After years of fanfare and a few false starts, the era of genomic medicine has finally arrived.
Across the country, thousands of patients are being treated, or having their treatment changed, based on information gleaned from their genome. It’s a revolution that has been promised since the human genome was first published in 2001. But making it real required advances in information technology infrastructure and a precipitous drop in price.
Today, the cost of whole exome sequencing, which reveals the entire protein-coding portion of DNA, is roughly equivalent to an MRI exam in many parts of the country, says Louanne Hudgins, M.D., president of the American College of Medical Genetics and Genomics and director of perinatal genetics at Lucile Packard Children's Hospital Stanford, Palo Alto, Calif.
“Genomic sequencing is a tool like any other tool in medicine, and it’s a noninvasive tool that continues to provide useful information for years after it is performed,” she says.
Cancer screening and treatment
Nowhere is this genomic transformation more apparent than in the realm of cancer treatment.
Companies like Menlo Park, Calif.-based Grail Inc. are forging ahead with large-scale genomic sequencing projects in collaboration with both academic medical centers and community health systems. Grail’s Circulating Cell-free Genome Atlas study aims to identify genomic fingerprints shed from tumors that can be identified in a blood sample. The goal is to help identify cancers early — when they are more treatable — and to match a patient’s tumors to individualized treatment.
“We are finding great enthusiasm as people want to participate in this effort, both patients and physicians,” says Mark Lee, M.D., head of clinical development and medical affairs at Grail. Right now, he says, health systems and patients have an opportunity to participate in shaping the future of this genome-based medicine.
Backed by investing giants like Amazon and Bill Gates, Grail has partnered with the Mayo Clinic, the Cleveland Clinic, the U.S. Oncology Network and others to collect de-identified data from consenting patients for large-scale genomic studies.
And they have lots of company. The biotech company Regeneron has partnered with Pennsylvania-based Geisinger Health System to enroll interested patients in a project dubbed MyCode Community Health Initiative. A discovery-focused initiative, MyCode is also using genomic data to guide treatment decisions today. Currently, the project has enrolled more than 150,000 consenting patients and has returned what are considered “actionable” results to 340 patients and providers and counting.
For example, MyCode participant Barbara Barnes chose to have her reproductive organs removed after an analysis of her DNA determined that she was at increased risk for developing breast and ovarian cancer. The surgery revealed that she already had a fallopian tube tumor that required treatment, and the early intervention may have saved her life. She shared her story in a Facebook video produced by Geisinger.
While anecdotal success stories provide a taste of what’s possible, the Geisinger-Regeneron collaboration is aimed more toward matching genotypes with treatment on a population level, and that effort is starting to yield results.
In July, the group published a report in The New England Journal of Medicine describing a variant of the gene ANGPTL3 associated with a reduced risk of cardiovascular disease detected in some MyCode participants. The gene variant codes for a protein that seems to lower cholesterol, and the company has developed a targeted treatment, evinacumab, that mimics the action of this protein. Evinacumab earned breakthrough therapy designation by the Food and Drug Administration in April and is now in Phase 3 clinical trials for patients with an inherited tendency that manifests early in life to have high cholesterol levels, leading to deadly cardiovascular disease.
Another goal of Geisinger’s population-based study, says Andy Faucett, a principal investigator of MyCode and genomics researcher at Geisinger, is to determine how to scale the program and make it possible for more health systems to implement genomic screening for their patients.
“We probably have a health system a week call us and ask us for help [setting up a genomics program],” he says. “We think it’s something that should be offered to every patient.”
Treating genes, not organs
Genomic medicine has advanced to the point that genes and their variants now can be targets for drug treatments. Case in point: In May, the FDA approved pembrolizumab (Keytruda) to treat any unresectable or metastatic solid tumor with a specific genetic biomarker, irrespective of its location in the body.
“This is an important first for the cancer community,” Richard Pazdur, M.D., director of the FDA's Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement made at the time of the approval. “We have now approved a drug based on a tumor’s biomarker without regard to the tumor’s original location.”
Clinical trials matching genomic markers with targeted treatment are well underway and are only expected to increase, making identification of genomic targets an essential part of care.
Targeted therapies got another advance in July when an advisory panel convened by the FDA gave its unanimous recommendation for approval of the first gene-based medical treatment in the U.S. Chimeric antigen receptor T, or CAR-T, cell therapy, expected to be approved in November for a particularly aggressive form of leukemia, is the first in a wave of “living drugs” engineered to seek out and destroy cancerous tumors.
