CAR T Cell therapy has been years in development, but is now coming to myeloma prime time. Used in other hematology cancers, it is showing remarkable responses and remissions in patients who have stopped responding to traditional treatment. The exciting research shown at ASH last December showed up to a 90% response rate in leukemia patients who failed traditional treatment. In the Myeloma Crowd Radio interview, Dr. Einsele noted a leukemia patient who relapsed after a few short weeks following an allo (donor) transplant who was now in remission after 3 years.
How Does It Work?
The CAR T-Cell work uses a patient’s own immune system fighter cells (T-Cells) to seek and destroy myeloma. A blood sample is removed from the patient and the T Cells are removed from that sample. The cells are then trained or engineered to find and destroy a particular signal (CS1 and BCMA) that are found on the surface of the myeloma cells. Before they are given back to the patient, they are grown and expanded so they provide a maximum fighting chance when given back. Once inside, they seek for those targets and the T Cells killer mechanism kicks in to kill myeloma cells. They remain in the body with a memory of those targets to do their job over a long period of time – from months to several years. The cells can still be detected in patients receiving the CAR T cells up to three years ago. Dr. Hudecek explains in more detail:
The CAR receptor, that stands for Chimeric Antigen Receptor, it’s a synthetic receptor. It works like a sensor so it allows a cell that expresses the sensor to recognize a target molecule, we call it an antigen, on target cells. And if that antigen is being recognized, then the T cells get to work. T cells have several ways of how they work. They can lyse and destroy the target cells, it’s called cytotoxicity. They have other effective functions so they produce cytokines – so molecules that T cells use to communicate with each other and say, “Look, there’s something going on here and we have to work together on eradicating whatever that target is.” And the T cells proliferate and they proliferate until they reach sufficient numbers so they can very efficiently combat the tumor. And all this is triggered by the CAR receptor. Now the question is why do we need a CAR receptor to do that? The answer to that is that is a fundamental principle in immunology and this is that the immune system has learned to distinguish self from non-self. So the immune system will not attack the normal body so it is what we call tolerant to self. But as soon as it sees an intruder, a pathogen, typically a virus, it will start to get to work and eliminate it. The problem with tumors like myeloma is that the immune system is kind of torn. It doesn’t really know “Shall we attack this or shall we not” because the tumor or the malignant cells are deriving from normal cells in the body. Still we clearly think these myeloma cells, these malignant cells do not belong there and they should be attacked. So with the CAR receptor, we help the immune system out a little bit. So we introduce this receptor and say, “Look, the myeloma has to be attacked and this is what the CAR does.” Just a few words on what the CAR receptor then looks like. It’s a chimera because it binds to a surface molecule like an antibody. But then it is coupled of course to the killing machinery of the T cells so the immune response is a lot stronger. The T cells can divide and amplify in the body so it’s like a living drug that we generate and they can also form memory. Then it’s a very particular feature about these T cells. So it’s not only that we give these T cells to a patient and they get to work against the myeloma or the tumor, they can also form memory and protect the patient from a relapse. And this is why we’re so excited about this strategy because it might be possible that with a single infusion of these CAR T cells, you can not only eradicate the tumor but you can also protect the patient from a relapse. And that’s why the CAR is needed because it mediates that recognition of malignant cells and in our case, myeloma cells.
Why CS1 and BCMA?
Dr. Einsele and Dr. Hudecek are now working on using the treatment in multiple myeloma, but instead of going after the CD19 target common in leukemia, they will be mainly targeting the CS1 protein. According to Dr. Hudecek, finding the right target is critical.
Immune-based therapiesare very potent therapies, so selecting the right target molecule is an essential part in this process. You want to choose a target molecule that is ideally only expressed on the malignant cells, on myeloma, but not on any healthy tissues because otherwise you would see a lot of side effects, which we don’t want. In every cancer and also here in myeloma, we’ve been looking for target molecules that fulfill that in the best possible way and this is how we got interested in the CS1 molecule. There is work from other groups who’ve shown that and we’ve confirmed it in our own work, the CS1 molecule is very highly and almost uniformly expressed on myeloma cells. Every myeloma cell has the CS1 molecule on it. And this is true for patients who come for the first time to the doctor who have a new diagnosis. This is also true for patients who’ve undergone some treatment and this is also true for patients who have undergone a lot of treatment, intensive therapy, and have relapsed with the disease multiple times. So the CS1 molecule is really in our view a good target because it’s very uniformly expressed, independent from the treatment history of the patient and the disease stage of the myeloma.
BCMA (B cell maturation antigen) is an additional antigen the doctors are including in the study. They believe that BCMA is also a strong antigen target, but they see that CS1 expression is typically higher and more uniform compared to BCMA, so they favor CS1 as their primary target. However, the myeloma cells are smart and can start to evade immunotherapy treatment over time.
When we treat tumors with immunotherapy – the tumor, because the tumor now gets under pressure, can try to lose the antigen so that it is not visible anymore to the immune system. That’s a phenomenon that we call “immune escape” that can occur. We don’t know if that will occur in multiple myeloma but we think it’s always a good idea to be prepared. And in order to be prepared, we are investigating multiple antigens or an antigen that we can then select in the event that CS1 expression is getting lost. And then we think BCMA would be a strong target. Also we think that from our experience in our immunotherapy work and in our preclinical models that it can be a very strong strategy to do what we call combinatorial antigen targeting. So we’re not only hitting the tumor targeting one antigen but we’re hitting it targeting two antigens at the same time. So we think that targeting both CS1 and BCMA in combination is actually a very strong strategy and doesn’t give the myeloma time to adapt and start losing one antigen because it’s under pressure from two sides.
