Novartis needs special delivery for potent cell therapy By Eva von Schaper, Bloomberg News Bloomberg 9:20 p.m. CST, December 18, 2013MUNICH — Novartis AG has a promising therapy for cancer. It's just not sure how to get it to patients easily.The treatment is so potent that it cleared malignant cells in about 90 percent of patients facing almost certain death from the most common form of cancer in children. The approach involves taking T cells, part of the body's immune system, from the blood and engineering them to identify proteins on cancer cells. When returned to the patient's bloodstream, the revamped T cells seek and destroy cancer cells. It's so specific that a single mistake can mean death for a patient, and so turbo-charged that Novartis plans to set up a network of hospitals versed in treating the spiking fever, chills and flu-like symptoms that may come as side effects."The question is really if this is the right way to go at immunotherapy," a burgeoning field of medicine that empowers the immune system to fight diseases such as cancer, Michael Leuchten, an analyst at Barclays Plc in London, said in an interview. Cancer cells can use proteins on their surfaces as biological cloaks of invisibility to elude detection by the immune-system cells policing the body. Immunotherapies include checkpoint agents, drugs that strip away such disguises and expose cancer cells to attack; products such as Dendreon Corp.'s Provenge, which combines a patient's immune cells with vaccine components in an infusion; and so-called biconjugated antibodies that help immune cells anchor themselves to cancerous ones.The total market may amount to a $35 billion "watershed" for cancer drugs, according to Andrew Baum, a pharmaceutical analyst for Citigroup Inc. in London. Baum sees Roche Holding AG and Bristol-Myers Squibb Co., based in New York, as the field's leaders. Roche — like Novartis, based in Basel, Switzerland — is developing an infused immunotherapy which blocks a protein that prevents the immune system from attacking cancer cells. Bristol-Myers sells the drug Yervoy, which helps the immune system fight melanoma.Unlike those therapies, Novartis's CTL019 isn't as easy to produce and transport. For the researchers and the company, the results are worth the effort. If they find a way to deliver the treatment to the masses, CTL019, also known as CART-19, has the potential to generate $10 billion a year if approved to treat multiple forms of cancer, according to Baum."CART-19 gives us a huge move into immunotherapy, a first- mover advantage," Chief Executive Officer Joe Jimenez said during a conference this year.Nineteen out of 22 children who had exhausted all drug treatment and bone-marrow transplant options for acute lymphoblastic leukemia went into remission after receiving the therapy, also known as CART-19, according to data presented this month at the American Society of Hematology meeting in New Orleans. Five patients later relapsed, including one whose new tumor cells produced a protein that enabled them to elude the souped-up T cells.In chronic lymphocytic leukemia, a much larger market, the therapy provoked a response in 47 percent of patients, with half of those patients experiencing a complete remission."There's never been a therapy that works after a bone- marrow transplant fails," Carl June, one of the treatment's developers at the University of Pennsylvania, said in a telephone interview. Novartis licensed the technology from the university. The therapy's money-making potential may be hampered by the complexity of its administration, as well as the emergence of powerful new drugs for leukemia, according to Richard Parkes, a London-based analyst at Deutsche Bank AG."CTL019 is likely to be used as a salvage treatment and we remain skeptical on its commercial opportunity," Parkes wrote in a Dec. 10 note to investors.Novartis plans to first develop CTL019 in acute lymphoblastic leukemia patients, then in the chronic lymphocytic form of the disease, followed by patients with lymphoma, another type of blood cancer, according to Herve Hoppenot, who heads Novartis's oncology unit. Hoppenot declined to comment on the treatment's commercial prospects."What we are planning to do is to make it a very easy and practical thing to use," he said in an interview. "We are certainly going to start in centers that are specialized in sophisticated treatments. They won't find it difficult. The burden will be on us to organize and calibrate the process."The Novartis treatment first grabbed attention last year after the doctors reported that nine of 12 patients had been pulled from death's door.The company bought a plant for manufacturing immunotherapies from Dendreon for $43 million last year. The Seattle-based company sold the plant because it has struggled to persuade doctors to use Provenge, which it produced there. Like CART-19, Provenge is a treatment that uses altered cells to fight cancer.Novartis plans to conduct a larger trial next year, Jimenez said at a Morgan Stanley conference in September. If the results are positive, Novartis would then ask regulators in 2016 for permission to market the therapy."The effectiveness gets people really excited, including me," Bill Chambers, interim national vice president of extramural research at the American Cancer Society, said in a telephone interview. "It seems like things are being put in place. I'm very hopeful about this."
