Leukemia breakthrough-Serial Killer T cells wipe out tumors In small Trial

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In a small process of advanced chronic lymphocytic leukemia (CLL) patients, genetically modified versions of their own t cells behave like "serial killers" and hunted down and wiped out tumors, resulting in lasting remissions of up to one year. The breakthrough in gene therapy treatment is already 20 years in the making, and offers a roadmap for other forms of cancer, say researchers from the University of Pennsylvania Abramson Cancer Center and Perelman School of Medicine, which report the results in a study published today, August 11, in two magazines: the New England Journal of Medicine and Science Translational Medicine.

The pilot trial of three patients is the first to show how to transfer gene therapy "serial killer" T cells aimed at cancer tumors can create, and the team, led by senior author Dr. Carl June, Director of translational research and a professor of pathology and Laboratory Medicine in the Abramson Cancer Center, according to the protocol that they have developed can be used for the development of treatments for other cancers, including ovarian and lung cancers, and myeloma and melanoma.

The three patients in the process had advanced CLL and their only hope of a cure was a bone marrow transplant, a procedure that long stays in the hospital and carries a probability of 1 in 5 of the death. Even then, said the chances of a cure is a maximum of 50%, the researchers.

For the study, the researchers patients own t cells (a type of white blood cell) deleted, modified them Penn's vaccine production labs, than them back into the patients body after chemotherapy.

June told the press that the treatment worked much better than they thought it would be:

"Within three weeks, the tumors had been blown away, in a way that was much more violent than we ever expected."

Co-senior researcher Dr. David Porter, professor of medicine and Director of blood and bone marrow transplantation on Penn, said:

"Most of what I do is treatment of patients with no other options, with a very, very risky therapy with the intention to heal."

"This approach has the potential to do the same thing but in a safer way," he explained.

June said after the patients their modified T-cells, they were more than 1,000-fold replicated in each patient. "Drugs don't do that," he said.

The T-cells are not only replicated themselves abundant, but each t cell killed thousands of tumor cells: they were literally "serial killers". On the whole, they at least two pounds of tumor destroyed in each patient, according to June.

The reason this process seems to have achieved amazing results when other tests using T-cells are modified is disappointing, due to various "secret ingredients" as June describes them. These include the fact the modified t cells specific targeted cells only, leaving healthy cells intact, so fewer side effects, and also, if it conforms to a target cell, the modified t cell sends signals that lead to other T-cells to replicate, the result is a huge, self-growth multiplying in numbers of t cells that overwhelm the tumour and destroying.

The researchers writing about the immunotherapy and how they reprogrammed T-cells in science Translational Medicine paper, while the New England Journal of Medicine the effects of t cell replication in the case of one patient treats.

The researchers genetically the T-cells that they removed from the patients using a lentivirus vector. This gives the t cell the ability to express a chimeric antibody Antigen receptor (car). The car, which on the surface of the cell, with a part also immersed in the cell, binds to a specific antigen, called CD19, which only on certain other cells, including tumor cells and normal CLL b cells (another type of white blood cell) is expressed. The Act of the car to bind to CD19 initiates cell death in the target cell.

Once they start to auto focus, the T-cells all their assassination of cells that express CD19, ignoring all the other cells. This helps immensely to minimize the side effects normally seen in standard therapies.

But the team went further than enter the T-cells the ability to auto: they designed a signalling molecule in the car, the part that is in the cell. This signalling molecule is activated when the car binds to CD19 and cytokines that tell other T-cells to multiply, produces an avalanche of serial killer T-cells.

The NEJM paper describes how one patient, a 64-year-old man, responded to this treatment. When he became a member of the study, was his bone marrow riddled with tumor cells. Then he received his treatment, and for the first two weeks, nothing seemed to happen.

But, on day 14, he started with chills, nausea, fever, and other symptoms and testing showed a massive increase in T-cells in his blood. He had tumor lysis syndrome, which is when a lot of cancer cells to die in a short time.

But just two weeks later, by day 28 after treatment, he had recovered from tumor lysis syndrome, and tests his blood and bone marrow showed no symptoms of leukemia.

Porter said:

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

The cell culture method that researchers use too excited t cells that the leukemia had suppressed, allowing the generation of "memory" T cells, which they hope patients continuous protection against the cancer recurring.

Although this study is not designed to test the long-term effects of the treatment, there is evidence, though, that months after infusion, the new cells had replicated and could continue killing cancer cells in the entire bodies of the patients.

The team is now planning to their car-CD19 test method on patients with other types of CD19-positive cancer, such as non-Hodgkin's lymphoma and acute lymphoblastic leukemia, and they plan to study how they can apply to leukemia paediatric patients, where standard therapy has not been able to help them.

The team also has a car-vector that binds to another protein, mesothelin, expressed by Mesothelioma Cancer cells, and also by ovarian and pancreatic cancer cells.

Funds of the Leukemia Lymphoma Society &, and the Alliance for gene therapy for cancer, founded by Penn graduates Barbara and Edward Netter, helped pay for the study.

Written by Catharine Paddock, PhD
Copyright: Medical News today
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Article reference:

"T cells with chimeric Antigen receptors potent antitumoral effects and memory in patients with advanced leukemia."
Michael Kalos, Bruce l. Levine, David l. Porter, Sharyn Katz, Stephan a. Grupp, Adam Bagg and Carl h. June.
Sci Transl Med, published online August 10, 2011 3: 95ra73; DOI: 10.1126/3002842 scitranslmed.
Link to Abstract.

"Chimeric Receptor modified T-cells in chronic lymphoid leukemia."
David l. Porter, Bruce l. Levine, Michael Kalos, Adam Bagg, Carl h. June.
NEJM, published online August 10, 2011; DOI: 10.1056/NEJMoa1103849
Link to article

Additional source: University of Pennsylvania School of Medicine.