May 2014, Vol 3, No 3
A Breakthrough Treatment for ALL and CLL: The New Biologic Agent, CTL019
Interview with the Innovators
An Interview With David L. Porter, MD, of the University of Pennsylvania
David L. Porter, MD, is Jodi Fisher Horowitz Professor in Leukemia Care Excellence in the Perelman School of Medicine at the University of Pennsylvania; and Director, Blood and Marrow Transplantation at the Abramson Cancer Center.
The number of patients was small and the therapy still investigational, but the results of research on personalized cellular therapy CTL019 stunned the oncology community. With only 70 patients treated to date, a research team at the University of Pennsylvania announced the results of their clinical trials that constitute a radical change coming to the leukemia treatment model, and the practicing oncologist should start getting ready for it now. The agent of change was the topic of an interview with study author David L. Porter, MD, from Penn’s Abramson Cancer Center.
Given the cautious, incremental pace of most current research, replete with understatement and qualifiers to substantiate claims of effectiveness, safety, and value, the announcement was unusually bold and sweeping. Thus, the announcement at last December’s American Society of Hematology annual meeting reverberated through the medical community. After decades of experimentation with T cells to make them vehicles for delivering a master stroke against cancer, a new cellular agent has emerged to treat chronic lymphocytic leukemia (CLL) and acute lymphocytic leukemia (ALL) so effectively and distinct from precedent that its researchers bluntly describe it as “…a completely new modality, a completely new approach to leukemia that we believe certainly has the potential to change the paradigm of treating leukemia.”
“Completely new modality.” “Paradigm shift.” Lofty claims heard infrequently in today’s climate of modest advances and evidence-based scrutiny of research claims, making it seem as if research has retreated to a state of safe and unspectacular incrementalism. This breakthrough therefore has important implications for appreciating the power of personalized medicine to keep its promise to heal in ways thought impossible until very recently.
The modality is genetically modified T cells directed against CD19 in the treatment of both CLL and ALL. The research team making the discovery refers to them as CTL019 cells. In our interview, Dr Porter describes the cause of the enthusiasm surrounding the results of early trials.
PMO Thank you for meeting with us, Dr Porter. We understand you are quite encouraged by early results from the trials of CTL019.
Dr Porter Yes, we are seeing really impressive response rates with this therapy in CLL patients with far advanced, heavily pretreated disease. These patients often had extensive and bulky disease, and yet these cells were able to induce remission in a very significant number of patients. Even more remarkable is the response rate we’ve seen in patients with relapsed and refractory ALL.
PMO Just how clinically significant is the advantage offered by CTL019?
Dr Porter For the ALL population there really have been no good, effective alternative treatment options; once somebody relapses with ALL, the prognosis is abysmal. Many of these patients have had 3 and 4 prior attempts at treatment – half of them actually relapsed after an allogeneic bone marrow transplant. The complete remission rates to CTL019 cell therapy were over 85%, which was astounding. When no other conventional therapy was effective, we were getting complete remission rates of over 80%, and there is really no precedent for this.
The consistently deadly nature of CLL and ALL makes the small numbers of patients take on a significant proportion in framing expectations for this remedy. In diseases consistently deadly, even small patient sample sizes provide useful expectations for the results of larger trials to follow. Hence the enthusiasm for treatment on this small scale. Between our adult and pediatric programs, we’ve treated just over 70 patients with both CLL and ALL – a little over 40 patients with CLL and almost 30 now with ALL.
PMO Can you provide a description of the scientific dynamics in play that have produced these unprecedented clinical results?
Dr Porter The CTL019 cells have the capacity for dramatic in vivo expansion and proliferation, which is probably important for magnifying or amplifying any antitumor response. We have seen that these cells can expand up to 3 logs. At the peak of their expansion, they can represent over 70% of all the T cells in the body, or at least of all the T cells in the blood. And they persist for long periods, and this was one of the new findings presented in our CLL patients. We have now been able to detect these cells surviving out beyond 3 years.
