T-cell therapy eradicates an aggressive leukemia in 2 childrenPublic release date: 25-Mar-2013 [ | E-mail | Share ]
Contact: Holly Auer holly.auer@uphs.upenn.edu 215-200-2313 University of Pennsylvania School of Medicine
CHOP/PennMedicine Oncology team reports complete remission in pediatric ALL patients
Philadelphia, March 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 2 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.
A Joint Press Release from The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania
Contacts:
Rachel Salis-Silverman
The Children's Hospital of Philadelphia
Phone: 267-426-6063 Salis@email.chop.edu
Holly Auer
Perelman School of Medicine, University of Pennsylvania
[ | E-mail | Share ]
?
AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
T-cell therapy eradicates an aggressive leukemia in 2 childrenPublic release date: 25-Mar-2013 [ | E-mail | Share ]
Contact: Holly Auer holly.auer@uphs.upenn.edu 215-200-2313 University of Pennsylvania School of Medicine
CHOP/PennMedicine Oncology team reports complete remission in pediatric ALL patients
Philadelphia, March 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 2 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.
A Joint Press Release from The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania
Contacts:
Rachel Salis-Silverman
The Children's Hospital of Philadelphia
Phone: 267-426-6063 Salis@email.chop.edu
Holly Auer
Perelman School of Medicine, University of Pennsylvania
[ | E-mail | Share ]
?
AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
ISTANBUL (AFP) -- Israel and Turkey have "a thousand reasons" to be on friendly terms again following an air-clearing apology over the deaths of nine Turks in a 2010 raid on a Gaza-bound flotilla, Israeli President Shimon Peres said on Turkish television Sunday.
"I can think of a thousand reasons why Turkey and Israel should be friends; I cannot find one reason why they shouldn't be friends," Peres said in an interview with CNN Turk.
The diplomatic rift between the two former allies was sparked by the raid by Israeli commandos on the aid ship heading to the Gaza Strip. Israeli Prime Minister Benjamin apologized on Friday to Turkish leader Recep Tayyip Erdogan for what Peres called a "misunderstanding".
"I think somehow both countries wanted to put an end to this misunderstanding and return to the good relations that have existed between Turkey and ourselves for many good years," he said.
Peres said both nations, which will now resume full diplomatic ties, were united in their concerns over the possible use of chemical weapons in Syria.
"Unluckily the chemical arsenal remains. It is a danger to the people of Syria, to Lebanon, to the whole world. Everyone feels uneasy. It's not a simple problem. Turkey, being a leading force in the region, is worried like we are."
Asked whether he would soon be able to make up with Turkish President Abdullah Gul, Peres replied: "It can happen soon. I mean, we never interrupted the relations with Turkey."
While Erdogan welcomed the apology, the move has been criticized by Hamas and Israel's former foreign minister Avigdor Lieberman.
Go to a workshop on how to pay for your kids? college education, and you?ll see more gray hair in the audience than in years past.
It?s not because parents of college-bound students are older ? it?s because more grandparents are there, taking notes.
By all accounts, Grandma and Grandpa are more active than ever in funding their grandkids? educations, including sinking money into 529 college savings plans.
Michael Parker, executive director of the state agency that administers Oregon?s 529 plan, said attending workshops is one way grandparents show what a big deal it is to them that their grandkids get a degree.
?They?re very interested in making sure that their kids, the parents, know this is hugely important, that the grandkids be financially prepared to get a college education,? he said.
By the end of 2012, American families had a record $190.7 billion socked away in 529 college savings plans, according to a March 13 report from the College Savings Plans Network. More than 11 million of the accounts have been started since they were first offered 17 years ago.
Parents still contribute the lion?s share of funds invested in 529 accounts. But contributions from grandparents now make up about 9.5 percent of the total, according to the most recent data from the Financial Research Corp, which tracks 529 investments.?It was a substantial enough increase that FRC started keeping track of which types of relatives were funding 529s for the first time last year.
Source: Financial Research Corp., a Division of Strategic Insight
The trend isn?t lost on financial services companies, and many are starting to market 529 investment opportunities directly to grandparents as a result.
In February, AARP and financial services provider TIAA-CREF launched just such a campaign. It includes a section on the AARP website that members can use to look up college savings plans in all 50 states and get help with investment options and tax questions.
?Our goal is to elevate awareness in how 529 plans can help people save for college, and encourage more people, including grandparents, to save,? said Chad Peterson, a TIAA-CREF spokesman.
Franklin Templeton Investments, which administers New Jersey?s 10-year-old 529 plan, also is marketing to grandparents directly, through seminars and information on its website.
In some cases, grandparents are stepping in to help foot the bill because their adult children haven?t saved, got hit by the recession and have yet to recover, or are too tapped out paying current bills and saving for their own retirement to stash much away for college expenses.
"In this economy, it?s much harder to save for college, so if grandparents give that nudge, or give some money, it?s helping their children do it," said Reyna Gobel, a college finance expert and author of the audiobook "How Smart Students Pay for School."
Depending on their own circumstances, grandparents might find it more beneficial either to set up 529 accounts for their grandkids or contribute to existing accounts created by parents of college-bound students. When grandparents create accounts, they maintain control over where funds are invested, and can take money out at any time without penalty, according to Parker, the Oregon 529 plan director.
Once funds are transferred to pay for tuition or books, the money is recognized as student income, which could affect how much financial aid the student receives the following year, he said.
Money that grandparents deposit into a 529 account set up by a student?s parents shows up as the parents? assets on the student?s financial aid applications, which could adversely affect how much they receive in scholarships or grants.
Either way, tax law changes that took effect this year allow grandparents to put a maximum of $14,000 a year per grandchild into a 529 account. They can also make a one-time gift of five years? worth of contributions per person. That means a married couple could conceivably give a lump sum of $140,000 to each grandchild once every five years.
Not all grandparents make such major contributions. At Franklin Templeton Investments, people can open 529 accounts with as little as $25. The firm encourages parents and grandparents to contribute on a regular basis. As a present for a birthday or holiday, it?s a gift that ?makes more of an impact,? said Roger Michaud, senior vice president for Franklin Templeton Investments' North America advisory services division and current chair of the College Savings Foundation.
There?s some evidence that grandparents may be aiding their offspring?s offspring at their own expense. Sixty-two percent of grandparents report providing money or other financial support to grandkids within the past five years, according to a September 2012 MetLife survey of 1,008 U.S. grandparents ages 45 and older. Of that number, a third said they gave financial support even though it had a negative effect on their own financial security, according to the report.
It?s harder to determine to what extent grandparents are working longer to provide that financial assistance, said Kathleen Christensen, program director at the Alfred P. Sloan Foundation, which provides grants for research on aging and work. ?We do know it?s happening, and I think it?s an important trend to recognize,? she said.
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Public release date: 25-Mar-2013
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