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CAR T-cells: an exciting frontier in cancer therapy
Editorial
iStock Wavebreakmedia 650148650
Pushing the boundaries in paediatric surgery
See Comment page 1012 See Series pages 1061 and 1072
Aside from the difficult psychosocial aspects of illness in babies and children, paediatric surgery and paediatric surgical research face inimitable challenges. These include the consequences of anaesthesia and radiation exposure in children, the implications of long-term complications, and, in many cases, the necessity of long-term care despite the inevitability of a transition to adult services. Diseases requiring paediatric surgery are sometimes rare and heterogenous in nature, with complex cases requiring multidisciplinary management. The physical and physiological differences in children mean that outcomes cannot be inferred from results of research in larger adult populations, and dedicated research is required. Today’s surgery-themed issue of The Lancet contains a two-part Series on paediatric surgery. The Series focuses on paediatric urological and gastrointestinal surgery, two subspecialties selected because they encompass some of the most common paediatric surgical conditions (appendicitis, vesicoureteric reflux, and necrotising enterocolitis) and highlight the exciting research underway in this specialty, despite the challenges. In the urological surgery paper,
David Diamond and colleagues debate the growing interest in the role of fetal surgery for the treatment of urethral valves, a technique operating at the extremes of minimally invasive surgery. Paul Tam and colleagues, in their paper on gastrointestinal surgery, discuss the possibility of cell-based therapies for conditions with a strong genetic contribution and the contribution of the microbiome in necrotising enterocolitis. They also challenge the role of surgery in appendicitis. In many ways, paediatric surgery represents a frontier in surgery—it is possibly the most challenging subspecialty in which to conduct research, and yet it is pushing the boundaries of biomedical science, seeking innovative, often non-surgical, solutions for intractable problems. Today’s Series, written by an international group of experts, demonstrates the willingness of paediatric surgeons to come together to define best practice and examine current controversies in the field. It is collaborations such as these, which can drive the high-quality clinical trials in this difficult setting, that are so urgently required by surgeons, patients, and parents. n The Lancet
CAR T-cells: an exciting frontier in cancer therapy
Science Photo Library STEVE GSCHMEISSNER
On Aug 30, the US Food and Drug Administration (FDA) approved tisagenlecleucel (marketed by Novartis as Kymriah) as the first ever treatment that genetically modifies patients’ own T cells. The approval is for children and young adults (up to 25 years of age) with relapsed or refractory acute B-cell lymphoblastic leukaemia—a leading cause of childhood cancer deaths. This treatment option is currently limited to 20 specially certified centres in the USA because of the complexity of the procedure and potentially serious side-effects. The patient’s own T cells will be removed by leukapheresis and transported to Novartis’s laboratory in Morris Plains, NJ, USA. In the laboratory, T cells will be genetically altered to produce receptors on their surface called chimeric antigen receptors (CAR), multiplied, and then will be reinfused into the patient after a lymphodepleting chemotherapy regimen. These receptors allow T cells, which further replicate in the patient’s body, to recognise the B-cell antigen CD19 on the tumour cell surface and 1006
kill these cancer cells. As a side-effect, this process can also cause the so-called cytokine release syndrome, which can be treated with supportive therapy, steroids, or the specific interleukin-6 blocker tocilizumab. B-cell aplasia (normal B cells also express CD19) and cerebral oedema have been observed as other serious side-effects. FDA approval follows early results of a continuing small (63 patients) phase 2 study, in which 52 patients achieved complete remission in the 3 months after drug administration. Longer-term data will be needed to allow true comparison of benefit-risk outcomes and cost benefit. The treatment is expensive at US$475 000. Novartis will waive the fee if there is no response at 1 month. This remarkable technical advance is exciting scientific progress in a disorder with few treatment options. But given the limited data supporting its use, the introduction of tisagenlecleucel should be seen as a first cautious step in an approach that needs much more refinement and research for this and other indications. n The Lancet www.thelancet.com Vol 390 September 9, 2017
