个性化细胞治疗百分之90急性淋巴细胞白血病患者的研究

2014年10月15日-儿童和成人急性淋巴细胞白血病（ALL）曾百分之九十多次复发或没有回应的标准疗法缓解了接受调查的个性化细胞治疗，输后，在宾夕法尼亚大学医学院的发展。本周公布的结果新英国医学杂志。

The new data, which builds on preliminary findings presented at the American Society of Hematology’s annual meeting in December 2013, include results from the first 25 children和young adults (ages 5 to 22) treated at The Children’s Hospital of Philadelphia (CHOP)和first five adults (ages 26 to 60) treated at the Hospital of the University of Pennsylvania。 Twenty-seven of the 30 patients in the studies achieved a complete remission after receiving an infusion of these engineered “hunter” cells,和78 percent of the patients were alive six months after treatment。

“The patients who participated in these trials had relapsed as many as four times, including 60 percent whose cancers came back even after stem cell transplants。 Their cancers were so aggressive they had no treatment options left,” said the study’s senior author, Stephan Grupp, MD, PhD, director of Translational Research in the Center for Childhood Cancer Research at The Children's Hospital of Philadelphia和a professor of Pediatrics in Penn’s Perelman School of Medicine。 “The durable responses we have observed with CTL019 therapy are unprecedented。”

Shannon Maude, MD, PhD, a pediatric oncologist at CHOP和an assistant professor of Pediatrics,和Noelle Frey, MD, MSCE, an assistant professor of Medicine和an oncologist at Penn’s Abramson’s Cancer Center, are co-first authors of the new study。 The research team is led by Carl June, MD, the Richard W。 Vague Professor in Immunotherapy in the department of Pathology和Laboratory Medicine和director of Translational Research in the Abramson Cancer Center, along with David Porter, MD, the Jodi Fisher Horowitz Professor in Leukemia Care Excellence和director of Blood和Marrow Transplantation in the Abramson Cancer Center。

CTL019 manufacturing begins with a patient’s own T cells, which are collected via an apheresis process similar to blood donation, then reprogrammed in Penn’s Clinical Cell和Vaccine Production Facility with a gene transfer technique that teaches the T cells to target和kill tumor cells。 The engineered cells contain an antibody-like protein known as a chimeric antigen receptor (CAR), which is designed to bind to a protein called CD19 found on the surface of B cells, including the cancerous B cells that characterize several types of leukemia。 The modified “hunter” cells are then infused back into the patient's body, where they both multiply和attack the cancer cells。 A signaling domain built into the CAR promotes rapid multiplication of the “hunter” cells, building an army of tumor-killing cells that tests reveal can grow to more than 10,000 new cells for each single engineered cell patients receive。

Nineteen patients in the study remain in remission, 15 with this therapy alone, including a 9 year old who was the first ALL patient to receive the therapy more than two years ago。 The follow-up periods reported in the study are more than six months for most patients, with a range from 1。4 to 24 months。 Five patients went off-study for alternate therapy, three of whom proceeded to allogeneic stem cell transplants while in remission。 Seven patients relapsed, between 6 weeks和8。5 months after their infusions, including three whose cancers returned as CD19-negative leukemia that would not have been targeted by the modified cells。

All patients who received the CTL019 “hunter” cells experienced a cytokine release syndrome (CRS) within a few days after receiving their infusions — a key indicator that the engineered cells have begun proliferating和killing tumor cells in the body。 During this time, 22 of 30 patients experienced mild to moderate CRS, which included varying degrees of flu-like symptoms, with high fevers, nausea,和muscle pain。 Eight patients developed severe CRS, which required treatment for low blood pressure和breathing difficulties。 Nine patients were treated with tocilizumab, an immunosuppressant drug that blocks the effects of the inflammatory cytokine IL-6, which have been found to spike during the most robust phase of the engineered cells’ expansion in the body。 Six patients also received short courses of steroids to combat CRS symptoms。 All patients on these studies fully recovered from the CRS。

