Preliminary Data Show Promise
Medscape: What are the results to date of studies of the gene-transfer technology?
Dr. June: We have 3 phase 1 clinical trials that are ongoing: 2 at the University of Pennsylvania in adults with leukemia and 1 at Children's Hospital of Philadelphia (CHOP) in children with leukemia. We are planning to extend these studies to other centers.
The first 2 studies include 12 adults with chronic lymphocytic leukemia (CLL), and thus far, 9 of the 12 have had good responses to the gene transfer treatment. We have just concluded the initial study, and the first patient we ever treated, in July 2010, remains in remission. Actually, 2 of the first 3 patients we treated remain in remission, demonstrating that the results are durable.
We have treated more adult patients recently, but the results remain too preliminary to evaluate.
In the children's study, led by Dr. Stephan Grupp at CHOP, 4 of the first 5 children we have treated have had complete remissions. The results in children are very exciting and beyond our expectations. The first child treated was Emily "Emma" Whitehead. We reported results showing her complete remission at the 2012 meeting of ASH, and at the same time the New York Times carried a front-page article about Emma and the treatment. The results from the first 2 children were recently published.
Recently, the Philadelphia Inquirer ran a front-page story about the fifth child, who also entered into remission -- a 7-year-old named Maddie, from Washington, DC. We had not yet released the results regarding Maddie's remission, when a reporter found them on Facebook, where her family has a page to keep friends and family up-to-date about her treatment. Social media are changing the way these results become known and accelerating the process of scientific disclosure, since patients and families are now reporting their experiences in real-time in a public-facing way. We have not yet reported results of the last 3 children in remission because we are waiting for the data to mature and don't want to raise hope prematurely, but social media change our ability to protect privacy prior to publication. We plan to continue to study this technique and obtain more mature results, and if they are as encouraging as our phase 1 results indicate to date, we will be able to study the gene transfer technique earlier in the course of leukemia, rather than only the advanced refractory cases at present.
Medscape: What challenges remain in this treatment?
Dr. June: Just as we would with other treatments, we need more experience. We don't know the optimal dose of T cells yet. This is more difficult to calculate than for drugs that are metabolized, because the genetically engineered T cells proliferate once they are reinfused into the patient. At the moment, it appears that we have to give a certain threshold number of T cells to the patient. A trial has just begun at the University of Pennsylvania, led by Dr. David Porter, who has been studying this approach in adults to identify the optimal dose.
We also don't know whether 1 treatment is enough to achieve remission. It may be that maintenance therapy is needed. We don't know yet whether the patients in remission will ever need another treatment. The answers to these questions related to delivery of treatment may be different in children vs adults.
Another challenge is to figure out how we can introduce this treatment more broadly to patients in community cancer centers and all over the world, not just to patients who seek treatment at boutique cancer centers. I think this is achievable. If you look at the history of bone marrow transplantation (BMT), in the early 1980s there were only 2 centers in the United States that provided this option, and now there are centers all over the world that offer BMT.
If the genetically engineered T cells obtain US Food and Drug Administration (FDA) approval, the therapy could eventually be delivered at community hospitals.
Medscape: What is needed for FDA approval?
Dr. June: There is no precedent for FDA approval, so we can only speculate. This would be the first cell-based gene transfer therapy for cancer, representing new ground at FDA. Thus, our main challenge is probably how to go about obtaining FDA approval.
Heretofore, gene transfer therapy was in the "valley of death," with no investment beyond National Institutes of Health grants at specific academic centers, and therefore without the ability to extend the studies beyond single-center studies. The pharmaceutical industry had no interest in this Fed Ex-like business model, which required shipping cells to a central manufacturing facility and then back to the patient.
Our technique uses each patient's own T cells. Initially we had no interest from pharma when I attempted to get financial support to commercialize this technology. But in August 2011, when we reported on 3 patients treated with the technique, this turned out to be "the tipping point." After that, Novartis made a major commitment, and now other biotechnology companies have expressed interest in investing in the technology as well.
I am optimistic that the recent industry investment will lead to the eventual widespread availability of the treatment on a broader scale. Our initial results have held up. Excellent results in the first 3 treated patients could have been a chance finding or a statistical fluke, but now we have treated 12 adults and 5 children and have continued to observe a potent activity of the treatment. Perhaps the most important finding is that the responses are durable.
Medscape: What are the characteristics of the patients who have received the treatment?
Dr. June: We were required by the FDA to initiate the treatment in adults; children were not treated until a year later. In both adults and children, the patients were "end of the line" with advanced leukemia and with no other proven therapeutic options that were available.
Our hope is that if the treatment is effective in patients with late-stage disease, we will be successful, eventually, using it upfront as first-line therapy. Perhaps we could arrive at a point where leukemia can be treated without chemotherapy. Gene transfer therapy with engineered T cells may be an alternative to allogeneic BMT, when BMT is the only resort at present.
However, there is still a subset of patients who have been transplanted and then relapse after allogeneic stem cell transplants, and because there is no proven treatment option in this setting, the technique may be useful in those patients as well.
One of the children with pre B-acute lymphoblastic leukemia (ALL) in the phase 1 trial that I alluded to had relapsed after allogeneic BMT, and the CAR T cells induced a complete remission.
Medscape: As with other leukemia treatments, it appears that children have better responses than adults.
Dr. June: In general, with the exception of leukemia in infants, the prognosis is better for children who develop leukemia than for adults who develop leukemia. About 80% of children will be cured with current treatment. We don't really know why children do better, but it may have to do with their having simpler mutations and that children can withstand higher levels of chemotherapy than adults. Chemotherapy regimens that put children in remission generally are not tolerated by adults because of their high intensity.
Medscape: Do you envision using the genetically engineered T-cell treatment in cancers other than leukemia?
Dr. June: Early-stage pilot trials are being conducted in other cancers at the University of Pennsylvania, Memorial Sloan-Kettering Cancer Center, MD Anderson Cancer Center, Baylor College of Medicine, and the Fred Hutchinson Cancer Center. Animal models suggest that the treatment works in other cancers, but we are in the very early days of learning whether it holds promise for non-B-cell blood cancers and other cancers in humans.
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