Cientista cria alternativa para o uso de animais no teste de medicamentos

A mucosa artificial (à direita) é um hidrogel que permitirá que os candidatos a medicamentos sejam comparados com maior grau de certeza, sem a variabilidade dos tecidos dos animais sacrificados.

Uso de cobaias

Pesquisadores britânicos desenvolveram uma nova forma para testar as qualidades de candidatos a medicamentos em laboratório que poderá substituir a prática atual de utilização de tecido animal.

Inúmeros grupos de pesquisas ao redor do mundo estão trabalhando em formas de evitar o uso de animais em pesquisas científicas.

Recentemente, um comitê de cientistas também da Grã-Bretanha divulgou um relatório com sérias preocupações éticas sobre as pesquisas com animais, sobretudo com a possibilidade de criação de animais híbridos com células humanas.

Hidrogel que imita mucosa

O grupo do Dr. Vitaliy Khutoryanskiy, da Universidade de Reading, criou um tecido sintético, um hidrogel, que imita as propriedades dos tecidos das mucosas, como as encontradas na boca e no estômago.

Mucosas retiradas de animais são normalmente usadas na fase de desenvolvimento de novos medicamentos, para avaliar como a droga vai reagir no corpo.

Normalmente, comprimidos são administrados por via oral aos pacientes para o tratamento de várias doenças.

Essas drogas passam através do sistema digestivo do paciente, que quebra a droga em seus componentes constituintes e despacha o resto do composto para fora do corpo.

Consequentemente, apenas uma pequena porcentagem do medicamento entra efetivamente no sistema circulatório do paciente, limitando a eficácia da droga e forçando o uso de doses mais elevados do componente ativo.

Comprimidos adesivos

Uma alternativa são comprimidos capazes de grudar no tecido da mucosa.

Isso aumenta a absorção das drogas e o tempo que elas permanecem no corpo, reduzindo a frequência de administração, além de oferecer a possibilidade de atingir locais específicos do corpo.

Condições comumente tratadas por drogas mucoadesivas incluem a angina e doenças inflamatórias.

Alternativa ao uso de animais

É por isso que os cientistas precisam das mucosas, valendo-se das mucosas de animais sacrificados. Se isto é sempre ruim para as cobaias, também nem sempre dá os melhores resultados para os humanos.

"A utilização de tecidos animais em experimentos de adesão nem sempre produz os melhores resultados devido às suas propriedades variáveis," explica o Dr. Khutoryanskiy.

Isso significa que a comparação entre diferentes candidatos a medicamentos tem um alto grau de incerteza, devido à variação das mucosas coletadas dos diversos animais.

"Os novos hidrogéis sintéticos imitam os tecidos da mucosa suína que usamos em nossos estudos melhor do que qualquer outro material que testamos, e poderia ser uma alternativa real ao uso do material animal para testar as propriedades mucoadesivas de medicamentos no futuro," conclui ele.

Como lidar com os efeitos colaterais da quimioterapia

Cuidados naturais

O Instituto do Câncer de São Paulo (ICESP) elaborou uma série de dicas para que pacientes com câncer controlem os efeitos colaterais dos medicamentos.

Os tratamentos quimioterápicos, radioterápicos e de radioiodoterapia provocam variadas sensações desagradáveis, mas a alimentação pode ajudar no alívio destes sintomas.

Náuseas e vômitos, diarréia, constipação, boca seca ou com feridas, dor para engolir, ausência ou alteração de paladar podem ser amenizados com informações simples e pequenas mudanças nos hábitos alimentares.

"O acompanhamento do médico e, em alguns casos, a prescrição de medicamentos para possíveis reações temporárias negativas é fundamental, mas, em conjunto com isso, o auxílio pode vir da cozinha de casa," comenta Suzana Camacho, gerente do Serviço de Nutrição e Dietética do Icesp.

Náuseas e vômitos

O que você deve fazer:

• Prefira alimentos gelados ou em temperatura ambiente.
• Faça pequenas refeições em menor intervalo de tempo.
• Coma devagar e mastigue bem os alimentos.
• Beba sucos ou chupe gelo ou picolé de frutas cítricas, como limão (se não estiver com feridas na boca) nos intervalos das refeições.
• Realize suas refeições em lugares bem arejados.

