Oncology




Major breakthrough in treatment of chronic lymphocytic leukaemia

 

Protocol offers roadmap for treatment of other cancers

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 leukaemia (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 tumour-attack roadmap for the treatment of other cancers including those of the lung and ovaries and myeloma and melanoma. The findings, published simultaneously 10 August 2011 in the New England Journal of Medicine and Science Translational Medicine, are the first demonstration of the use of gene transfer therapy to create “serial killer” T cells aimed at cancerous tumours.

“Within three weeks, the tumours 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. “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 hospitalisation and carries at least a 20% mortality risk – and even then offers only about a 50% 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

Dr June thinks there were several “secret ingredients” that made the difference between the lacklustre 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 tumour 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 tumour 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 signalling 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 tumour are destroyed.

Serial killers

“We saw at least a 1,000-fold increase in the number of modified T cells in each of the patients. Drugs don’t do that,” Dr 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 tumour cells – and overall, destroyed at least two pounds of tumour in each patient.”

The importance of the T cell self-replication is illustrated in the New 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 tumour 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 tumour lysis syndrome, which occurs when a large number of cancer cells die all at once. By day 28, the patient had recovered from the tumour lysis syndrome – and his blood and marrow showed no evidence of leukaemia.

“This massive killing of tumour is a direct proof of principle of the concept,” Dr 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 leukaemia and stimulate the generation of so-called “memory” T cells, which the team hopes will provide on-going 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 seekand- 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 tumours, including non-Hodgkin’s lymphoma and acute lymphocytic leukaemia. They also plan to study the approach in paediatric leukaemia 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.

doi: 10.1056/NEJMoa1103849  


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ate of upload: 18th Oct 2011

 

                                  
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