer during his presentation. “If you’re sick, you come to the Brigham to get the best care.”

Turning the Dark Matter of the Genome into RNA Drugs

In this session, Anna Krichevsky, PhD, led a panel in a discussion about the “darkest” and least investigated parts of the human genome. Recent discoveries in the field suggest that RNA molecules may provide a new class of therapeutic targets for diseases ranging from cardiovascular to neurodegenerative to cancer.

  • There’s no correlation between how complex an organism is and the number of protein coding genes. The human genome has 22k protein coding genes. But so does the roundworm. Tomatoes have more than 40k.
  • 77 percent of the human genome is transcribed to RNA that doesn’t code for proteins
  • There is a huge diversity of these non-coding RNAs. Some are very tiny, some are long.
  • They may regulate a variety of functions that influence how the genome is read and what proteins are created.
  • Many are involved in the brain, our most complex organ.
  • Therapeutic opportunities: there are already RNA drugs that have been approved for the clinic but very few of them.

“If you’re thinking only about the world of proteins, it’s time to adjust your vision. Life on this planet originated from RNA. We live in an RNA world. And we believe RNAs are the future.” – Anna Krichevsky

  • Paul Anderson, MD, PhD, runs a lab that is working on a project related to ALS. There are two approved drugs for ALS but no known cure. Insights from the lab have led to the development of a synthesized version of an enzyme that helps break down RNA and may be able to help protect neuron cells from the toxic effects of cellular stress. The lab’s goal is to develop a compound that could be given to patients to enhance protection of motor neurons.
  • Mark Feinberg, MD, described how non-coding RNAs make up 98 percent of the genome and provide important levels of regulation for investigators to think about. Feinberg focused his remarks on miRNA therapeutics in atherosclerosis.
  • Clemens Scherzer, PhD, noted that everything we have learned about the brain until now is based on proteins. Scherzer and his colleagues are working on BRAINCODE, a project that focuses on the dark and darkest matter, including enhancer RNAs, in the brain. The team has found that risk factors for Parkinson’s Disease are especially common in these enhancer RNAs.

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