O que você deve evitar:

• Frituras e alimentos gordurosos.
• Doces concentrados, como compotas, goiabada, marmelada.
• Condimentos fortes (pimenta, catchup, mostarda, molho inglês, por exemplo).
• Deitar-se após as refeições.
• Ficar próximo à cozinha durante o preparo das refeições.

Diarreia

O que você deve fazer:

• Consuma líquidos em abundância: chás, sucos coados e principalmente água.
• Procure ingerir alimentos como batatas, chuchu, cenoura cozida, aipim, inhame, cará, creme de arroz, arroz, macarrão com molho caseiro coado, farinhas, torradas, biscoito água e sal ou de maisena, carnes grelhadas (frango, peixe ou boi).
• Prefira sucos de frutas coados: limonada, caju, maçã e laranja sem açúcar.
• Prefira leite de soja.
• Consuma as frutas: banana-maçã, maçã e pêra sem casca, goiaba sem casca e semente, caju.
• Consuma apenas o caldo de leguminosas (feijão, ervilha, lentilha, grão de bico).

O que você deve evitar:

• Leite e derivados.
• Alimentos gordurosos (manteiga, toucinho, banha, creme de leite, por exemplo).
• Frutas cruas em geral.
• Frutas e sementes oleaginosas (abacate, coco, nozes, amêndoas, amendoim, castanhas).
• Condimentos picantes (páprica, pimenta, mostarda, catchup, por exemplo).
• Conservas em geral (picles, azeitona, palmito, aspargos, milho e ervilha).
• Embutidos (salsicha, lingüiça, presunto, salame, mortadela, por exemplo).
• Leguminosas (feijão, ervilha, lentilha, grão de bico).
• Hortaliças cruas: legumes e verduras folhosas.
• Alimentos de causam flatulência (gases), como couve-flor, brócolis, repolho e ovo.

Intestino preso (constipação)

O que você deve fazer:

• Consuma líquidos em abundância (chás, sucos diluídos e principalmente água).
• Prefira frutas laxativas: ameixa, laranja, mamão, abacate, ameixa seca, manga, banana nanica.
• Consuma as frutas com casca e bagaço, quando possível.
• Consuma preferencialmente hortaliças cruas (legumes e verduras).
• Consuma farelo de cereais (arroz, aveia ou trigo).
• Consuma produtos integrais (arroz, pães e torradas).
• Consuma leguminosas regularmente (ervilha, feijão, grão de bico, lentilha, soja, por exemplo).
• Consuma leite e derivados: iogurte, leite fermentado, mingau de aveia.

O que você deve evitar:

• Alimentos constipantes, como ricota fresca, queijo branco, sagu, tapioca, maisena, arrozinha, banana prata, banana maçã, pêra, goiaba e maçã sem casca e sem sementes, caju.

Boca seca (xerostomia)

O que você deve fazer:

• Prepare as refeições com caldos ou molhos.
• Se não houver feridas na boca, chupe balas azedas e/ou ácidas, picolés ou gelo e mastigue chicletes (de preferência sabor menta), que podem ajudar a produzir mais saliva.
• Consumir líquidos em abundância: chás, sucos diluídos e, principalmente, água.

O que você deve evitar:

• Comer alimentos secos.

Feridas na boca (mucosite)

O que você deve fazer:

• Consuma alimentos macios e pastosos.
• Prefira alimentos gelados ou à temperatura ambiente.
• Se necessário, utilize alimentos líquidos ou liquidificados.

O que você deve evitar:

• Alimentos ácidos, picantes ou muito salgados.
• Alimentos muito quentes.

Dor para engolir (odinofagia)

O que você deve fazer:

• Preparar sua refeição na consistência que for mais bem tolerada, que ofereça menor dificuldade para mastigar ou engolir, podendo variar entre branda, pastosa ou líquida (conforme avaliação da fonoaudióloga).
• Tomar pequenos goles de água ou suco durante as refeições podem ajudar a engolir.
• Faça as refeições em pequenas quantidades, várias vezes ao dia.

