For more than 25 years, Dr Bruce Levine has worked alongside Professor Carl June – the doyen of immunotherapy – on the development of CAR T-cell therapy*, which he describes as “a living and dividing drug”. 

In his role as Deputy Director of the Center for Cellular Immunotherapies at the Perelman School of Medicine (Philadelphia, U.S.) Dr Levine’s focus is on technology innovation and assessment.

“CAR T-cells FDA version 1.0 is approved but how do we get to version 2.0 integrating new technologies?” he says.

Dr Levine’s analogy is that CAR T-cells are now at the Model T stage. “It takes a lot of effort to make them.”

“It took decades for car manufacturers to integrate automation systems, and now we’re moving into the era of Tesla and Google self-driving cars. That’s where we want to be, thinking of these T-cells not only as tumour killers and drug delivery vehicles, but self-driving drugs. Smart drugs.”

Dr Levine spoke to Lymphoma News when he was in Australia last year to present at the Leukaemia Foundation-hosted New Directions in Leukaemia Research  (NDLR**) conference in Brisbane.

What in simple English is immunotherapy and how does it work?

It’s the manipulation of the immune system to fight disease. In simple terms, the earliest immunotherapy was the vaccine for small pox and the next generation of immunotherapy began to look at chemical messengers that the immune system uses to communicate amongst cells. The thinking was… could we repurpose some of those that could be manufactured in laboratories to administer to patients to fight disease, cancer among them.

More recently, beginning in the 1980s and 1990s, this concept of cellular immunotherapy began to emerge out of what may have been the first cell therapy – bone marrow transplantation and stem cell transplantation (SCT). We’ve taken that a step further in that we’re manipulating immune cells to redirect them, to endow them with functions they would not ordinarily have – to see antigens, and targets they would not ordinarily have, and potentially to carry drugs or to be resistant to HIV or to fight off or reverse auto-immunity, and so we’re creating a new type of immunotherapy to treat disease.

Can you summarise your NDLR presentation?

What we’ve been able to do is take patients’ immune cells and modify them using genetic technology to express a receptor (chimeric antigen receptor, CAR) that redirects those cells to kill cancer.  The CAR is composed of a cell external portion that is an antibody directed towards a tumour antigen, and a cell internal portion designed to signal and activate immune cells. This is a living therapy that in many cases has durable benefit. It’s unique in that it is a bespoke therapy; we are using each patient’s own cells.

It’s a new class of drugs, even though it is a cell, and it is viewed by regulatory authorities as a drug.

CAR T-cell therapy is used in a type of acute lymphoblastic leukaemia (ALL), in paediatric and young adults up to the age of 25, and in non-Hodgkin lymphoma (NHL) – diffuse large B-cell lymphoma.

We’re also developing this therapy in other blood cancers – in adult ALL, and chronic lymphocytic leukaemia (CLL), and myeloma. In myeloma, there’s a different target, called BCMA (B-cell maturation antigen). We’ve conducted a pilot trial targeting CD123 in AML and there’s more work to be done there using another target, CD33, and we have a new technology to integrate into that trial. And in solid cancers, there’s a panoply of targets depending on the type of cancer. The challenge in solid cancers is finding a target that covers all cancer cells but is not expressed on other tissues.

When you move to a new target, you just swap out the antibody portion of the CAR but the rest of the design and the production of this therapy is the same. It’s a platform technology in that sense.

How well does the public understand CAR T-cell therapy?

When [data on] our first three patients were published in 2011, some journalists were confused with the role of HIV in this cancer therapy. We use a disabled form of HIV as a gene vector. Its only purpose is to convey the genetic material and coding the chimeric receptor inside the cell, and that’s all it can do.

What I have found fascinating about genetically modified organisms is the misrepresented fear of people, for example, who buy GMO-free breakfast cereal, thinking it’s better, but if you’re genetically modifying an organism to treat their cancer, then that’s ok. Speaking to one of our patients over dinner, I said – ‘how do you feel about being a genetically modified organism?’ She said she’d never thought about it. Sometime later, I said ‘you should buy a T-shirt that says, “I’m a GMO”, and she did!

That is what it is, because the CAR transgene lentivirus insertion into the genome is permanent for that cell and all the daughter cells, so the CAR is carried forward in the progeny of every T-cell. It’s durable activity from one dose. We don’t know how long one dose will last but the data we have in HIV is 10 or 11 years, and the data in cancer with our first treated patients is 8.5 years. So, in some patients, those CAR T-cells continue to exist. In others we can’t detect them. They may be there, but they are inaccessible or beyond the level of detection.

How many patients worldwide have been treated with CAR T-cell therapy?

