Looking back, looking forward: Penn’s CAR-T program continues path of progress
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In 2018, at the height of the chimeric antigen receptor T-cell therapy revolution and in the heart of its implementation, Healio’s Cell Therapy Next staff went onsite to University of Pennsylvania’s newly minted center.
In this tour, experts from Penn walked through the manufacturing, patient involvement and clinical trial boon happening in their daily lives.
Since that time, more therapies have been FDA approved, more disease states found hopes of remissions and the previously unthinkable “cure,” and both real-world and clinical trial data amassed.Healio recently sat down with Don L. Siegel, PhD, MD, director of the Clinical Cell and Vaccine Production Facility, Center for Advanced Cellular Therapeutics, at University of Pennsylvania Perelman School of Medicine, to discuss all those changes and the ones to come.
“An enormous amount of progress has happened since you were here,” Siegel said, acknowledging even his own sister-in-law received CAR-T and is currently in remission.
“I believe in it,” he said.
Q: The first recollection you had of meeting with Carl H. June, MD, was in 1999 where you discussed cell therapy production at an institution like Penn. Is what we have seen over the past 25 years the reality you expected?
Siegel: It happened overnight in just 25 years. Certainly, none of us had any idea what to expect.
A lot of it sounded a lot like science fiction in the beginning, and it was unclear that any of it would come to fruition. We had no expectations when the first patients with chronic lymphocytic leukemia were given the CD19-directed cells.
When initially there was nothing happening and then the first patient developed some significant side effects — fever, low blood pressure, difficulty breathing, etc. — the thought was that it was progression of the disease or the treatment was failing — until it was determined, in fact, it was working a lot more aggressively than anyone thought it would.
As much as seven pounds of tumor was being destroyed, so you can imagine your body is going to have some sort of reaction to it, and that led to the phenomenon described as cytokine storm or cytokine release syndrome (CRS).
None of this was really expected. Fortunately, since the first few patients, standardized algorithms for treating CRS (should it occur) have been developed.
Q: How has the application of CAR-T changed in oncology?
Siegel: In 2018, when we spoke last, that was right after the FDA approval of the first CAR-T, tisagenlecleucel, or Kymriah (Novartis). This approval followed years of clinical trials which basically showed that it was possible to make these engineered cells, give them safely, and actually see a therapeutic effect.
The first child received the treatment in 2012, and I understand that about 35,000 other children have received similar treatments since then, which is amazing.
We are trying to improve the overall performance of the CAR-Ts, even to the traditional CD19 ones for leukemia and lymphoma; trying to develop CAR-Ts for other kinds of cancers, particularly solid tumors, which has been an issue and involves coming up with new targets to go after; and improving overall manufacturing processes.
Solid tumors present issues quite distinct from those in blood cancers in terms of the environment of the tumor being inhospitable to cells, and the solid tumors expressing molecules that tend to antagonize the effectiveness of T cells. Additionally, T cells being able to get into the tumor because it’s a solid mass is another hurdle. A lot of what we’ve done and what’s currently going on is trying to deal with those issues.
Since we began, we have seen major improvements in manufacturing.
Though, in many respects, CAR-T cell manufacturing is similar to what it was in 2018, a major advance has been recognizing that the cells may actually do better growing inside of the patient than in a bioreactor bag in the lab.
The original time span for growing the cells in the lab was around 9 days, but now we have trials that are using a 3-day protocol. This saves time for people working in the lab. It uses fewer reagents. It’s less expensive and also allows us to produce more products for more patients in the same amount of time. On top of all of that, and perhaps most importantly, the performance of the cells may turn out to be better.
There is also research going on to make a 1-day process. Though it may be a number of years off, in the future it may be possible to avoid apheresis cell collections entirely and create these engineered cells from a smaller number of cells such as those present in a conventional whole blood donation. A lofty goal is to conduct the entire process vein-to-vein in a single day.
Additionally, with the advent of the COVID vaccine developed at University of Pennsylvania, we are looking at the use of mRNA/LNP (liponanoparticle) technology to create CAR-T cells in the patient’s own body.
