CAR-T therapy has been hailed as a cure for cancer, but what really is this “miraculous technology” and what can we actually expect from it?
The field of immuno-oncology is booming with billions of euros in investment. The ability to rewire our own immune system to fight cancer has certainly created huge expectations. After the success of the first checkpoint inhibitors on the market, many are turning their attention to CAR-T therapy, the next big cancer treatment to hit the market.
The first two CAR-T therapies have recently been approved — the first from Novartis and the second from Gilead and Kite Pharma. The field is now booming, with over 240 CAR-T clinical trials running. But is this therapy really a cure for cancer, as many seem to believe? Can the technology meet such high expectations? Are the severe side effects and deaths in clinical trials a sign that CAR-T is not yet ready? Is it worth the huge price tag? To answer the most burning questions, I talked with some of the leaders in this field to draw an overview of the current state of CAR-T technology.
How does this “miracle cure” work?
“CAR therapy is at the same time cell therapy, gene therapy, and immunotherapy. It represents a radical departure from all forms of medicine in existence until now,” Michel Sadelain, co-founder of Juno Therapeutics, told The Scientist.
A CAR-T therapy consists in the infusion of engineered T cells that express a Chimeric Antigen Receptor (CAR) on their cell membrane. This receptor counts with an external target-binding domain designed to recognize a specific tumor antigen and an internal activation domain responsible for activating the T cell when the CAR-T binds its target. Second and third generation CAR-Ts have additional costimulatory domains that further enhance the immune response.
The most common procedure for CAR-T cell therapy starts with the extraction of T cells from the own patient, a process called leukapheresis. The T cells are then genetically modified to express a CAR and expanded in vitro. Finally, they are reinfused into the patient, ready to fight the tumor.
How have CAR-T cells changed the scene?
Immunotherapies based on checkpoint inhibitors have already been successful. They block a mechanism that tumor cells use to hide from T cells. Immunotherapies based on CAR-T cells go one step further by engineering the T cells themselves to enhance the response from the immune system against a specific tumor antigen.
CAR-T clinical trials have shown huge remission rates, of up to 94%, in severe cancer types. This is particularly impressive considering most CAR-T clinical trials recruit cancer patients that have not responded to many if not all other available treatments. These results have fed the expectations of patients and investors alike, but it’s important to remember that the therapy can also have flaws.
André Choulika, CEO of Cellectis, said it bluntly during an interview. “I’m just trying to be realistic, CAR-T is not the miracle cure for cancer.”
Indeed, CAR-T cells have in fact been linked to severe side-effects, such as neurotoxicity and cytokine release syndrome. In 2016, several companies reported multiple deaths in late-stage clinical trials with CAR-T therapy. This made many realize that the technology might not be as perfect as they had originally expected.
These results mostly come from the most studied application of CAR-T cells, which targets the CD19 antigen found in B-cells. All the leading CAR-T companies target the CD19 antigen to treat B-cell malignancies, which include several forms of lymphoma and leukemia.
“The initial furor and excitement of CAR-T has led to extensive and rapid clinical development in the CD19 target space,” says David Gilham, R&D VP at Celyad. “Research is busy catching up at the moment, in particular concerning toxicity. The lack of good preclinical models hampers this work, but with clinical samples available, ongoing investigations are now closer to identifying the underlying mechanisms and further refining the approach.”
Who’s doing CAR-T?
Novartis was the first to launch a CAR-T therapy, called Kymriah, last August. It is a one-time treatment for B-cell acute lymphoblastic leukemia (ALL) that has shown an 83% remission rate after three months in clinical trials with patients that do not respond to standard treatments. However, 49% of the patients suffered strong cytokine release syndrome (CRS). This side effect has been responsible for several deaths in clinical trials run by Novartis’ competitors. For example, Juno Therapeutics had to terminate its lead CAR-T program last March after a total of 5 patients died of cerebral edema caused by the therapy.
Gilead was the second to bring a CAR-T therapy to the market. The big pharma acquired Kite Pharma just weeks before the FDA approved its CAR-T cell therapy, Yescarta. The therapy induced remission in 72% of patients with another form of blood cancer called aggressive B-cell non-Hodgkin lymphoma. However, the trial reported three deaths linked to the side effects of the therapy.