iStock Wavebreakmedia 650148650
Pushing the boundaries in paediatric surgery
See Comment page 1012 See Series pages 1061 and 1072
Aside from the difficult psychosocial aspects of illness in babies and children, paediatric surgery and paediatric surgical research face inimitable challenges. These include the consequences of anaesthesia and radiation exposure in children, the implications of long-term complications, and, in many cases, the necessity of long-term care despite the inevitability of a transition to adult services. Diseases requiring paediatric surgery are sometimes rare and heterogenous in nature, with complex cases requiring multidisciplinary management. The physical and physiological differences in children mean that outcomes cannot be inferred from results of research in larger adult populations, and dedicated research is required. Today’s surgery-themed issue of The Lancet contains a two-part Series on paediatric surgery. The Series focuses on paediatric urological and gastrointestinal surgery, two subspecialties selected because they encompass some of the most common paediatric surgical conditions (appendicitis, vesicoureteric reflux, and necrotising enterocolitis) and highlight the exciting research underway in this specialty, despite the challenges. In the urological surgery paper,
David Diamond and colleagues debate the growing interest in the role of fetal surgery for the treatment of urethral valves, a technique operating at the extremes of minimally invasive surgery. Paul Tam and colleagues, in their paper on gastrointestinal surgery, discuss the possibility of cell-based therapies for conditions with a strong genetic contribution and the contribution of the microbiome in necrotising enterocolitis. They also challenge the role of surgery in appendicitis. In many ways, paediatric surgery represents a frontier in surgery—it is possibly the most challenging subspecialty in which to conduct research, and yet it is pushing the boundaries of biomedical science, seeking innovative, often non-surgical, solutions for intractable problems. Today’s Series, written by an international group of experts, demonstrates the willingness of paediatric surgeons to come together to define best practice and examine current controversies in the field. It is collaborations such as these, which can drive the high-quality clinical trials in this difficult setting, that are so urgently required by surgeons, patients, and parents. n The Lancet
CAR T-cells: an exciting frontier in cancer therapy
Science Photo Library STEVE GSCHMEISSNER
On Aug 30, the US Food and Drug Administration (FDA) approved tisagenlecleucel (marketed by Novartis as Kymriah) as the first ever treatment that genetically modifies patients’ own T cells. The approval is for children and young adults (up to 25 years of age) with relapsed or refractory acute B-cell lymphoblastic leukaemia—a leading cause of childhood cancer deaths. This treatment option is currently limited to 20 specially certified centres in the USA because of the complexity of the procedure and potentially serious side-effects. The patient’s own T cells will be removed by leukapheresis and transported to Novartis’s laboratory in Morris Plains, NJ, USA. In the laboratory, T cells will be genetically altered to produce receptors on their surface called chimeric antigen receptors (CAR), multiplied, and then will be reinfused into the patient after a lymphodepleting chemotherapy regimen. These receptors allow T cells, which further replicate in the patient’s body, to recognise the B-cell antigen CD19 on the tumour cell surface and 1006
kill these cancer cells. As a side-effect, this process can also cause the so-called cytokine release syndrome, which can be treated with supportive therapy, steroids, or the specific interleukin-6 blocker tocilizumab. B-cell aplasia (normal B cells also express CD19) and cerebral oedema have been observed as other serious side-effects. FDA approval follows early results of a continuing small (63 patients) phase 2 study, in which 52 patients achieved complete remission in the 3 months after drug administration. Longer-term data will be needed to allow true comparison of benefit-risk outcomes and cost benefit. The treatment is expensive at US$475 000. Novartis will waive the fee if there is no response at 1 month. This remarkable technical advance is exciting scientific progress in a disorder with few treatment options. But given the limited data supporting its use, the introduction of tisagenlecleucel should be seen as a first cautious step in an approach that needs much more refinement and research for this and other indications. n The Lancet www.thelancet.com Vol 390 September 9, 2017