Instead of the mRNA in the particle encoding a viral protein to which your body would mount an immune response such as in the case of COVID19, the idea is that the mRNA could encode the CAR-T construct. The idea would be that one could potentially get a shot of mRNA lipid nanoparticles which enter the bloodstream and target certain immune cells converting them into CAR T cells.
They would be mRNA-based so they’re not going to be persistent forever, but they may be there long enough to do the job, or you can get additional shots. Again, it sounds like science fiction, but perhaps in the future one might be able to get CAR-T mRNA/LNP injections in a drugstore like getting a vaccine, and on the way home from the drugstore, the patient’s body already is starting to make CAR T cells to fight the cancer.
Another improvement relates to the creation of what we call armored CARs. One type of armored CAR that we have developed here at Penn known as an IL-18 CD19 CAR already has been showing efficacy in patients who have failed conventional CAR-Ts.
It sounds strange to refer to a “conventional” CAR-T as though CAR-T is already so old.
Q: What is the biggest achievement at Penn in the realm of cell therapy since we visited in 2018?
Siegel: First, we proved that technology like CRISPR editing can be done not just for research purposes but can be used to make clinical products.
In 2020, we published a paper where we used CRISPR to edit T cells at three different loci to make the cells potentially more potent and safer. Although the cells didn’t persist, it demonstrated a number of principles including successful manufacture of CRISPR-edited cells that appear safe and may offer desired therapeutic effects.
That had never been done before. It was the first successful demonstration that CRISPR editing can be performed in the lab and administered in the clinic.
Another major achievement is in the realm of solid tumors and was described in a recently released paper on glioblastoma, a very aggressive form of brain cancer.
Two fairly unique things gave the impressive results. First, the CAR T cells were engineered to express two different CARs against two different targets with the rationale similar to the way a serious bacterial infection might be treated with more than one antibiotic at the same time. In this case, one CAR was against a target known as EGFRvIII and the other one was against IL-13 receptor alpha 2.
The other novel aspect in this study had to do with the way the cells were administered. To get around constraints the blood-brain barrier may play in preventing cells administered intravenously from getting into the brain, in this study, the cells were introduced directly into the ventricles of the brain through a port installed through the patient’s skull.
Within 24 hours in some of these patients, there was evidence of CAR-T activity against the tumors. In one of these patients with a particularly serious form of GBM with expectation of survival on the order of weeks, about 10 months have already passed.
Lastly, on a personal level, I’ve been involved in bringing these technologies to the four-legged members of our families, namely our dogs.
Along with a colleague Nicola J. Mason, BVetMed, PhD, at the UPenn School of Veterinary Medicine, we’ve been developing immunotherapies for dogs analogous to those developed for humans. The challenge here is that the antibody components of the immunotherapies need to be dog-like not human-like, i.e. specific for canine targets and designed not to be rejected by the animals.
To date, we’ve made a large number of such antibody components including checkpoint inhibitor antibodies for dogs, specifically to canine CTLA-4 and PD-1. They’re currently being evaluated in clinical trials in dog patients — with informed consent from their owners — for malignant melanoma and bladder cancer. We’re also working on a CD19 antibody for dog leukemia/lymphoma CAR-Ts and also for canine autoimmune diseases. And we’re also going to expand to developing immunotherapies for other companion animals, notably cats.
Q: What new disease states do you hope to target?
Siegel: Another idea that’s emerged over the last 3 to 4 years is this idea that the use of CAR T cells might not be restricted to just the field of cancer therapy but, in a more general sense, for getting rid of any sort of cells that are harmful in some way. In some disorders, normal-appearing cells grow in a place you don’t want them to grow or do something you don’t want them to do. For example, fibrotic heart disease is where the function of the heart is impaired by fibrotic tissue — a proliferation of cells around it. If there were specific targets on those fibroblasts, and one made CAR T cells that targeted those cells, one could use CAR-T cells to treat heart disease.
Another field of medicine that’s evolving is called senolytic medicine related to aging. Simply put, there could be disorders caused by senescent cells that take up space, not really doing anything productive, yet are preventing younger cells from coming into play to rejuvenate. Theoretically, one could design CAR T cells to get rid of these senescent cells.
But perhaps one of the biggest non-cancer applications that many investigators are excited about is the use of CAR-T therapy for the treatment of autoimmune disease.