CAR-T cell therapy represents the culmination of decades of research to identify genetic features that are unique to each specific form of cancer that can be targeted by the immune system. The approach, coaxing a patient’s own immune system to recognize and attack cancerous cells, also delivers on the promise of personalized medicine, as T cells are harvested from each patient, re-engineered to recognize and attack cancer, and returned to the patient.
In the case of Novartis’ CTL019, the treatment on the cusp of FDA approval, complete response rates in clinical trials for patients with acute lymphoblastic leukemia who had relapsed despite multiple conventional treatments, reached 80-90 percent.
Physician-scientists like Brian Till of Seattle’s Fred Hutchinson Cancer Research Center, who has been working on CAR-T for years but was not involved in the development of CTL019, say these early results are encouraging.
“We have enough data right now to be optimistic that this could become standard of care for some cancers,” says Till.
He quickly added that there will likely always be a role for chemotherapy or other standard treatments and that CAR-T will probably be limited in its early days to centers that have experience managing potential toxicities. But, he added, CAR-T has the potential to be given as an outpatient treatment with careful management of side effects.
Many questions remain about whether it makes sense for healthy people to learn the secrets hidden in their DNA, but those concerns are likely to be overshadowed by a cavalcade of genomic sequencing projects and targeted therapies now hitting clinics nationwide. Simply put, genomic sequencing will be part of standard care within the next decade.
In the realm of rare-disease diagnoses and treatment, genomics already has been transformative. As recently as five years ago, patients with myriad vague symptoms, mostly infants and children, could bounce from doctor to doctor and invasive procedure to invasive procedure without ever receiving a definitive diagnosis. While some disorders still do evade diagnosis, whole genome sequencing has dramatically reduced that number.
“Our ability to diagnose genetic conditions has improved dramatically,” says Hudgins. “And we are gaining a much better understanding of the biology behind these genetic changes. Because of these advances, therapy and management of these diseases are much improved. So the idea that there is no treatment for genetic disorders is just not true anymore.”
The speed of DNA sequencing and analysis now permits near real-time diagnosis, moving it into the clinical workflow.
At Rady Children’s Hospital–San Diego, an array of Illumina sequencing machines churns through clinical samples in as few as 37 hours, according to Stephen Kingsmore, M.D., director of its Institute for Genomic Medicine.
The rapid sequence analysis has resulted in almost half of patients receiving a genomic diagnosis, while 80 percent had their care altered as a result of sequencing.
Kingsmore is consulting with a dozen other children’s hospitals that want to offer real-time genomic testing to their patients within the next year. Every hospital should have access to rapid sequencing and analysis within a few years, he says.
For prospective parents, prenatal and perinatal diagnosis has entered a new realm as well.
“Cell-free DNA prenatal screening has dramatically decreased the number of invasive procedures such as amniocentesis and chorionic villus sampling that pregnant women undergo,” Hudgins says. “In the last few years, it has decreased fivefold in many areas of the U.S.”
Gene therapy redux
Even the granddaddy of all genomic medicine, gene therapy, is enjoying a renaissance. Early efforts to treat disease by replacing defective genes suffered many setbacks over the years, mainly due to the difficulty of efficiently delivering genes to affected tissues and organs. But next-generation modified viral delivery systems have shown they can get the job done safely and efficiently.
Philadelphia-based Spark Therapeutics’ biologics license application for voretigene neparvovec (Luxturna) for inherited retinal disease has been accepted for review by the FDA with a decision expected early next year. The experimental treatment of 31 patients was the first successful randomized, controlled Phase 3 gene therapy clinical trial, leading to FDA orphan drug designation in July.
Spark is one of several companies developing gene-based treatment for vision loss in the U.S. and Europe.
Similarly, Bluebird Bio Inc.'s gene-therapy treatment for thalassemia and sickle cell disease has shown promise. Results presented at the European Hematology Association meeting in Vienna in June suggested that a child treated for severe sickle cell disease in France might have been cured.
The company is running clinical trials to treat severe sickle cell disease at six hospitals in the U.S., including the Medical University of South Carolina. Julie Kanter, M.D., director of sickle cell research at MUSC and a primary investigator on the U.S. trial, says the new generation of gene-delivery systems is more efficient with fewer side effects.
“I think we’ve made incredible headway, and we are going to see some great things coming,” she says.
Amid tumbling genomic sequencing costs, more people are having their DNA sequenced to match an underlying genetic defect with an increasing variety of targeted treatment options. From an estimated 1,000 genetic tests available only five years ago, the field has exploded to more than 52,000 available in the U.S., and that number grows daily. To find out more about what's out there, visit the National Center for Biotechnology Information's Genetic Testing Registry website at www.ncbi.nlm.nih.gov/gtr.