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Old 12-10-2012, 01:38 PM
gdpawel gdpawel is offline
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Default Can "altered" immune cells beat leukemia?

PHILIPSBURG, Pa. -- Emma Whitehead has been bounding around the house lately, practicing somersaults and rugby-style tumbles that make her parents wince.

It is hard to believe, but last spring Emma, then 6, was near death from leukemia. She had relapsed twice after chemotherapy, and doctors had run out of options.

Desperate to save her, her parents sought an experimental treatment at the Children’s Hospital of Philadelphia, one that had never before been tried in a child, or in anyone with the type of leukemia Emma had. The experiment, in April, used a disabled form of the virus that causes AIDS to reprogram Emma’s immune system genetically to kill cancer cells.

The treatment very nearly killed her. But she emerged from it cancer-free, and about seven months later is still in complete remission. She is the first child and one of the first humans ever in whom new techniques have achieved a long-sought goal — giving a patient’s own immune system the lasting ability to fight cancer.

Emma had been ill with acute lymphoblastic leukemia since 2010, when she was 5, said her parents, Kari and Tom. She is their only child.

She is among just a dozen patients with advanced leukemiato have received the experimental treatment, which was developed at the University of Pennsylvania. Similar approaches are also being tried at other centers, including the National Cancer Institute and Memorial Sloan-Kettering Cancer Center in New York.

“Our goal is to have a cure, but we can’t say that word,” said Dr. Carl June, who leads the research team at the University of Pennsylvania. He hopes the new treatment will eventually replace bone-marrow transplantation, an even more arduous, risky and expensive procedure that is now the last hope when other treatments fail in leukemia and related diseases.

Three adults with chronic leukemia treated at the University of Pennsylvania have also had complete remissions, with no signs of disease; two of them have been well for more than two years, said Dr. David Porter. Four adults improved but did not have full remissions, and one was treated too recently to evaluate. A child improved and then relapsed. In two adults, the treatment did not work at all. The Pennsylvania researchers were presenting their results on Sunday and Monday in Atlanta at a meeting of the American Society of Hematology.

Despite the mixed results, cancer experts not involved with the research say it has tremendous promise, because even in this early phase of testing it has worked in seemingly hopeless cases. “I think this is a major breakthrough,” said Dr. Ivan Borrello, a cancer expert and associate professor of medicine at the Johns Hopkins University School of Medicine.

Dr. John Wagner, the director of pediatric blood and marrow transplantation at the University of Minnesota, called the Pennsylvania results “phenomenal” and said they were “what we’ve all been working and hoping for but not seeing to this extent.”

A major drug company, Novartis, is betting on the Pennsylvania team and has committed $20 million to building a research center on the university’s campus to bring the treatment to market.

Hervé Hoppenot, the president of Novartis Oncology, called the research “fantastic” and said it had the potential — if the early results held up — to revolutionize the treatment of leukemia and related blood cancers. Researchers say the same approach, reprogramming the patient’s immune system, may also eventually be used against tumors like breast and prostate cancer.

To perform the treatment, doctors remove millions of the patient’s T-cells — a type of white blood cell — and insert new genes that enable the T-cells to kill cancer cells. The technique employs a disabled form of H.I.V. because it is very good at carrying genetic material into T-cells. The new genes program the T-cells to attack B-cells, a normal part of the immune system that turn malignant in leukemia.

The altered T-cells — called chimeric antigen receptor cells — are then dripped back into the patient’s veins, and if all goes well they multiply and start destroying the cancer.

The T-cells home in on a protein called CD-19 that is found on the surface of most B-cells, whether they are healthy or malignant.

A sign that the treatment is working is that the patient becomes terribly ill, with raging fevers and chills — a reaction that oncologists call “shake and bake,” Dr. June said. Its medical name is cytokine-release syndrome, or cytokine storm, referring to the natural chemicals that pour out of cells in the immune system as they are being activated, causing fevers and other symptoms. The storm can also flood the lungs and cause perilous drops in blood pressure — effects that nearly killed Emma.

Steroids sometimes ease the reaction, but they did not help Emma. Her temperature hit 105. She wound up on a ventilator, unconscious and swollen almost beyond recognition, surrounded by friends and family who had come to say goodbye.

But at the 11th hour, a battery of blood tests gave the researchers a clue as to what might help save Emma: her level of one of the cytokines, interleukin-6 or IL-6, had shot up a thousandfold. Doctors had never seen such a spike before and thought it might be what was making her so sick.

Dr. June knew that a drug could lower IL-6 — his daughter takes it for rheumatoid arthritis. It had never been used for a crisis like Emma’s, but there was little to lose. Her oncologist, Dr. Stephan A. Grupp, ordered the drug. The response, he said, was “amazing.”