Ausência ou alteração de paladar

O que você deve fazer:

• Enxágue a boca com água pura antes das refeições ou faça bochechos com chá de camomila antes das refeições.
• Experimente balas azedas e/ou ácidas ou gotas de limão (30 gotas em 1 copo de 200ml) ou gelatina de limão (caso não apresente feridas na boca).
• Use temperos naturais em maior quantidade, como: manjericão, orégano, salsinha, hortelã, alecrim, coentro, por exemplo.
• Substitua os talheres de metal pelos de plástico, caso sinta sabor residual metálico.
• Mantenha boa higiene bucal.

O que você deve evitar:

• Consumir alimentos muito quentes ou muito gelados.

Radioiodoterapia

É o tratamento que utiliza iodo radioativo (Iodo-131) para o controle dos carcinomas diferenciados da glândula tireóide.

O objetivo é combater às células cancerígenas que ainda restaram na tireoide após a cirurgia (tireoidectomia) ou metástases, sendo destruídas através da radiação emitida pelo iodo.

Os pacientes recebem orientação para realização de uma dieta pobre em iodo, no período que antecede a internação, através do nutricionista ambulatorial. Evite o consumo de sal iodado, sal marinho e alimentos salgados, pois são fontes de iodo.

Receitas especiais

O Icesp disponibilizou também, gratuitamente, um cardápio especial, que inclui preparações salgadas, doces e bebidas, voltado a pacientes em tratamento de quimioterapia.

O objetivo do cardápio é controlar ou minimizar os efeitos colaterais do tratamento do câncer e incentivar a alimentação dos pacientes, evitando perda de peso.

Veja as receitas, que também vão muito bem para quem não está doente.

• Receitas para pacientes com câncer. Ou sem.

Mulheres são mais prejudicadas pelo cigarro do que homens

Pior para as mulheres

Nova má notícia para os fumantes, especialmente mulheres.

O aumento no risco de desenvolver doenças coronarianas por causa do vício de fumar é 25% maior para mulheres do que para homens.

A afirmação é de um estudo publicado hoje na revista The Lancet, por Rachel Huxley, da Universidade de Minnesota, e Mark Woodward, da Universidade Johns Hopkins, nos Estados Unidos.

Os dois realizaram uma meta-análise de 86 estudos, que reúnem dados de 67 mil casos de doenças coronarianas em uma amostragem total de mais de 4 milhões de pessoas.

Diferenças fisiológicas entre sexos

Os autores sugerem que o aumento no risco para o público feminino pode estar relacionado com diferenças fisiológicas entre os sexos, com toxinas presentes no cigarro tendo possivelmente efeitos mais potentes em mulheres do que nos homens.

"Mulheres podem extrair quantidades maiores de carcinogênicos e de outros agentes tóxicos a partir do mesmo número de cigarros do que os homens. Isso poderia explicar por que mulheres que fumam têm duas vezes mais risco de desenvolver câncer de pulmão do que os homens", disseram.

O cenário tende a piorar com o tempo. Segundo o estudo, para cada ano que uma mulher fumar há um aumento na relação ajustada de risco entre mulheres e homens.

Isso significa que, quanto mais tempo uma mulher fumar, maior será o risco de desenvolver doenças coronarianas em comparação com um homem que tiver fumado durante o mesmo período.

Mau exemplo

"O cigarro é uma das principais causas de doenças coronarianas em todo o mundo e continuará a ser, uma vez que populações que até então não estavam sendo tão afetadas pela epidemia do fumo começaram a usar o cigarro em níveis até então presentes apenas em países mais ricos", disseram os autores.

"Essa expectativa é especialmente preocupante para mulheres mais jovens, entre as quais a popularidade do cigarro, particularmente em países de menor renda per capita, pode estar aumentando", destacaram.