CTL019 therapy provides components of other types of therapy; it uses antibody-directed targeting. Thus, through its antibody put on the T cell, you have all the advantages of targeting via antibody therapy. Because it is a living drug, if you will, it has the potential to grow and expand, and that magnifies and amplifies any potential response, which gives you all the advantages that people have hoped for with cell therapy. And we now know that these cells can persist for long periods and remain biologically active. It gives all the advantages of long-term control that you might get with vaccine therapy. Consequently, we think it has potential to combine antibody targeting, cell therapy amplification, and vaccine-like memory activity.
PMO How closely did the results in patients match your team’s expectations as they began formulating this new agent, and how much did they discover along
Dr Porter We anticipated from mouse models that these cells could have very potent antileukemia activity and that they could proliferate. I don’t think any of us really anticipated the magnitude of cell killing that we’re seeing, and we certainly didn’t anticipate these really high response rates. It’s so unusual when testing new cancer therapies to see it actually be effective at this level with the first try, and while we knew that these cells could survive over periods of time, we had no expectation that they were going to survive on the order of many months or years.
Some activity was expected, but the extent of what we found really has been remarkable. In a fascinating way, we have discovered something different with every single patient we have treated, and it does get to the notion of personalized therapy. This is unique in the sense that every patient has a drug manufactured that’s unique for them. If you think of these cells just like we think of a drug, each lot is specific and individual for the patient. In addition, each response has been unique and personal, and it has allowed us to learn something new with every single patient.
PMO The individualized response in each patient is absolutely remarkable in itself. It means you have an ongoing learning process the more the drug is used. Has this led you to the point where you are able to start summarizing a body of knowledge from this that can guide clinical practice nuances as well as future research of engineering T cells and other biotech agents?
Dr Porter Absolutely. Between our adult and pediatric programs, we can start to summarize expectations and anticipated side effects and even now have a good strategy and plan for toxicity management. So I do think it’s moving far enough along that we are understanding at least some of the early events, how to anticipate responses, and how to anticipate and mitigate side effects.
PMO Where do diagnostics enter into the picture to help you to identify which patients are most likely to respond to CTL019?
Dr Porter Diagnostics will be critical. We are doing extensive work to try and figure out why this may be effective in one patient and not another and how to predict when it may or may not be effective, and also how to predict which patients may not get significant side effects. As of yet, we have not been able to identify any specific characteristic that has correlated with response or has predicted which patient may or may not respond.
Again, we have treated relatively small numbers of patients, and in that setting patterns may not yet be obvious. But it’s pretty clear that it’s not related to patient age or the dose of T cells within some range for a particular patient. There is nothing that we have been able to identify about a patient specifically, no previous specific features that we have yet identified that predict why it works in one person or another. But that work is ongoing and is going to be critical through this whole endeavor.
PMO Just how broad a net do you cast for diagnostics in terms of forming your expectations for a patient’s response to CTL019 treatment and explaining the underlying causes of these effects?
Dr Porter Diagnostics have been absolutely critical in understanding how this therapy is effective, what’s happening when patients are responding, and in fact what is causing some of the side effects.
The vast majority of responding patients develop a cytokine syndrome. They get very severe flu-like symptoms with high persistent fevers, but it can also evolve to hypotension and hypoxia, and we have had some patients become critically ill. Diagnostic testing has been critical to identify for us in a rapid fashion that these symptoms have been coincident with very rapid and aggressive T-cell proliferation.
They happen right at the time when we see T cells expanding to very high levels, and we have identified very specific cytokines present at high levels in the blood that we think mediate these symptoms. One of the cytokines that was completely unexpected to be found at such high levels was interleukin-6 (IL-6). It turns out there are drugs that block IL-6 activity. Specifically, there’s a drug called tocilizumab, which is an IL-6 receptor antagonist and is an FDA-approved medication for arthritis.
PMO This is very important in informing physicians on the biological basis for the clinical effects and side effects of treatment. Would you please elaborate on this?
Dr Porter We learned very early on at the height of this reaction that IL-6 levels were very high in patients who were critically ill, and we started treating patients in the throes of this reaction with the anti–IL-6 therapy. We found that it works dramatically in the vast majority of patients – in fact, responses were almost instantaneous. Within a matter of an hour or two, patients who had had high fevers for days suddenly became afebrile; those who had been hypotensive in an ICU suddenly normalized their blood pressure.