Tests of all patients who experienced complete remissions also showed that their normal, non-cancerous B cells, which also express the CD19 protein, had been eliminated along with their tumors。 The researchers note that persistent absence of normal B cells following CTL019 treatment indicates continued activity of the gene-modified T cells, which are thought to provide long-term, vaccine-like activity preventing tumor recurrence。 Since B cells play a role in helping fight infection, patients typically receive immunoglobulin replacement to maintain healthy immune function。

“Our results support that CTL019 can produce long-lasting remissions for certain heavily pre-treated ALL patients without further therapy,” Frey said。 “For our patients who have already relapsed after stem cell transplants, or don’t have any options for donors, this option has provided new hope。”

In July 2014, the U。S。 Food和Drug Administration granted CTL019 its Breakthrough Therapy designation for the treatment of relapsed和refractory adult和pediatric ALL, a step which is intended to expedite the development和review of new medicines that treat serious or life-threatening conditions, if a therapy has demonstrated substantial advantages over available treatments。 CTL019 is the first personalized cellular therapy to receive the designation。 The first multicenter CTL019 trial has recently opened in the U。S。,和additional multisite trials are expected to initiate by the end of the year。

The study was supported by the National Institutes of Health (1R01CA165206, R01CA102646和R01CA116660), the Leukemia和Lymphoma Society,和a Stand Up To Cancer-St。 Baldrick’s Pediatric Dream Team Translational Research Grant。

编者注：The University of Pennsylvania has licensed technologies involved in this trial to Novartis。 Some of the scientists involved in these trials are inventors of these technologies, including Drs。 June, Porter,和Grupp。 As a result of the licensing relationship with Novartis, the University of Pennsylvania和the Children’s Hospital of Philadelphia receive significant financial benefit,和the inventors have benefitted financially and/or may benefit financially in the future。

接触

The Children's Hospital of PhiladelphiaRachel Salis-Silverman, 267-426-6063 or Salis@email。chop。edu

潘医学Holly Auer,  215-349-5659 (office), 215-200-2313 (cell) or holly。auer@uphs。upenn。edu

关于费城儿童医院

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和pioneering major research initiatives, Children’s Hospital has fostered many discoveries that have benefited children worldwide。 Its pediatric research program receives the highest amount of National Institutes of Health funding among all U。S。 children’s hospitals。 In addition, its unique family-centered care和public service programs have brought the 535-bed hospital recognition as a leading advocate for children和adolescents。

费城儿童医院是美国最大的儿童癌症项目之一，在美国排名靠前U。S。 News & World Report和父母 杂志。 Its large basic和clinical research programs are particularly strong in pediatric neuro-oncology, neuroblastoma, leukemia和lymphoma,和sarcomas。 Of all pediatric institutions, Children's Hospital enrolls the most patients in national clinical trials, working in close collaboration with national organizations such as the Children's Oncology Group。 Physicians at Children's Hospital have had pioneering roles in developing international standards for diagnosing和treating neuroblastoma,和in developing programs for survivors of childhood cancer。 For more information, visit http://www。chop。edu/cancer。

潘医学

is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research,和excellence in patient care。 潘医学 consists of the Raymond和Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school)和the University of Pennsylvania Health System, which together form a $4。3 billion enterprise。

医学院一直排名前五位的医疗学校在美国过去的17年中，根据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 $392 million awarded in the 2013 fiscal year。

宾夕法尼亚大学医疗卫生系统的病人护理设施包括：宾夕法尼亚大学医院--公认为全国最顶尖的“荣誉辊”医院U。S。 News & World Report; Penn Presbyterian Medical Center; Chester County Hospital; Penn Wissahickon Hospice;和Pennsylvania Hospital — the nation's first hospital, founded in 1751。 Additional affiliated inpatient care facilities和services throughout the Philadelphia region include Chestnut Hill Hospital和Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network和潘医学。

潘医学 is committed to improving lives和health through a variety of community-based programs和activities。 In fiscal year 2013, 潘医学 provided $814 million to benefit our community。

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