Genetically Engineered Spider Silk for Gene Therapy

ScienceDaily (Aug. 10, 2011) — Genetically engineered spider silk could help overcome a major barrier to the use of gene therapy in everyday medicine, according to a new study that reported development and successful initial laboratory tests of such a material. It appears in ACS' journalBioconjugate Chemistry.

Fluorescent signals indicate that a gene in a gene therapy experiment has successfully reached its target — human breast cancer cells growing in lab mice.

David Kaplan and colleagues note that gene therapy -- the use of beneficial genes to prevent or treat disease -- requires safe and efficient carriers or "vectors." Those carriers are the counterparts to pills and capsules, transporting therapeutic genes into cells in the body. Safety and other concerns surround the experimental use of viruses to insert genes. The lack of good gene delivery systems is a main reason why there are no FDA-approved gene therapies, despite almost 1,500 clinical trials since 1989. The new study focused on one promising prospect, silk proteins, which are biocompatible and have been used in everyday medicine and medical research for decades.

The scientists describe modifying spider silk proteins so that they attach to diseased cells and not healthy cells. They also engineered the spider silk to contain a gene that codes for the protein that makes fireflies glow in order to provide a visual signal (seen using special equipment) that the gene has reached its intended target. In lab studies using mice containing human breast cancer cells, the spider-silk proteins attached to the cancer cells and injected the DNA material into the cells without harming the mice.

The results suggest that the genetically-engineered spider-silk proteins represent "a versatile and useful new platform polymer for nonviral gene delivery," the article notes.

The authors acknowledged funding from the National Institutes of Health and the National Science Foundation.

Leaky Heart Valves: First in Vitro Study of Tricuspid Valve Mechanics Uncovers Causes for Leakage

ScienceDaily (Aug. 10, 2011) — A new study into the causes of leakage in one of the heart's most complex valve structures could lead to improved diagnosis and treatment of the condition.

This is a heart model with an arrow pointing to the white tricuspid valve. A new study found that either dilating the tricuspid valve opening or displacing the papillary muscles that control its operation can cause the valve to leak. A combination of the two actions can increase the severity of the leakage, which is called tricuspid regurgitation.

An estimated 1.6 million Americans suffer moderate to severe leakage through their tricuspid valve, a complex structure that closes off the heart's right ventricle from the right atrium. Most people have at least some leakage in the valve, but what causes the problem is not well understood.

A new study, published online in the journal Circulation on August 1, 2011, found that either dilating the tricuspid valve opening or displacing the papillary muscles that control its operation can cause the valve to leak. A combination of the two actions can increase the severity of the leakage, which is called tricuspid regurgitation.

"We think this is the first in vitro investigation into the mechanics of the tricuspid valve, and that our findings into the mechanisms that cause tricuspid regurgitation could lead to improved diagnosis and treatment," said Ajit Yoganathan, Regents professor and Wallace H. Coulter Distinguished Faculty Chair in Biomedical Engineering in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.

The tricuspid valve consists of three flaps that open to allow blood to flow from the heart's upper right chamber to the ventricle. To close the valve, the flaps re-cover the opening, keeping blood from flowing back into the chamber it just left. When the valve is leaky or doesn't close tightly enough, blood flows backward into the chamber just after the heart contracts.

Tricuspid regurgitation has been increasingly recognized as a source of disease in patients with chronic mitral valve regurgitation, but surgical repair of the tricuspid valve alone is recommended only in rare cases. If an individual suffers from severe tricuspid regurgitation, surgeons will sometimes repair the tricuspid valve during a surgery to repair other leaky heart valves.

"Standard clinical procedures that detail when and how tricuspid valve repairs should be performed need to be developed and this study suggests several items that should be considered," said one of the study's co-authors David H. Adam, chair of the Department of Cardiothoracic Surgery at Mount Sinai Medical Center in New York City. "Current repairs for tricuspid regurgitation focus mainly on remodeling the valve's opening to correct enlargement, but this study shows that it may also be important to restore the position of the papillary muscles, providing as much overlap as possible, in order to conduct effective and durable tricuspid valve repairs."