Other companies running clinical trials with CAR-T therapy include Juno Therapeutics, Celgene and Mustang Bio in the US, Celyad in Belgium and the French Servier in partnership with Pfizer.
Let’s make CAR-T therapy better
Despite severe side effects and several deaths in clinical trials, some argue that CAR-T therapy is worth the risk when a patient does not respond to any other available treatments. But some players are already developing improved CAR-T cells that are safer for patients.
One of them is Cellectis, in France. Its CAR-T therapy UCART19, now licensed to Servier and Pfizer, includes a switch control system that only activates the engineered T cells when the patient is given the drug rapamycin. The therapy is in Phase I, after saving two babies with aggressive forms of leukemia in compassionate cases. Bellicum Pharmaceuticals, in the US, is developing a similar technology called GoCAR-T that requires the drug rimiducid for CAR-T cell activation.
For its part, Celyad is developing a version of CAR-T that makes engineered T cells express natural killer receptors (NKRs). “It’s disruptive because NKR-2 binds to 8 different ligands that are expressed on above 80% of solid and hematological malignancies,” says Christian Homsy, CEO and co-founder of Celyad. “We’ve started one of the largest and broadest trials in the sector, targeting 7 indications.”
If successful, Celyad’s CAR-T cells would be a big deal, since targeting solid tumors is a big challenge in the field of immuno-oncology. The main reasons being that low T cell infiltration and the immunosuppressive environment that tumor cells create to evade immune cells.
Bluebird bio, in partnership with Scottish biotech TC Biopharm, is also targeting solid tumors with an improved version of CAR-T that uses a specific class of T cells known as gamma delta T cells. They selectively target cancer cells without attacking healthy cells, which could significantly reduce the toxicity of the therapy.
Another strategy is to combine CAR-T cells with other types of cancer immunotherapy. For example, by infusing them along with checkpoint inhibitors that block cancer’s defense mechanisms against T cells, their efficacy could be improved and the dose lowered.
Zelig Eshhar, pioneer of CAR-T technology, told The Scientist that he will be investigating these combinations of CAR-T cells and checkpoint inhibitors. However, adding on therapies on top could make prices, which are already extremely high, skyrocket. But more affordable alternatives are on its way.
Fighting prohibitive pricing with off-the-shelf CAR-T cells
The pricing of the two CAR-T therapies already in the market has sparked the debate on whether these therapies are worth the huge price tags that come with them. Novartis’ Kymriah is priced at $475,000 (€400,000) and Gilead’s Yescarta at $373,000 (€316,000). And experts estimate that, after factoring in the hospitalization and other medications required for the procedure, the price goes up to about $1.5M per patient.
A possible solution is allogeneic CAR-T therapy. That is, sourcing T cells from a healthy donor so that they are ready to go when the patient needs it, as opposed to engineering each patient’s T cells individually.
Cellectis and Celyad are developing their own allogeneic CAR-T cells each, which has created friction between them. Cellectis has been the first to test two of these off-the-shelf CAR-T cells in clinical trials — one of them now licensed to Servier and Pfizer. For its part, Celyad is still in the preclinical stage with its allogeneic CAR-T cells, which have been licensed to Novartis.
The technology promises a faster and cheaper approach to CAR-T, but developing an off-the-shelf therapy is a “scientifically challenging avenue” according to Celyad’s CEO Christian Homsy.
“I doubt that allogeneic CAR-T can be a real off-the-shelf therapy,” he told me. “There are still some significant scientific challenges with regards to immunology, as well as manufacturing, transportation, traceability and banking solutions necessary to reach the scale needed for widespread patient treatment.”
While scientists figure out how to overcome technical challenges, the therapies also face challenges in term of regulations. As a brand new type of therapy, CAR-T cells fall between several regulatory frameworks, which can widely vary from one country to another.
The challenges are many, and the technology is clearly not perfect yet, but CAR-T cells offer hope for patients that had none before. With the first therapies already in the market, the way is open for more and better alternatives to arrive in the next few years.
Images from CI Photos /Shutterstock; Kite Pharma; Klebanoff et al. (2014) Nature Reviews Clinical Oncology 11, 685–686; Bellicum Pharmaceuticals
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