At the University of Pennsylvania, we’ve treated over 600 patients, and Novartis, in their clinical trials and commercial setting, is now well above that number. Then there are all the other industry developers – Kite/Gilead’s Yescarta®(axicabtagene ciloleucel), for example– and academic institutions around the world. To hazard a guess, I’d say 2000-3000 patients.

What is the survival rate of CAR T-cell therapy?

That depends on the disease. The best response is in paediatric ALL. At one month (after CAR T-cell therapy) in relapsed/refractory ALL, there is an 83% complete response rate – it’s really striking compared with any other therapy. In lymphoma and CLL, the response is lower – generally in the 45-50% range – but keep in mind these are patients who are relapsed and refractory, with no other options.

Are CARS likely to be used as a front-line treatment?

I think that’s some ways away. We’re working at shortening the manufacturing and simplifying things. I think the next leap will be in second-line therapy, and then we’ll see.

How do you see CAR T-cell therapy, which is very expensive, having a wider application to more patients?

I think the key is the setting and right now we’re in the relapsed/refractory setting. If you look at expenditure on patients in the leukaemias and lymphomas, the ones that are eligible for CAR- T-cells are at the very top of the curve. Whether it’s multiple rounds of high-dose chemo or a SCT, if you look at the cost to the health system for those patients, especially those who go to SCT, and the cost of CAR T-cells, it’s really not that unfavourable, especially when you look at a one-time infusion for durable benefit. Are they expensive? Yes, but I would argue, it’s financially complex because it’s expensive up front, but the longer a patient responds, the lower the expense per quality of life year gained.

Do you expect this new type of living drug to have application across the other blood cancers?

Yes.

What’s it like being involved in the first-in-human trials of CAR T-cell therapies?

We’ve done a number of first-in-human trials, and with the first patient you’re never sure what’s going to happen. It could be nothing, it could be a glimmer of something, and it could be what you draw up on the board as your dream for what’s the best that could possibly happen. So, I remember quite well the first patient we treated, in August 2010. We were excited to give him the cells and then you wait. You wait for the blood counts, and you wait for the bone marrow biopsy, and the pathology on the bone marrow biopsy.

The pathology report emailed by the study investigator, David Porter, to Carl June, me, and others said: ‘shows no evidence of leukaemia’. Carl June wrote back and said, ‘I don’t believe it. Do it again’. Dr Porter had to go back to the patient and say, ‘the lab screwed up your sample, we’re going to have to take another bone marrow biopsy’, which is not very comfortable. The patient agreed fortunately, and it came back again with ‘no evidence of leukaemia’. So then, you say, ‘okay. It’s one patient. It could be a fluke, let’s see what happens the next time’. Then it happened again, and it happened again in patients with heavy leukaemia burden, and eventually you begin to see something very special is happening.

But you’re not quite believing how good this could be. And then we had a run of patients who didn’t respond, and it was… why is this happening, are we making the cells differently? But it just turned out that the first three patients were responders and others weren’t, and in the end the CLL response was what it was – around 45-50%. At that point, we made the decision to move into ALL and that’s really where we’ve seen the most amazing results to date – in paediatric ALL.

And there was the event with Emily [the first paediatric patient to be treated with T-cell therapy, on 17 April 2012], where she got very very sick with cytokine release syndrome (CRS). So sick that her physicians told her parents to call the family in because she wasn’t going to be around in the morning. Fortunately, at Carl June’s suggestion, administering an antidote – tocilizumab – was the cause of her recovery from CRS. If that had not happened, that would have set back the field immensely. We are indebted to Emily and her family, and we are as investigators, and I think the field is extraordinarily fortunate – that that antidote to this side-effect of the T-cells being very active was discovered.

In 2017, Kymriah® (tissagenleclelucel) received Breakthrough Designation status and FDA Approval in the U.S. and is now in commercial development. How did you feel about this achievement?

It’s hard to put into words, when something you’ve worked on for 20+ years you see as an FDA-approved therapy. I attended the FDA hearing of the oncology drug advisory committee in July 2017 and Emily [Whitehead] and her parents were there, and other parents were there and testified. At that hearing the advisory committee voted to recommend FDA approval. It was a unanimous vote and I’m getting choked up now…

How did you get involved in blood cancer research?

My father was a cell biologist, and as an undergraduate, thinking of what area of science to go into, I asked my professors “what will be ‘the’ field in 15-20 years?”.Their answer was ‘immunology.’

I applied to graduate schools in immunology and infectious diseases and did my thesis on signalling in T-cells when I was at the bone marrow transplantation research lab at Johns Hopkins Hospital (Maryland, U.S.). I’d read articles by a guy called Carl June. I applied for and was accepted for a post-doctoral fellowship in his lab in 1992 and we’ve worked together ever since. When he asked if I’d like to run a lab that grew cells for an immunotherapy trial (in HIV) I said, “sure, that’s exactly what I want to do”.