With funding from the American Heart Association, Yoganathan and Coulter Department graduate student Erin Spinner conducted experiments with porcine tricuspid valves to determine possible causes of tricuspid regurgitation. The valves were attached to a plate designed to create physiological dilation and then placed inside a right heart simulator.

The researchers first investigated the effect of dilating the opening of the tricuspid valves. When the openings stretched to an area 40 percent larger than their normal size, a hole appeared in the central region of the valve. The hole caused leakage, and increased in size with further dilatation. This finding surprised the researchers because similar studies using the same method had shown that the heart's mitral valve could withstand dilation of 75 percent before leaking.

"These results tell us that the tricuspid valve is a much more complex valve than the mitral valve, which only has two flaps," explained Spinner. "Forming a proper seal over the valve opening might be more difficult with three flaps, which could be why such a large percentage of the population experiences some level of tricuspid regurgitation and why some individuals with annular dilation have tricuspid regurgitation and others do not."

The research team also investigated the effect of displacing the valve's three papillary muscles, which attach to the valve via threads. Contraction of the papillary muscles opens the valve and relaxation of the muscles closes the valve. The study showed that papillary displacement alone resulted in significant tricuspid leakage.

"While isolated displacement of the papillary muscles is rare, these results are relevant toward understanding what may happen if the size of the valve opening is repaired, but the papillary muscles are left displaced," noted Yoganathan.

The study also showed that higher levels of tricuspid leakage resulted when the researchers combined the conditions -- dilation of 40 percent or greater and displacement of all papillary muscles.

In their future work, the Coulter Department researchers plan to look at the effect of pulmonary hypertension on the tricuspid valve, because tricuspid regurgitation usually develops in association with pulmonary hypertension -- which is abnormally high blood pressure in the lungs. They also plan to work with their clinical collaborators to extend their findings to humans.

"In our in vitro study we were able to select specific porcine valves, but with human subjects there will be more anatomical variety. For example, two people may have valves of the same diameter, but one person may have longer flaps that are able to compensate for dilation whereas the other might not," noted Yoganathan.

In addition to those already mentioned, Pedro del Nido, a professor in the Department of Cardiothoracic Surgery at Children's Hospital Boston; Emir Veledar, an assistant professor with a joint appointment in the Division of Cardiology and Division of Epidemiology at Emory University; and Coulter Department research engineer Jorge Jimenez and undergraduate students Patrick Shannon and Dana Buice also contributed to this work.

Multiple Sclerosis Research Doubles Number of Genes Associated With the Disease, Increasing the Number to Over 50

ScienceDaily (Aug. 10, 2011) — Dr. John Rioux, researcher at the Montreal Heart Institute, Associate Professor of Medicine at the Université de Montréal and original co-founder of the International Multiple Sclerosis Genetics Consortium is one of the scientists who have identified 29 new genetic variants linked to multiple sclerosis, providing key insights into the biology of a very debilitating neurological disease. Many of the genes implicated in the study are relevant to the immune system, shedding light onto the immunological pathways that underlie the development of multiple sclerosis.

Scientists have identified 29 new genetic variants linked to multiple sclerosis, providing key insights into the biology of a very debilitating neurological disease. Many of the genes ¬implicated in the study are relevant to the immune system, shedding light onto the immunological pathways that underlie the development of multiple sclerosis.

The research, involving an international team of investigators led by the Universities of Cambridge and Oxford, and funded by the Wellcome Trust, was published August 10 in the journal Nature. This is the largest MS genetics study ever undertaken and includes contributions from almost 250 researchers as members of the International Multiple Sclerosis Genetics Consortium and the Wellcome Trust Case Control Consortium.

Multiple sclerosis is one of the most common neurological conditions among young adults, affecting around 2.5 million individuals worldwide. The disease results from damage to nerve fibres and their protective insulation, the myelin sheath, in the brain and spinal cord. The affected pathways -- responsible in health for everyday activities such as seeing, walking, feeling, thinking and controlling the bowel and bladder -- are prevented from 'firing' properly and eventually are destroyed. The new findings focus attention on the pivotal role of the immune system in causing the damage and help to explain the nature of the immune attack on the brain and spinal cord.