I think of it as making lemonade out of lemons. As successful as it is, the original CD19-directed CAR-T for leukemia/lymphoma is not the “ideal CAR-T” because its target — CD19 — is also present on normal B cells that our bodies use to make protective antibodies.
Those cancer patients who seem to be the most successful at being treated with these CD19 CAR-Ts are actually losing their repertoire of normal B cells – but this is fortunately manageable.
But autoimmune disorders like lupus, myasthenia gravis, scleroderma and nephritis, are caused by abnormal B cells going awry and producing autoantibodies against our own tissues.
We may be able to take the same CD19 CAR-T used for leukemia/lymphoma in a patient with serious antibody-mediated autoimmune disease. A number of papers initially from Europe showed remarkable results with patients with lupus, scleroderma and myositis where their autoantibodies disappeared and their disease scores drastically improved.
In these patients, symptoms went away and they were able to go off immunosuppression. Interestingly, for these initial groups of patients, their normal repertoire of B cells came back after a number of months — without evidence of autoantibodies returning — as though one had pressed the reboot button on a computer.
This is a really hot area and now being looked at in the area of transplantation as well. Just like B cells can make unwanted autoantibodies that cause autoimmunity, our B cells can make antibodies against other people’s cells in their effort to protect us. Referred to as alloantibodies, there are times we want to get rid of these kinds of antibodies as well. For example, people are on waiting lists to get kidney transplants for decades because they’ve made antibodies against other people’s tissue types known as HLA. Some patients have so many of these types of HLA antibodies a compatible donor can never be found.
A big effort led here by Penn faculty, Vijay Bhoj, MD, PhD and Ali Naji, MD, is the use CD19 CAR-Ts used in combination with BCMA CAR-Ts to eliminate the cells that are making such alloantibodies, so patients in need of a solid organ transplant may be able to get a compatible crossmatch. We have just treated the first patient in this trial here at Penn and are anxious to see the results.
If successful, this will be a major advance and a use of CAR-T cells that no one had ever anticipated.
Q: In 2018, you said, “This is an enormous enterprise. ... It is like a biotech operation within a university that directly interfaces with a health system and a physician practice.” Does that still describe the operations at Penn? What is the biggest change that you have seen?
Siegel: The success here at Penn has clearly led to an enormous growth in the Philadelphia area of both major pharmaceutical companies as well as a very large number of new biotech startups creating what has been referred to initially by Penn’s Bruce Levine, PhD as “Cellicon Valley”. Many of these startups have come out of the University of Pennsylvania.
Ironically, an unintended consequence that has created for us is competition for our highly skilled workforce we invest significant amounts of time to train.
Going back to the very original idea in 1999: Could you create a biotech-like research and clinical development enterprise in a university? Well, yes, but there are certain aspects we have learned that a university may not entirely know how to handle. A university is quite different from industry. For example, they are not generally set up to pay employees like industry.
One of the things I’m personally proud of is being able to work through these issues with university administration including leaders from the Dean’s office, Health System, and Human Resources by discussing how different our cell therapy scientists and technologists are from those that work in conventional university research labs. In a research lab, if a mouse passes away or a polyacrylamide gel tears, you treat another mouse or run another gel. But our workers are more akin to medical technologists in a hospital, notably those that prepare blood components for transfusion or those that prepare blood stem cells for transplantation.
Our workers are actually creating drugs with their own hands. It’s a different level of responsibility and acuity that requires strict following of standard operating procedures (SOPs).
As a result of our efforts, the university acknowledged these distinctions and need to create new types of laboratory technical track positions with appropriate titles and compensation. Since putting this new system in place, we haven’t had anyone leave because of the issues that we had before.
It turns out that this type of workforce issue was a problem not unique to Penn but found at other academic institutions across the country that work in the field of cellular therapy. We hope Penn can serve as a model for how to address these sorts of human resource issues.
Personally, I continue to be very excited being a member of a team that started out with perhaps half a dozen individuals and has grown to well over 300 individuals that comprise our Center for Cellular Immunotherapy that Carl June, MD created not too many years ago.
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Don Siegel, PhD, MD, can be reached at siegeld@pennmedicine.upenn.edu.
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