Because its source is B-cell derived, they also consider BCMA to be a very safe antigen.
The Engineering Process
Car T-Cells are an engineered technology, so not all CAR T Cells are the same. Using the right receptor is an important part of the manufacturing process according to Dr. Hudecek.
We’ve learned many things about how to design these receptors because they are essentially synthetic molecules. These CAR receptors do not exist in nature so they are assembled of amino acids and it’s an entirely synthetic modular receptor. So you take a targeting domain, put it in a membrane to put on a surface of a T cell and then you add to it a little signaling module that can activate the T cell once it sees an antigen. There is a lot of freedom about how to engineer these receptors and we learned some of the rules that are important so that this receptor works well. I had the privilege to design some of these receptors that are now actually in clinical application and clinical use.
Who Is it For?
CS1 is found on newly diagnosed patients, patients who have had prior treatment and those who have relapsed several times. It is uniformly expressed, independent of specific genetic features. Its first use in leukemia clinical trials is for patients who have relapsed or patients who have become resistant to current drugs. In multiple myeloma, new treatments always begin for patients with relapsed or refractory (current drugs are no longer working) patients. This will be used in these high-risk patients when used in the first clinical trials. The exciting part about this project is that CAR T Cells are being found to be effective even in patients who have had many prior therapies. In a recent article by Vicki Bower in The Scientist, she mentions a recent paper presented at last year’s ASH conference.
In an ongoing Phase 1 trial, its chimeric antigen receptor (CAR) T-cell therapy, JCAR015, put 24 of 27 adults with refractive acute lymphoblastic leukemia (ALL) into remission, with six patients remaining disease free for more than a year . This disease is extremely hard to treat and progresses rapidly when it becomes refractory; most patients die within a few months. “This response rate is unprecedented for patients who had stopped responding to all other treatments,” says Michel Sadelain, a founding director of Memorial Sloan Kettering’s Center for Cell Engineering and a cofounder of Juno. Whether in leukemia or in myeloma, the idea is the same – extract a patient’s T-cells and train them to recognize and kill cancer cells by engineering them to express an artificial, or chimeric, receptor specific for a particular cancer-associated antigen.
The therapy is now coming to multiple myeloma prime time, with slight variations. According to Dr. Hermann Einsele and Dr. Michael Hudecek, the target used in the first studies in leukemia (CD19) may not be the best for multiple myeloma. This approach is not the first in their lab. They have been working for over a decade with related immunotherapies.
So we took T cells that were, for example, specific for influenza virus or cytomegalovirus and by using a new antibody constructs, we forced these T cells to actually attack tumor cells. That was the strategy which is kind of a precursor of the CAR T cell program and we started this already in the early 2000s. And because we actually developed this strategy, I think we are very well prepared to use CAR T cells in the clinic because this strategy of biospecific antibodies has a similar approach to redirect T cells to attack the tumor cell and also to learn about the side effects of the strategy.
Another blood cancer specialist and Co-founder of Juno Therapeutics, Dr. Michael Sadelain, says CAR T-Cell therapy is a combination of powerful tools, now just one tool.
“CAR therapy is at the same time cell therapy, gene therapy, and immunotherapy,” says Sadelain. “It represents a radical departure from all forms of medicine in existence until now.”
The powerful therapy comes with some risks that need to be acknowledged and planned for. Drs. Einsele and Hudecek have created an antibody they can give if they see any toxic effects of cytokine release syndrome, a condition that can happen in a small number of patients when the T cells do their killing job quickly. The fast cell death can cause toxicity in the body. CAR T cell therapy is surrounded by corporate excitement and competition – creating a fast manufacturing process is on everyone’s minds. With it comes financial support which companies like Juno are experiencing. According to Bower:
A few weeks after the ASH meeting, Juno went public for a whopping $264.6 million, the largest biotech initial public offering (IPO) of 2014. Within a month, the company’s valuation rose from $2 billion to $4.7 billion, the largest among biotechs in a decade. By the end of 2016, the company plans to have 10 drug trials for six diseases up and running using CAR T cells produced in a brand-new manufacturing facility. And Juno is not alone. This relatively new sector is experiencing a frenzy of scientific activity, corporate partnering, and financing that took off in late 2013, continued throughout 2014, and moved straight into the new year with no sign of letting up. By now, most major pharmaceutical companies have jumped into the CAR T-cell arena. In the past two years alone, at least half a dozen companies have made deals worth hundreds of millions of dollars up front, with much more expected in the future as products move through the pipeline. (See chart below.) This influx of funding is now supporting dozens of clinical trials. While most of these studies are currently aimed at late-stage disease for which other therapeutic options have failed, researchers in the field anticipate that these immunotherapies could replace standard cancer treatments in the future. “While we are evaluating these therapies in advanced cancer now, we absolutely believe that they have the potential to become frontline therapies,” Sadelain says.
It’s an exciting time and we look forward to Dr. Einsele and Dr. Hudecek’s progress on this important work.