In this multi-population study, researchers studied the DNA from 9,772 individuals with multiple sclerosis and 17,376 unrelated healthy controls. They were able to confirm 23 previously known genetic associations and identified a further 29 new genetic variants (and an additional five that are strongly suspected) conferring susceptibility to the disease.

A large number of the genes implicated by these findings play pivotal roles in the workings of the immune system, specifically in the function of T-cells (one type of white blood cell responsible for mounting an immune response against foreign substances in the body but also involved in autoimmunity) as well as the activation of 'interleukins' (chemicals that ensure interactions between different types of immune cell). Interestingly, one third of the genes identified in this research have previously been implicated in playing a role in other autoimmune diseases (such as Crohn's Disease and Type 1 diabetes) indicating that, perhaps as expected, the same general processes occur in more than one type of autoimmune disease.

Previous research has suggested a link between Vitamin D deficiency and an increased risk of multiple sclerosis. Along with the many genes which play a direct role in the immune system, the researchers identified two involved in the metabolism of Vitamin D, providing additional insight into a possible link between genetic and environmental risk factors.

Dr. Alastair Compston from the University of Cambridge who, on behalf of the International Multiple Sclerosis Genetics Consortium, who led the study jointly with Dr. Peter Donnelly from the Wellcome Trust Centre for Human Genetics, University of Oxford, said: "Identifying the basis for genetic susceptibility to any medical condition provides reliable insights into the disease mechanisms. Our research settles a longstanding debate on what happens first in the complex sequence of events that leads to disability in multiple sclerosis. It is now clear that multiple sclerosis is primarily an immunological disease. This has important implications for future treatment strategies."

Dr. Donnelly added: "Our findings highlight the value of large genetic studies in uncovering key biological mechanisms underlying common human diseases. This would simply not have been possible without a large international network of collaborators, and the participation of many thousands of patients suffering from this debilitating disease."

Dr. John Rioux, holder of the Canada Research Chair in Genetics and Genomic Medicine, furthermore stated that "the integration of the genetic information emerging from studies of this and other chronic inflammatory diseases such as Crohn's disease, ulcerative colitis, arthritis and many others is revealing what is shared across these diseases and what is disease-specific. This is but one of the key bits of information emerging from these studies that will guide the research of disease biology for years to come and be the basis for the development of a more personalized approach to medicine."

Genetically Modified 'Serial Killer' T-Cells Obliterate Tumors in Leukemia Patients

ScienceDaily (Aug. 10, 2011) — In a cancer treatment breakthrough 20 years in the making, researchers from the University of Pennsylvania's Abramson Cancer Center and Perelman School of Medicine have shown sustained remissions of up to a year among a small group of advanced chronic lymphocytic leukemia (CLL) patients treated with genetically engineered versions of their own T cells. The protocol, which involves removing patients' cells and modifying them in Penn's vaccine production facility, then infusing the new cells back into the patient's body following chemotherapy, provides a tumor-attack roadmap for the treatment of other cancers including those of the lung and ovaries and myeloma and melanoma.

The protocol, which involves removing patients' cells and modifying them in Penn's vaccine production facility, then infusing the new cells back into the patient's body following chemotherapy, provides a tumor-attack roadmap for the treatment of other cancers including those of the lung and ovaries and myeloma and melanoma.

The findings, published simultaneously in the New England Journal of Medicine and Science Translational Medicine on August 10, are the first demonstration of the use of gene transfer therapy to create "serial killer" T cells aimed at cancerous tumors.

"Within three weeks, the tumors had been blown away, in a way that was much more violent than we ever expected," said senior author Carl June, MD, director of Translational Research and a professor of Pathology and Laboratory Medicine in the Abramson Cancer Center, who led the work. "It worked much better than we thought it would."

The results of the pilot trial of three patients are a stark contrast to existing therapies for CLL. The patients involved in the new study had few other treatment options. The only potential curative therapy would have involved a bone marrow transplant, a procedure which requires a lengthy hospitalization and carries at least a 20 percent mortality risk -- and even then offers only about a 50 percent chance of a cure, at best.