Within hours, Emma began to stabilize. She woke up a week later, on May 2, the day she turned 7; the intensive-care staff sang “Happy Birthday.”

Since then, the research team has used the same drug, tocilizumab, in several other patients.

In patients with lasting remissions after the treatment, the altered T-cells persist in the bloodstream, though in smaller numbers than when they were fighting the disease. Some patients have had the cells for years.

Dr. Michel Sadelain, who conducts similar studies at the Sloan-Kettering Institute, said: “These T-cells are living drugs. With a pill, you take it, it’s eliminated from your body and you have to take it again.” But T-cells, he said, “could potentially be given only once, maybe only once or twice or three times.”

The Pennsylvania researchers said they were surprised to find any big drug company interested in their work, because a new batch of T-cells must be created for each patient — a far cry from the familiar commercial strategy of developing products like Viagra or cholesterol medicines, in which millions of people take the same drug.

But Mr. Hoppenot said Novartis was taking a different path with cancer drugs, looking for treatments that would have a big, unmistakable impact on a small number of patients. Such home-run drugs can be approved more quickly and efficiently, he said, with smaller studies than are needed for drugs with less obvious benefits.

“The economic model is totally acceptable,” Mr. Hoppenot said.

But such drugs tend to be extremely expensive. A prime example is the Novartis drug Gleevec, which won rapid approval in 2001 for use against certain types of leukemia and gastrointestinal tumors. It can cost more than $5,000 a month, depending on the dosage.

Dr. June said that producing engineered T-cells costs about $20,000 per patient — far less than the cost of a bone-marrow transplant. Scaling up the procedure should make it even less expensive, he said, but he added, “Our costs do not include any profit margin, facility depreciation costs or other clinical care costs, and other research costs.”

The research is still in its early stages, and many questions remain. The researchers are not entirely sure why the treatment works, or why it sometimes fails. One patient had a remission after being treated only twice, and even then the reaction was so delayed that it took the researchers by surprise. For the patients who had no response whatsoever, the team suspects a flawed batch of T-cells. The child who had a temporary remission apparently relapsed because not all of her leukemic cells had the marker that was targeted by the altered T-cells.

It is not clear whether a patient’s body needs the altered T-cells forever. The cells do have a drawback: they destroy healthy B-cells as well as cancerous ones, leaving patients vulnerable to certain types of infections, so Emma and the other patients need regular treatments with immune globulins to prevent illness.
So far, her parents say, Emma seems to have taken it all in stride. She went back to school this year with her second-grade classmates, and though her grades are high and she reads about 50 books a month, she insists impishly that her favorite subjects are lunch and recess.

“It’s time for her to be a kid again and get her childhood back,” Mr. Whitehead said.

This article, "In girl's last hope, altered immune cells beat leukemia" first appeared in The New York Times.
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Old 12-22-2012, 11:59 AM
gdpawel gdpawel is offline
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Default A biotech "embedded" in an academic setting?

GlaxoSmithKline (GSK) has gained rights to a preclinical program from the renowned MD Anderson Cancer Center, in a pact focused on antibodies that trigger immune attacks against cancer. The deal delivers up to $335 million in payments in addition to royalties to the University of Texas's cancer center from GSK, which is among a pack of large drugmakers seeking juicy assets in oncology from leading academic hubs.

MD Anderson has grabbed an undisclosed upfront sum from GSK and funding to continue research of immune therapies for cancer. It's the first major pharma deal for the center's Institute for Applied Cancer Sciences, which was set up last year to operate as a translational research unit that is akin to "a biotech embedded" in an academic setting, a spokesman for the center said in an email. The prized antibodies in the deal act on OX40 receptors on T cells, helping the ninjas of the immune system recognize tumor cells as enemies in need of an ass kicking. Like all preclinical programs, the merits of the therapies must pass some initial tests before they advance to human clinical studies.

Amid angst about NIH funding in academia, some university scientists have turned to Big Pharma to support their research and pay for rights to develop and commercialize new therapies from their labs. MD Anderson's immune-triggering antibodies emerged from the research of Dr. Yong-Jun Liu during his stint at the Houston cancer center. He's since moved on to become the chief scientist of the Baylor Research Institute in Dallas.

Over the summer Novartis struck a $20 million accord with the University of Pennsylvania to collaborate on cancer immunotherapies, after researchers reported some early success in patients with chronic lymphocytic leukemia. And Yale University last year landed an initial $40 million collaboration with Gilead Sciences to aid the HIV drug leader's early efforts in oncology research.

