The doctors who have spent years studying the case call it “a series of fortunate events.” What began as a remarkable response to chimeric antigen receptor (CAR) T cell therapy is now providing evidence about the human genome and immune response that could help turn gene therapy non-responders into responders.
Researchers at the University of Pennsylvania’s Abramson Cancer Center say a patient treated for chronic lymphocytic leukemia (CLL) in 2013 went into remission because of a single CAR T cell and the cells it produced as it multiplied, and has stayed cancer free in the five years since, with CAR T cells still present in his immune system. The findings, published today in Nature, show the response is tied to where the CAR gene inserted itself into the patient’s T cell DNA, a key factor that may help improve response rates to the therapy.
CLL is a type of cancer that starts in cells that become certain white blood cells in the bone marrow, and then move into the blood and lymph nodes. These cancer cells reproduce too quickly and crowd out other cells in the bone marrow. They also don’t mature properly and thus don’t fight off infection as well as they should. The American Cancer Society estimates there will be about 21,000 new CLL cases in 2018 and around 4,500 deaths from the disease. Many of these patients will undergo a bone marrow transplant, but a potential additional treatment is CAR T cell therapy, which involves collecting patients’ own immune T cells, reprogramming them to recognize and kill cancer, and then infusing them back into patients’ bodies.
The approach is approved by the U.S. Food and Drug Administration for certain acute lymphoblastic leukemia patients as well as some non-Hodgkin’s lymphoma patients, but is not currently approved for treatment of CLL. Patients typically receive three consecutive infusions with increasing doses — 10 percent, 30 percent, and 60 percent — to control for cytokine release syndrome (CRS). CRS is a common toxicity associated with CAR T therapy and includes varying degrees of flu-like symptoms, with fevers, nausea, and muscle pain, and can require ICU-level care.
The patient in this report received the first two infusions of 10 and 30 percent, but did not initially respond. “It wasn’t until day 50 that the patient experienced CRS, which indicated the CAR T cells were active and may be having an anti-tumor effect,” said the study’s senior author J. Joseph Melenhorst, PhD, an associate professor of Pathology and Laboratory Medicine in Penn’s Perelman School of Medicine and a member of Penn’s Center for Cellular Immunotherapies.
Imaging showed the tumor had gotten smaller, so doctors decided to infuse the patient with the final 60 percent. The patient went into remission and has stayed there for five years and counting. “It’s the outcome we’re always hoping for, but we know we can learn so much from every single patient no matter what. We brought this from the bedside back to the bench to understand as much as we could about what happened and why,” said study co-senior author Carl June, MD, the Richard W. Vague Professor in Immunotherapy, a professor of Pathology and Laboratory Medicine, and director of the Center for Cellular Immunotherapies. “The first thing we found was that we could trace the lineage of the patient’s CAR T cells back to a single, original cell,” said the study’s lead author Joseph A. Fraietta, PhD, an assistant professor of Pathology and Laboratory Medicine and a member of the Center for Cellular Immunotherapies.
“It’s a truly remarkable finding, and essentially tells us the minimum dose needed for CAR T cells to do their job is one.”
This patient’s CAR T cells were engineered to seek out a protein on leukemia cells known as CD19. In this strategy, the genetic code for the CAR that recognizes CD19 protein is randomly inserted into the patient’s DNA by a genetically-modified virus. In this particular case, researchers found the CAR sequence inserted into a gene called TET2 that normally regulates blood cell formation and keeps growth of these cells in check. Once the TET2 gene was disrupted, the single CAR T cell expanded massively and wiped out this patient’s leukemia. “Killer T cells that normally fight off infection generally can’t beat cancer alone because they’re older, past their prime, and often outnumbered,” Fraietta said.
“However, younger cells make the difference because of their ability to expand massively into an army of effectors. In this case, they got a chance to do their work because TET2 was inhibited which affected epigenetic pathways to drive this response.”
“This analysis required a huge collaboration between immunologists, cell biologists, T cell experts, cancer biologists, and clinicians,” Melenhorst said. “Fortunately, we have all of that expertise here, and it proved invaluable.”
Other co-authors of the study include Frederic Bushman, PhD, the William Maul Measey Professor and chair of Microbiology, Shelley Berger, PhD, the Daniel S. Och University Professor and a Penn Integrates Knowledge Professor with appointments in the Perelman School of Medicine’s department of Cell and Developmental Biology and the School of Arts and Sciences department of Biology, and David Porter, MD, the Jodi Fisher Horowitz Professor in Leukemia Care Excellence and director of Blood and Marrow Transplantation in the Abramson Cancer Center. In 2012, Penn and Novartis entered into a global collaboration to further research, develop and commercialize Kymriah, formerly known as CTL019, and other CAR T cell therapies for the treatment of cancers.
In August 2017, the U.S. Food and Drug Administration approved Kymriah for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or relapsed. In May of 2018, the approval was expanded to include the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) — the most common form of non-Hodgkin’s lymphoma — as well as high grade B-cell lymphoma and DLBCL arising from follicular lymphoma.
This work was supported by funding from National Cancer Institute (T32CA009140, P01CA214278, AI104400, AI 082020, AI045008, AI117950), the National Institute of Allergy and Infectious Diseases (K08AI101008), the National Institute of General Medical Sciences (R01GM118501, R01CA165206), a Stand Up to Cancer Phillip A. Sharp Innovation in Collaboration Award, and Novartis. Editor’s note: The University of Pennsylvania has licensed technologies involved in these trials to Novartis. Some of the scientists involved in these trials are inventors of these technologies. As a result of the licensing relationship with Novartis, the University of Pennsylvania receives significant financial benefit, and these inventers have benefitted financially and/or may benefit financially in the future.
Like Us on Facebook
Paternal Transmission Of Epigenetic Memory Via Sperm
Studies of human populations and animal models suggest that a father’s experiences such as diet or environmental stress can influence...
Father’s Nicotine Use Can Cause Cognitive Problems In Children And Grandchildren
A father’s exposure to nicotine may cause cognitive deficits in his children and even grandchildren, according to a study in...
Nutrition Has A Greater Impact On Bone Strength Than Exercise
ANN ARBOR—One question that scientists and fitness experts alike would love to answer is whether exercise or nutrition has a...
Breastfeeding Protects Infants From Antibiotic-Resistant Bacteria
Globally, more than 200,000 newborns die annually of infections caused by antibiotic-resistant bacteria. However, a new study shows that breastfeeding...
Combining Genetic and Sun Exposure Data Improves Skin Cancer Risk
SAN DIEGO, Calif. – By combining data on individuals’ lifetime sun exposure and their genetics, researchers can generate improved predictions...
More Clues Revealed In Link Between Normal Breast Changes And Invasive Breast Cancer
A research team, led by investigators from Georgetown Lombardi Comprehensive Cancer Center, details how a natural and dramatic process —...
Kids’ Sleep May Suffer From Moms’ Tight Work Schedules
It may be tough for working moms to get a good night’s sleep, but working tight hours may affect their...
LISTS8 months ago
12 Types of Consultants You Will Meet
LISTS5 months ago
9 Medical Terms You Can Use Everyday To Sound Smarter 🤓
LISTS8 months ago
13 Things You Did The First Time You Started Seeing Patients
LISTS7 months ago
13 Types of Students You Meet at Medical School
LISTS5 months ago
10 Types of Medical Students During Exams
NEUROLOGY6 months ago
Soccer Heading Shown To Impair Players Cognitively
ENDOCRINOLOGY8 months ago
Researchers Identified The Body’s Glucostat
LISTS8 months ago
13 Things You Thought at Your First Lecture in Medical School