T-Cell Therapy Eradicates an Aggressive Leukemia in Two Children Mar. 25, 2013 — Two children with an aggressive form of childhood leukemia had a complete remission of their disease -- showing no evidence of cancer cells in their bodies -- after treatment with a novel cell therapy that reprogrammed their immune cells to rapidly multiply and destroy leukemia cells. A research team from The Children's Hospital of Philadelphia and the University of Pennsylvania published the case report of two pediatric patients Online First today in The New England Journal of Medicine. It will appear in the April 18 print issue. One of the patients, 7-year-old Emily Whitehead, was featured in news stories in December 2012 after the experimental therapy led to her dramatic recovery after she relapsed following conventional treatment. Emily remains healthy and cancer-free, 11 months after receiving bioengineered T cells that zeroed in on a target found in this type of leukemia, called acute lymphoblastic leukemia (ALL). The other patient, a 10-year-old girl, who also had a complete response to the same treatment, suffered a relapse two months later when other leukemia cells appeared that did not harbor the specific cell receptor targeted by the therapy."This study describes how these cells have a potent anticancer effect in children," said co-first author Stephan A. Grupp, M.D., Ph.D., of The Children's Hospital of Philadelphia, where both patients were treated in this clinical trial. "However, we also learned that in some patients with ALL, we will need to further modify the treatment to target other molecules on the surface of leukemia cells."Grupp is the director of Translational Research for the Center for Childhood Cancer Research at The Children's Hospital of Philadelphia, and a professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. Michael Kalos, Ph.D., an adjunct associate professor in the department of Pathology and Laboratory Medicine in the Perelman School of Medicine at Penn, is co-first author on the study. The current study builds on Grupp's ongoing collaboration with Penn Medicine scientists who originally developed the modified T cells as a treatment for B-cell leukemias. The Penn team reported on early successful results of a trial using this cell therapy in three adult chronic lymphocytic leukemia (CLL) patients in August of 2011. Two of those patients remain in remission more than 2½ years following their treatment, and as the Penn researchers reported in December 2012 at the annual meeting of the American Society of Hematology, seven out of ten adult patients treated at that point responded to the therapy. The team is led by the current study's senior author, Carl H. June, M.D., the Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine and the Perelman School of Medicine at the University of Pennsylvania and director of Translational Research in Penn's Abramson Cancer Center. "We're hopeful that our efforts to treat patients with these personalized cellular therapies will reduce or even replace the need for bone marrow transplants, which carry a high mortality risk and require long hospitalizations," June said. "In the long run, if the treatment is effective in these late-stage patients, we would like to explore using it up front, and perhaps arrive at a point where leukemia can be treated without chemotherapy." The research team colleagues adapted the original CLL treatment to combat another B-cell leukemia: ALL, which is the most common childhood cancer. After decades of research, oncologists can currently cure 85 percent of children with ALL. Both children in the current study had a high-risk type of ALL that stubbornly resists conventional treatments.The new study used a relatively new approach in cancer treatment: immunotherapy, which manipulates the immune system to increase its cancer-fighting capabilities. Here the researchers engineered T cells to selectively kill another type of immune cell called B cells, which had become cancerous.
T cells are the workhorses of the immune system, recognizing and attacking invading disease cells. However, cancer cells fly under the radar of immune surveillance, evading detection by T cells. The new approach custom-designs T cells to "see" and attack the cancer cells. The researchers removed some of each patient's own T cells and modified them in the laboratory to create a type of CAR (chimeric antigen receptor) cell called a CTL019 cell. These cells are designed to attack a protein called CD19 that occurs only on the surface of certain B cells. By creating an antibody that recognizes CD19 and then connecting that antibody to T cells, the researchers created in CTL019 cells a sort of guided missile that locks in on and kills B cells, thereby attacking B-cell leukemia. After being returned to the patient's body, the CTL019 cells multiply a thousand times over and circulate throughout the body. Importantly, they persist for months afterward, guarding against a recurrence of this specific type of leukemia. While the CTL019 cells eliminate leukemia, they also can generate an overactive immune response, called a cytokine release syndrome, involving dangerously high fever, low blood pressure, and other side effects. This complication was especially severe in Emily, and her hospital team needed to provide her with treatments that rapidly relieved the treatment-related symptoms by blunting the immune overresponse, while still preserving the modified T cells' anti-leukemia activity.
"The comprehensive testing plan that we have put in place to study patients' blood and bone marrow while they're undergoing this therapy is allowing us to be able to follow how the T cells are behaving in patients in real time, and guides us to be able to design more detailed and specific experiments to answer critical questions that come up from our studies," Kalos said. The CTL019 therapy eliminates all B cells that carry the CD19 cell receptor: healthy cells as well as those with leukemia. Patients can live without B cells, although they require regular replacement infusions of immunoglobulin, which can be given at home, to perform the immune function normally provided by B cells. The research team continues to refine their approach using this new technology and explore reasons why some patients may not respond to the therapy or may experience a recurrence of their disease. Grupp said the appearance of the CD19-negative leukemia cells in the second child may have resulted from her prior treatments. Unlike Emily, the second patient had received an umbilical cord cell transplant from a matched donor, so her engineered T cells were derived from her donor (transplanted) cells, with no additional side effects. Oncologists had previously treated her with blinatumomab, a monoclonal antibody, in hopes of fighting the cancer. The prior treatments may have selectively favored a population of CD19-negative T cells. "The emergence of tumor cells that no longer contain the target protein suggests that in particular patients with high-risk ALL, we may need to broaden the treatment to include additional T cells that may go after additional targets," added Grupp. "However, the initial results with this immune-based approach are encouraging, and may later even be developed into treatments for other types of cancer." Funding from the National Institutes of Health (grants 1RO1 CA165206, R01 CA102646 and R01 CA116660), the Leukemia and Lymphoma Society, and the Alliance for Cancer Gene Therapy supported this study. In August 2012, the University of Pennsylvania and Novartis announced an exclusive global research and licensing agreement to further study and commercialize these novel cellular immunotherapies using chimeric antigen receptor (CAR) technologies. As part of the transaction, Novartis acquired exclusive rights from Penn to CART-19, the therapy that was the subject of this clinical trial and which is now known as CTL019.
"Chimeric Antigen Receptor-Modified T Cells for Acute Lymphoid Leukemia," New England Journal of Medicine, Online First, March 25, 2013. To appear in print April 18, 2013.
About The Children's Hospital of Philadelphia: The Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking third in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 516-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu.
About Penn Medicine: Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 16 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $398 million awarded in the 2012 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2012, Penn Medicine provided $827 million to benefit our community.
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