Therefore, diagnostics have been critical to understanding the activity of the cells and also some of the factors that resulted in toxicity, and furthermore how to intervene when those toxicities come about. I think that one of the unique things about our program at Penn is the ability to have these comprehensive analyses to try to understand this very early in the development of the therapy.
PMO What enabled you to hit the nail on the head immediately and select tocilizumab rather than any other agent as the appropriate companion drug to eliminate these side effects – and not only ameliorate but actually get to the root of them and understand their genesis? Why weren’t you stumbling around in the dark awhile before finding it?
Dr Porter We knew that T cells, when they become activated, have the potential to release cytokines, and this project was designed with correlative laboratory testing that would analyze the cytokine profile after T cells were infused. We saw the first few patients, in fact, the first pediatric patient treated with ALL, become critically ill. We looked in the lab at what some of these inflammatory cytokines were doing and found extraordinary high levels of IL-6 that were out of proportion to everything else, and out of proportion to what we expected.
We first tried corticosteroids, which are probably the most traditional way of inhibiting T-cell activity and cytokine-induced inflammation, and found that the steroids had little impact, at least for several hours. This led us to try to do something extraordinary, because in the very first case we had a patient who was critically ill. It worked almost immediately, which is what really gave us the clue to continue to use that in subsequent patients. At this point, every patient we have treated has responded to 1 or sometimes 2 doses of the medication.
PMO And having administered that, is there a need for any other additional palliative care, or is this sufficient?
Dr Porter This is a relevant consideration, for in fact there is the need for very intensive care after the patient is treated. Another side effect that we have seen in these patients is a tumor lysis syndrome, which I think is really a testament to the potency of these cells. As the T cells are proliferating, they kill large numbers of cells very quickly. That requires very careful management and therapy, but that is quite feasible, and oncologists are very experienced in that complication. But these patients can become critically ill, and it requires a very high level of monitoring and supportive care, though anti–IL-6 therapy seems to be at the focus point of managing side effects. But the bottom line is that the strategy is really an anticytokine-directed approach to side effects. There may be other ways to do it, and this may not be the only drug. There are other anti–IL-6 drugs. There may be other anticytokine drugs, but I think the approach is to try to interrupt the cytokine-induced activity.
PMO Will you give us a thumbnail sketch of the history of researching genetically engineered T cells?
Dr Porter This idea of using genetically modified T cells against cancer in fact wasn’t new. It’s been around since the late 1990s. There have been several trials and iterations of this idea. Work to optimize and design this approach in a way that it would be clinically effective really has been led by Carl June in our group for the better part of the decade.
Previous attempts at this weren’t successful for a few reasons. Initially, there were no efficient ways to introduce new genetic material into the T cells, and even when you could, there were no efficient ways to grow those T cells in the lab to numbers high enough to be used therapeutically.
In the past several years, very effective and efficient methods have been developed to introduce new genetic material through the T cells. We are using a lentivirus vector, which is a retrovirus vector based on an HIV backbone. Others are using just more pure retroviruses, and there are other techniques like electroporation and other ways to get new genetic materials to cells efficiently.
Carl June and Bruce Levine, now at Penn, developed a technology a number of years ago that allows one to grow T cells in a physiologically appropriate manner through a process of activation and costimulation so that they don’t grow and become senescent or exhausted; they can grow several 100-fold in the laboratory in a matter of 2 weeks. So overall, the technology has improved dramatically.
One problem always had been that the cells would not proliferate very well in the body and would not persist for long periods. There were trials that showed these cells were detectable at low levels for a few weeks, and responses were very modest. One of the unique features about our therapy is using a chimeric antigen receptor that has a signaling domain and a very potent costimulating domain. It is the 4-1BB fragment of the CD137 molecule, and it is a very potent signaling molecule. This had been tested over a number of years in the lab and in mouse models, showing that when you include it as part of the signaling function of the protein of the chimeric antigen receptor, these cells grow to high levels, and they persist and survive for much longer periods.
We don’t know for sure, but we think that the biological properties of the specific chimeric antigen receptor that we are using drives this very high level of proliferation and expansion in the body and provides a survival signal to these T cells that allowed them to survive at relatively high levels for very long periods, and this really has not been seen with genetically modified cell therapy in prior trials.
