In August 2011, researchers from the University of Pennsylvania published their breakthrough findings of a pilot study showing sustained remissions of up to 1 year in a small number of patients with advanced chronic lymphocytic leukemia (CLL) who had been treated with genetically engineered versions of their own T cells. The study results, published in both The New England Journal of Medicine1 and Science Translational Medicine,2 were the first to show prolonged responses using gene transfer therapy to create “serial killer” T cells aimed at cancerous tumors.
The treatment, which is now known as CTL019, involves isolating patients’ T cells and genetically modifying them using a lentiviral vector expressing an antibody-like protein called chimeric antigen receptor (CAR), pioneered by the University of Pennsylvania researchers. CAR is expressed on the surface of the T cells and binds to CD19, a protein expressed on lymphoma and leukemia cells and also on normal B cells. The reengineered T cells are then infused back into patients to kill cells expressing CD19.
There were 12 patients in the pilot study, including 10 with advanced CLL and two children with acute lymphoblastic leukemia (ALL). Last December, David L. Porter, MD, Director of Blood and Marrow Transplantation and Professor of Medicine at the Abramson Cancer Center of the University of Pennsylvania, and principal investigator of the study, presented updated study results at the 2012 Annual Meeting of the American Society of Hematology. Dr. Porter’s presentation showed longer-term outcomes in 10 patients treated with CTL019, including 9 CLL patients with relapsed/refractory disease who had received a median of five previous therapies and a 7-year-old girl with relapsed/refractory ALL. Only three patients in the study had no response at all to the therapy.
The ASCO Post talked with Dr. Porter about the long-term outcomes of patients treated with CTL019, how gene transfer therapy may be applicable in other cancers, and the next phase in the therapy’s development.
What is the current disease status of the patients treated with CTL019?
Three of the CLL patients and both of the ALL patients had a complete response to the therapy initially. Of the three adults with CLL who had a complete response, all are still in remission between 8 months and 2½ years later. Of the two patients with ALL, one remains in remission longer than 8 months and one has had a recurrence of her disease.
What is your next step in this research?
Our next step is to treat larger numbers of patients and get a better understanding of who this therapy works for, when it works, and to better understand the side effects, including their cause and how to manage them. We also want to understand issues relating to dosing and timing of T-cell administration. In addition, we are starting to treat other CD19-positive malignancies, including different types of non-Hodgkin lymphoma and ALL in adults.
Is gene transfer therapy applicable in other blood cancers such as multiple myeloma and in solid tumors?
Yes it is. We think that one of the critical aspects of our study is that the lentiviral vector can be used to genetically modify cells directed at other targets. It doesn’t have to be just CD19. The problem with some of these other cancers, of course, is identifying very specific tumor targets. In CLL and ALL, CD19 is an ideal tumor target because it only appears on the cancer cells and healthy B cells. In other tumors it is much more difficult to identify such restricted tumor-specific markers. But clinical trials are underway or being planned for solid tumors, including pancreatic and ovarian cancers and mesothelioma. Trials in breast cancer have already been conducted. If you have an effective vector and the appropriate target, this technique can absolutely be applied to other cancers.
Our group at the University of Pennsylvania has done trials with genetically modified T cells to target a couple of different antigens in multiple myeloma. CD19 is probably not going to be the ideal target for most cases, but there might be other targets that one can try to target.
Does CTL019 have the potential to replace bone marrow transplantation in the treatment of lymphoma and leukemia?
Certainly for CLL and maybe for ALL and some non-Hodgkin lymphomas, the only known curative therapy is an allogeneic bone marrow transplant. But transplants are associated with mortality rates that in the best of circumstances approach 20%. Obviously, if we had the ability to eradicate patients’ cancers in a safer and more effective way, the goal would be to treat them without bone marrow transplant.
We don’t know if we have done that at this point. The study follow-up is relatively short, and we have treated very small numbers of patients. That said, we have had patients who have had complete eradication of their tumor without a bone marrow transplant, when there was little else available to them. So we hope that this treatment has the potential to replace transplant, at least for these diseases.
What are the risks involved in gene transfer therapy?
The side effects we see with CTL019 largely involve cytokine release syndrome, in which patients exhibit profound cytokine symptoms such as very high fevers, rigors, nausea, and diarrhea, and in more extreme cases, capillary leak, hypoxia, and hypotension. We found that patients with cytokine release syndrome also have high levels of interleukin (IL)-6 and that by administering an anti–IL-6 receptor antibody called tocilizumab (Actemra), these reactions can be stopped almost instantaneously.
Some patients develop a tumor lysis syndrome, which on some level is a rather remarkable side effect. These cells are so potent that they can induce a delayed tumor lysis syndrome as they expand.
We know that the anticytokine therapy has been effective when needed, but we don’t know the optimal timing of its administration or whether administering it will inhibit the antitumor reaction. We are trying to learn more about this strategy as we treat more patients.
The other side effect of the therapy is that it destroys healthy B cells along with the cancerous cells. This is potentially an ongoing problem. Patients develop B-cell aplasia and hypogammaglobulinemia, and potentially become more prone to certain kinds of infections.
We manage this problem by giving patients intravenous immunoglobulin infusions. We believe that CTL019 essentially provides a prolonged vaccine effect, and that as long as the reengineered T cells are there, patients won’t be able to develop normal B cells. They won’t develop a recurrence of CLL either, which is a good thing, but they won’t be able to develop normal B cells, so it is a potential long-term complication of the therapy that so far we have been able to manage.
The treatment does not work for everyone. Do you know why?
No, we don’t. We are trying to figure out whether there is any difference in tumor properties that may account for differences in response, or whether there are differences in the biologic properties of the cell products that are infused into these patients.
Are the patients who experienced complete remissions cured of their cancer?
There is no way of knowing. These are patients who had not had a complete remission after several prior, very potent therapies. After CTL019 therapy, they have no detectable CLL. But it’s always hard to use a word like “cure” without longer follow-up. ■
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The error: ‘Jalal Abdolali Zade’
Should instead read: ‘Jalal Abdolalizadeh’
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Date: Tuesday, 11 June, 2019
Time: 09:30 – 13:00
Place: Fèlix Serratosa, Parc Cientific de Barcelona (PCB)
This short workshop will describe many aspects of heterologous expression in E.coli, from choice of construct design through to methods to improve the levels of soluble expression and options for co-expression. In addition, it will also address expression in eukaryotic hosts, including secreted proteins and ECDs, and options for co-expression.
The workshop will finish with a discussion an...