Cancer cells adapt to escape immune responses that eventually wear thin in patients and allow tumors to grow. By activating OX40, a secondary signal to alert attacker T cells of cancer, Liu's experimental antibodies aim to switch on the immune system to thwart elusive tumor cells.

"T cell recognition of a tumor antigen is not enough to activate the T cells against cancer cells; they need a secondary signal to tell them 'that antigen you have is a bad thing, you have to attack,'" Liu said in a statement.
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Old 03-20-2013, 08:01 PM
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Default Cell Therapy in Adults with Chemotherapy-Refractory Acute Lymphoblastic Leukemia

A treatment that genetically alters a patient’s own immune cells to fight cancer has, for the first time, produced remissions in adults with an acute leukemia, researchers are reporting.

In one patient who was severely ill, all traces of leukemia vanished in eight days. “We had hoped, but couldn’t have predicted that the response would be so profound and rapid,” said Dr. Renier J. Brentjens, the first author of a new study of the therapy and a specialist in leukemia at Memorial Sloan-Kettering Cancer Center.

The treatment is experimental, has been used in only a small number of patients and did not work in all of them. But experts consider it a highly promising approach for a variety of malignancies, including other blood cancers and tumors in organs like the prostate gland. The new study, in five adults with acute leukemia, was published in the journal Science Translational Medicine.

The treatment is similar to Emma Whitehead (above), and has had astounding success in several adults with chronic leukemia in whom chemotherapy had failed. Emma and those adults were treated at the University of Pennsylvania. Related studies have also been done at the National Cancer Institute.

But this cell-therapy approach had not been tried before in adults with the disease that Emma had, acute lymphoblastic leukemia. This type of blood cancer is worse in adults than in children, with a cure rate in adults of only about 40 percent, compared with 80 to 90 percent in children.

Three of the five adults have been in remission for 5 to 24 months. Two others died: one was in remission but died from a blood clot, and the other relapsed. The survivors have gone on to have bone-marrow transplants. This is the first report showing some real, clinically beneficial activity in adult acute lymphoblastic leukemia.

The treatment uses patients’ own T-cells, a type of white blood cell that normally fights viruses and cancer. The patient’s blood is run through a machine that extracts T-cells and returns the rest of the blood to the body. Researchers then do some genetic engineering: they use a disabled virus as a “vector” to carry new genetic material into the T cells, which reprograms them to recognize and kill any cell that carries a particular protein on its surface.

The protein, called CD19, is found on B-cells, which are part of the immune system. This target was chosen because the patients had a type of leukemia that affects B-cells, so the goal was to train the patients’ T-cells to destroy B-cells. Healthy B-cells, which make antibodies to fight infection, would be killed along with cancerous ones, but that side effect was treatable.

Sci Transl Med 20 March 2013: Vol. 5, Issue 177, p. 177ra38 Sci. Transl. Med. DOI: 10.1126/scitranslmed.3005930

CD19-Targeted T Cells Rapidly Induce Molecular Remissions in Adults with Chemotherapy-Refractory Acute Lymphoblastic Leukemia

Renier J. Brentjens 1,2,3, Marco L. Davila 1, Isabelle Riviere 1,2,3,4, Jae Park 1, Xiuyan Wang 3,4, Lindsay G. Cowell 5, Shirley Bartido 4, Jolanta Stefanski 4, Clare Taylor 4, Malgorzata Olszewska 4, Oriana Borquez-Ojeda 4, Jinrong Qu 4, Teresa Wasielewska 4, Qing He 4, Yvette Bernal 1, Ivelise V. Rijo 6, Cyrus Hedvat 6, Rachel Kobos 7, Kevin Curran 7, Peter Steinherz 7, Joseph Jurcic 1, Todd Rosenblat 1, Peter Maslak 1, Mark Frattini 1 and Michel Sadelain 1,2,3

1. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
2. Center for Cell Engineering, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
3. Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
4. Cell Therapy and Cell Engineering Facility, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
5. Department of Clinical Sciences, UT Southwestern, Dallas, TX 75390, USA.
6. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
7. Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