When we had data from the trial (in HIV) showing we could increase CD4 T-cell counts and increase immune function, the natural application was in cancer after high-dose chemotherapy and after stem cell transplantation. In 1999, at the University of Pennsylvania’s clinical cell and vaccine production facility, we started doing trials in cancer – first in leukaemia and lymphoma.

Carl directs the Center for Cellular Immunotherapies – a collection of laboratories and translational and clinical scientists and a manufacturing facility with about 250 staff. I was the director of the cellular production facility and in 2017 I took a new position in the centre focusing internally on new technologies for manufacturing, and externally focusing on national and global engagement. I am now the President-Elect of the International Society for Cell and Gene Therapy.

What does your role as Deputy Director involve?

To facilitate the development of the new technology, so we have wider access for patients inpaediatric and adult ALL and NHL, other blood cancers and beyond, including solid tumours. Some of them will work quite well and some won’t work, and there’ll be new technologies that we bring in, and combination treatments.

One thing that is encouraging in our lymphoma work is that we do have patients who don’t respond but when we give them checkpoint antibodies, then they do respond, and the T-cells wake up. So, by combining CAR T-cells with checkpoint antibodies, or with tumour vaccines, or with oncolytic viruses, or other agents, we have opportunities for increased responses than if we were only operating in isolation.

What is the main area of your work?

It’s several-fold. The Centre’s internal effort focuses on technology assessment and integration in manufacturing immune cell therapies directed at cancer, infectious disease and autoimmunity.

Next is coordinating efforts at our centre and at the Institute for Regenerative Medicine and other investigators and institutes at Penn including the engineering, business and vet schools. We have a CAR T-cell trial in dogs at the vet school. People can enroll their companion animals and what we learn in humans we can take to dogs, and what we learn in dogs we take back to humans.

The outer ring of my current effort is global – speaking at conferences like this (NDLR*) and participating in professional societies and in a leadership capacity in private consortia, moving the field as a whole forward. I can speak not only to manufacturing, testing the impact, the regulatory landscape and patient access, but also communicating to the public, so the public understands what we are doing and that it’s not a mystery or that we are creating some genetic adverse event or Frankenstein type of thing!

What are some of your major accomplishments?

The first-ever FDA approved gene therapy to treat people with untreatable cancers – that’s a highlight of my career. We were also the first centre anywhere in the world to use a lentivirus vector, using disabled HIV, to deliver a gene to cells, and that was a trial in HIV. And we were the first centre in the world to do any type of gene editing, that was also in HIV, using zinc finger nucleases. So, before CRISPR there was zinc finger nucleases and we used those to knock out a co-receptor that HIV needs to get inside a T-cell, and in effect, generate HIV-resistant T-cells. So, we took T-cells from HIV patients, generated HIV-resistant T-cells and gave them their own resistant immune system back. That work is continuing. A spin-out from the University of Pennsylvania, called Tmunity, takes our T-cell technology as a platform to further develop in oncology and infectious disease and auto-immunity. We’ve received funding for clinical trials in myeloma and prostate cancer and there will be others that we’re excited about.

What is the most exciting thing you are currently working on?

We are using a gene editing tool, called CRISPR combined with delivering a tumour targeting T-cell receptor, to create redirected T-cells that are resistant to one of the main immunosuppressive mechanisms that tumours use to evade the immune system. So we’re redirecting T-cells but we’re using CRISPR to knock out a receptor on T-cells, called PD-1, that tumours use to suppress T-cells. PD-1 is one of the targets of checkpoint antibodies that have been approved in solid cancers and some other cancers, and in this case, we’re making those T-cells resistant to one of the main tricks that tumours use to evade the immune system.

What is the Holy Grail for you – the one thing you’d like to achieve in your career?

The really big one occurred with the FDA approval [of CAR T-cell therapy]. What I’d like to see now is success in solid cancers and sustainability of this therapy so that we have as wide access to as many patients as possible. We’re really building a new pillar of medicine if you think about surgery, radiotherapy, chemotherapy, even targeted therapies with the kinase inhibitors. This is a new class of therapies that is more different than any of the others were. I would like to especially thank the patients who enroll in our clinical trials. They place their faith and hope in us, and we have an obligation to them to develop these new therapies in the safest and most practical and expeditious way possible. Without them volunteering for clinical trials, we could not develop new medicines.

* In CAR T-cell therapy, T-cells – a key part of the immune system – are removed from a patient, genetically modified in the laboratory to target a specific cancer and infused back into the person.  

** NDLR, considered one of the best haematological science meetings in the world, brings together scientists and clinicians to discuss and debate current concepts in our understanding of the molecular basis of leukaemia and other haematological malignancies, emerging paradigms and breakthroughs at the forefronts of research in these areas, and new therapies emerging in the clinic.