AAMC Reporter: January 2013
?By Sarah Mann
A new cancer therapy that genetically modifies patients? T cells to attack cancer cells could be a game changer for cancer patients. So far, researchers have used the therapy to treat 11 leukemia patients, whose only remaining treatment option was a bone marrow transplant. Researchers are hesitant to say they have developed a cure, but it could be a turning point.
?For the field this has been a paradigm shift,? said David Porter, M.D., a professor of medicine at the University of Pennsylvania Perelman School of Medicine, director of blood and bone marrow transplants at Penn?s Abramson Cancer Center, and co-principal investigator. ?This highlighted the fact that we are in an age where we can genetically modify cells and treat cancer. I think most people would agree that it?s realistic and should be studied rapidly whereas before there was much less interest.?
The findings are the first successful, sustained gene therapy that uses the body?s own immune cells to target cancer cells. In the research, detailed in the New England Journal of Medicine and Science Translational Medicine in 2011, T cells from leukemia patients were removed in a process similar to blood transfusion. Carl June, M.D., the lead investigator, and his research team then used a gene modification technique to encode the T cells with an antibody-like protein called a chimeric antigen receptor (CAR) that is designed to focus on cells that express CD19, which includes cancer cells and normal B cells. The modified cells were then put back into the patient?s body following chemotherapy. In addition to targeting the cancer cells, the CAR triggers other T cells to multiply?building an army of cells until all tumor cells are destroyed. The first patient who was treated with the therapy in July 2010 remains healthy.
According to June, a professor of immunotherapy at the Perelman school and director of translational research at the Abramson Cancer Center, a new therapy advancing from the bench to bedside without support from the pharmaceutical industry is unusual.
?This came out of an academic center; it was not done by the pharmaceutical industry,? June said, adding, ?It?s the first thing I know of to go that far without pharmaceutical involvement.? Last August, June and the team began working with the pharmaceutical company Novartis to scale up the treatment.
Behind the promising findings is a 20-year journey in research that included plenty of setbacks.
?When a breakthrough like [this] is announced, I?m reminded of the sudden fame of a new pop star with a breakout album,? said Louis J. DeGennaro, Ph.D., chief mission officer of the Leukemia & Lymphoma Society (LLS). ?When one ultimately digs into the new singer?s background, they have invariably been working at their craft for decades.?
June began research in gene therapy through ?serendipity.? Two decades ago, he was in the Navy, researching gene therapy as a possible treatment for HIV. He found that HIV patients who were treated with T cells that had been genetically engineered with CAR were healthy up to 11 years after receiving the initial therapy. Years later, when the cancer field began to look at gene therapy, June had a head start.
?It was fortuitous that I was in both fields and was able to take what I had learned in our HIV gene therapy trials and then apply that to cancer,? he said.
Funding, especially, was a major obstacle. Grants from the National Institutes of Health covered initial laboratory experiments but not clinical trials in patients. June had to apply for grants from foundations or philanthropists to fund trials.
?I had to be patient and stubborn. It was a lot easier just to do the experiments in the laboratory and not do the clinical trial,? June said.
LLS began funding June?s research in 1998, ultimately investing $21 million. The Alliance for Cancer Gene Therapy (ACGT) also funded a portion of the research.
In 2006, four years before the first patient was treated, June and Porter began creating the draft for the clinical trial. At first there was enough material to treat only three patients. It took another year to secure funding to manufacture enough material to treat additional patients, according to Porter.
?Once we had the suggestion that this was effective, the challenge was completely the opposite,? said Porter, a professor of medicine at the Perelman school and director of blood and bone marrow transplants at Penn?s Abramson Cancer Center. ?How do we manage all the patients who are potentially interested?? He added that the research team received about 3,000 e-mails in one month from interested patients. ?It was very difficult from a clinical standpoint, being a physician, getting so many inquiries for something that a patient, either rightly or wrongly, is convinced is their only hope and then having limited ability to treat them.?
Beginning this month, June and his team will start a phase two clinical trial to determine the optimal dose for the treatment. ?Right now, what we found is that one dose is safe, and we have a high response rate, so we?ll get experience with more patients,? June said.
Next, June hopes to translate the therapy to other cancers. ?The goal over the next five years is to determine how to adapt this to other cancers?breast cancer, lung cancer, ovarian cancer. We have a number of things to do.?
Now that there have been positive results, it?s time to use those findings to educate the public about the need for sustained research funding and the potential benefit of gene therapy, according to June.
?We had no idea what caused cancer before, and now in most cases we do,? he said. ?The genetic events are different from cancer to cancer, so now is not the time to pull back on the research. Now is when the public really is going to see the benefits.?
Barbara Netter, president and co-founder of ACGT, noted that the research should continue ?until we absolutely can say there is a cure. Now that there is some proof of concept, we need to move ourselves over that line until the point where we really feel sure there is a cure.?
Source: http://non-hodgkins-lymphoma.supportgroups.com/sg/non-hodgkins-lymphoma/two-decades-of-work-ch
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