ABSTRACT

Adults with relapsed B cell acute lymphoblastic leukemia (B-ALL) have a dismal prognosis. Only those patients able to achieve a second remission with no minimal residual disease (MRD) have a hope for long-term survival in the context of a subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have treated five relapsed B-ALL subjects with autologous T cells expressing a CD19-specific CD28/CD3ζ second-generation dual-signaling chimeric antigen receptor (CAR) termed 19-28z. All patients with persistent morphological disease or MRD+ disease upon T cell infusion demonstrated rapid tumor eradication and achieved MRD− complete remissions as assessed by deep sequencing polymerase chain reaction. Therapy was well tolerated, although significant cytokine elevations, specifically observed in those patients with morphologic evidence of disease at the time of treatment, required lymphotoxic steroid therapy to ameliorate cytokine-mediated toxicities. Indeed, cytokine elevations directly correlated to tumor burden at the time of CAR-modified T cell infusions. Tumor cells from one patient with relapsed disease after CAR-modified T cell therapy, who was ineligible for additional allo-HSCT or T cell therapy, exhibited persistent expression of CD19 and sensitivity to autologous 19-28z T cell–mediated cytotoxicity, which suggests potential clinical benefit of additional CAR-modified T cell infusions. These results demonstrate the marked antitumor efficacy of 19-28z CAR-modified T cells in patients with relapsed/refractory B-ALL and the reliability of this therapy to induce profound molecular remissions, forming a highly effective bridge to potentially curative therapy with subsequent allo-HSCT.

Source: American Association for the Advancement of Science

Citation: R. J. Brentjens, M. L. Davila, I. Riviere, J. Park, X. Wang, L. G. Cowell, S. Bartido, J. Stefanski, C. Taylor, M. Olszewska, O. Borquez-Ojeda, J. Qu, T. Wasielewska, Q. He, Y. Bernal, I. V. Rijo, C. Hedvat, R. Kobos, K. Curran, P. Steinherz, J. Jurcic, T. Rosenblat, P. Maslak, M. Frattini, M. Sadelain, CD19-Targeted T Cells Rapidly Induce Molecular Remissions in Adults with Chemotherapy-Refractory Acute Lymphoblastic Leukemia. Sci. Transl. Med. 5, 177ra38 (2013).

[url]http://stm.sciencemag.org/content/5/177/177ra38
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Old 03-19-2015, 09:51 AM
gdpawel gdpawel is offline
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Default Scientists Convert Cancer Cells Into Harmless Immune Cells

Laboratory studies do not often go as planned, and while this is usually a source of endless frustration amongst scientists, some wonderful discoveries have been made by accident in the past, such as the pacemaker and penicillin. Now, researchers may have happened upon something that could turn out to be a powerful agent against a particularly aggressive type of cancer.

After endeavoring to find ways to prevent cancerous cells from dying during experiments, scientists from Stanford have discovered that it is possible to force leukemia cells to mature into a type of immune cell that, ironically, may help the body clear up other tumor cells. The study has been published in Proceedings of the National Academy of Sciences.

Acute lymphocytic leukemia (ALL) is a rapidly-progressing cancer of the immature cells that differentiate into white blood cells, or lymphocytes. There are several different types of ALL, which are classified based on the type of lymphocyte (B cell or T cell) the cancer originates from, and how mature these cells are.

For the current study, scientists were investigating the most common type of acute lymphoblastic leukemia, known as as precursor B cell ALL, or B-ALL. As the name suggests, this cancer originates from a rogue B cell that became stuck at an early stage of maturation. These immature cells are unable to fully differentiate into normal B cells, partly because they lost some cellular molecules, known as transcription factors, which are required for their development. Transcription factors are proteins that stick to bits of DNA and then switch certain genes on or off.

B-ALL is a particularly aggressive cancer with a poor prognosis, so scientists from Stanford were keen to learn more about it with the hope of finding ways to tackle it, but they were struggling to keep cells isolated from a patient alive in the lab. “We were throwing everything at them to help them survive,” lead researcher Ravi Majeti said in a news release.

After exposing the cells to a certain transcription factor, the scientists observed that they began to change size and shape, adopting the characteristic morphology of a type of white blood cell responsible for gobbling up damaged cells or foreign material, known as a macrophage.

The team then began characterizing these cells in the lab, which revealed that they expressed similar genes to normal macrophages and were able to perform various macrophage functions, such as engulfing bacteria. Furthermore, when they added these reprogrammed cells into mice without immune systems, they did not cause cancer.

The researchers also have reason to believe that these converted cells will not only be neutralized with regards to their former identity as a cancerous cell, but they may also help the body mount an immune response against other cancerous cells lingering in the body. That’s because macrophages collect tags from abnormal cells or foreign material ready to flag down other members of the immune system for attack. Since these cells came from cancerous cells, they will possess signals that identify them as cancer.

The next stage of the project will therefore involve investigating ways to achieve this cell conversion in a clinically viable way, which has already been done for one other type of cancer.

Citation: Scientists Convert Cancer Cells Into Harmless Immune Cells. IFL Science March 17, 2015 by Justine Alford

[url]http://www.pnas.org/content/early/2015/03/12/1413383112

[url]http://med.stanford.edu/news/all-news/2015/03/scientists-discover-how-to-change-human-leukemia-cells.html
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