PMO So there is a pull-through/push-through process between the technology and the drug development: technology making possible drug development, and drug development suggesting new ways to refine technology. Is this a good way to view the process?
Dr Porter Absolutely – that’s the dynamic interplay we’re benefitting from.
PMO How will this redefine the hierarchy of treatments for CLL and ALL?
Dr Porter I think in CLL this is a completely new modality. There are a lot of new and different therapies being developed for CLL. I think it’s very early to know where this might fit in with all the newer biological agents, but it is a completely new, very personalized approach. While it is too early to know, our hope is that this might be a one-time therapy as opposed to a medication that one might have to take for life, for instance.
PMO You hope it will be a once-and-done process?
Dr Porter It may be a once and done, but this will be determined in long-term follow-up. That is the intent, in any case. Whether that proves to be true, we don’t know yet. At this point, CTL019 has been limited to patients with multiple relapsed/refractory CLL, offering them a completely new approach that has shown significant response rates.
PMO When will CTL019 be nudged into earlier usage? How long do you think it should be held in reserve before it is used?
Dr Porter I think that given these kinds of results, and as we learn more about the short- and long-term stage usage, it is absolutely reasonable to think about moving this kind of therapy earlier in the course of disease before patients are highly refractory – before they have extensive, bulky disease. We have some preliminary evidence that the side effects may be less if they have less leukemia, and all of that lends some support to explore using this earlier in the course of their disease.
PMO What are the plans for continuing research, and what is the scenario for patient access to this treatment in terms of where and when it will be available to all patients who need it?
Dr Porter We are now considering doing a larger multicenter trial. Right now our specific therapy is only at the University of Pennsylvania, though there are other centers with similar types of therapy. The CTL019 cell technology has been licensed by Novartis. We all hope to be able to manufacture this in large scale: they like to say not scale up but scale out. Each product is made for an individual patient, and we believe there will be facilities and strategies to be able to make these cells, so this could be available really in a relatively short time frame to people all over the country and, in fact, all over the world.
PMO You have given us incredible clarity on the results, nature, and future of CTL019. To complete the picture, I was wondering if you might suggest any lessons that this discovery holds for the practicing hematologist or oncologist at this point in time, both biologically and empirically. By biologically, I mean what lessons could they learn in terms of how they can familiarize themselves with disease pathophysiology to help them appreciate what this is doing, and what they should know to understand how it is so personal in the way each patient responds to it; and empirically, what lessons are there for them to revise their treatment strategies for ALL and CLL.
Dr Porter Biologically, one needs to understand that this therapy is targeted against a specific protein, so it is only effective if the cell has CD19. It’s biologically then expected that it results in B-cell aplasia, so these patients lose their B cells. Physicians have to be aware of that and learn how to manage that as a side effect. But it is also important to think that once we understand the biology of the cancer and identify unique molecules on the cancer surface, then this kind of technology can be applied not just for CLL or ALL but for other tumor types as well, and there is the potential for this to be a generalizable modality of cancer therapy in the future.
In terms of empiric lessons, I think mostly it’s important to understand this is still in the early stages of testing. There are a number of side effects that may require some specialized management, but as we treat more and more patients and disseminate this into multicenter clinical trials, there will be much more information about anticipated side effects and toxicity management, so that we can envision this therapy being applicable truly to patients all over the country if not all over the world.
PMO Thank you for sharing this extraordinary personalized medicine experience with CTL019. We will be looking forward to its continued movement through the research and development cycle and wish you and the entire research team continued success.
Dr Porter Thank you.
Within the oncology drug development pipeline, “multiple myeloma is one of the more intriguing spaces,” according to R. Donald Harvey, PharmD, who said one reason for his excitement is the emergence of monoclonal antibodies. Harvey, associate professor of hematology/oncology at Emory University, Atlanta, GA, and director of the Phase I [ Read More ]
Dear Colleague, One of the fascinating aspects of personalized medicine is the recognition of how each component relates to all other components. Take this month’s “The Last Word” column, where one of healthcare’s premier policy authorities, Kip Piper, weighs in on the impact of the Affordable Care Act on cancer [ Read More ]