"Most of what I do is treat patients with no other options, with a very, very risky therapy with the intent to cure them," says co-principal investigator David Porter, MD, professor of Medicine and director of Blood and Marrow Transplantation. "This approach has the potential to do the same thing, but in a safer manner."

Secret Ingredients

June thinks there were several "secret ingredients" that made the difference between the lackluster results that have been seen in previous trials with modified T cells and the remarkable responses seen in the current trial. The details of the new cancer immunotherapy are detailed in Science Translational Medicine.

After removing the patients' cells, the team reprogrammed them to attack tumor cells by genetically modifying them using a lentivirus vector. The vector encodes an antibody-like protein, called a chimeric antigen receptor (CAR), which is expressed on the surface of the T cells and designed to bind to a protein called CD19.

Once the T cells start expressing the CAR, they focus all of their killing activity on cells that express CD19, which includes CLL tumor cells and normal B cells. All of the other cells in the patient that do not express CD19 are ignored by the modified T cells, which limits side effects typically experienced during standard therapies.

The team engineered a signaling molecule into the part of the CAR that resides inside the cell. When it binds to CD19, initiating the cancer-cell death, it also tells the cell to produce cytokines that trigger other T cells to multiply -- building a bigger and bigger army until all the target cells in the tumor are destroyed.

Serial Killers

"We saw at least a 1000-fold increase in the number of modified T cells in each of the patients. Drugs don't do that," June says. "In addition to an extensive capacity for self-replication, the infused T cells are serial killers. On average, each infused T cell led to the killing of thousands of tumor cells -- and overall, destroyed at least two pounds of tumor in each patient."

The importance of the T cell self-replication is illustrated in theNew England Journal of Medicine paper, which describes the response of one patient, a 64-year old man. Prior to his T cell treatment, his blood and marrow were replete with tumor cells. For the first two weeks after treatment, nothing seemed to change. Then on day 14, the patient began experiencing chills, nausea, and increasing fever, among other symptoms. Tests during that time showed an enormous increase in the number of T cells in his blood that led to a tumor lysis syndrome, which occurs when a large number of cancer cells die all at once.

By day 28, the patient had recovered from the tumor lysis syndrome -- and his blood and marrow showed no evidence of leukemia.

"This massive killing of tumor is a direct proof of principle of the concept," Porter says.

The Penn team pioneered the use of the HIV-derived vector in a clinical trial in 2003 in which they treated HIV patients with an antisense version of the virus. That trial demonstrated the safety of the lentiviral vector used in the present work.

The cell culture methods used in this trial reawaken T cells that have been suppressed by the leukemia and stimulate the generation of so-called "memory" T cells, which the team hopes will provide ongoing protection against recurrence. Although long-term viability of the treatment is unknown, the doctors have found evidence that months after infusion, the new cells had multiplied and were capable of continuing their seek-and-destroy mission against cancerous cells throughout the patients' bodies.

Moving forward, the team plans to test the same CD19 CAR construct in patients with other types of CD19-positive tumors, including non-Hodgkin's lymphoma and acute lymphocytic leukemia. They also plan to study the approach in pediatric leukemia patients who have failed standard therapy. Additionally, the team has engineered a CAR vector that binds to mesothelin, a protein expressed on the surface of mesothelioma cancer cells, as well as on ovarian and pancreatic cancer cells.

In addition to June and Porter, co-authors on the NEJM paper include Bruce Levine, Michael Kalos, and Adam Bagg, all from Penn Medicine. Michael Kalos and Bruce Levine are co-first authors on the Science Translational Medicine paper. Other co-authors include June, Porter, Sharyn Katz and Adam Bagg from Penn and Stephan Grupp the Children's Hospital of Philadelphia.

The work was supported by the Alliance for Cancer Gene Therapy, a foundation started by Penn graduates, Barbara and Edward Netter, to promote gene therapy research to treat cancer, and the Leukemia & Lymphoma Society.